Belladonna; opium is a rectal suppository combination opioid agonist and antispasmodic agent indicated for the treatment of ureteral spasm pain severe enough to require an opioid analgesic. The belladonna extract component provides the active alkaloids atropine and scopolamine, while the opium component provides primarily morphine. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve belladonna; opium for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products) have not been tolerated or are not expected to be tolerated or have not provided adequate analgesia or are not expected to provide adequate analgesia.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Rectal Administration
-Instruct patient on proper use of suppository.
-Unwrap the suppository and moisten the suppository and finger with water prior to insertion.
Belladonna may cause photophobia and blurred vision.
Gastrointestinal adverse effects can occur with belladonna; opium. The active constituents of opium and belladonna are morphine and atropine, respectively. Constipation is a common adverse effect seen with both morphine and atropine. Constipation due to decreased GI motility and secretions is common during opioid agonist therapy. In some cases, patients can develop ileus or GI obstruction. Tolerance rarely develops to this effect; therefore, patients require a bowel regimen consisting of a stool softener and mild stimulant throughout opioid therapy. If the patient does not have a bowel movement for 3 days, an enema or suppository may be necessary to prevent impaction. Atropine antagonizes the actions of acetylcholine on gastrointestinal smooth muscle, thus causing constipation. Nausea and vomiting are also relatively common with morphine or atropine administration. With morphine, these effects are most commonly seen at the initiation of therapy. Opioid agonists affect the vestibular system and may cause more nausea and vomiting in ambulatory patients than bedridden patients. If patients have nausea associated with movement, an antivertigo agent such as meclizine may be appropriate. Atropine's anticholinergic effects on GI smooth muscle also contribute to nausea and vomiting.
Belladonna; opium may cause drowsiness or dizziness.
The active constituents of belladonna and opium are atropine and morphine, respectively. Morphine can cause cardiovascular adverse reactions. These reactions include sinus bradycardia, sinus tachycardia, palpitations, hypertension, hypotension, orthostatic hypotension, and syncope. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur. Morphine may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients as a result of peripheral vasodilation. Patients at increased risk for hypotensive effects include those whose ability to maintain blood pressure is already compromised by reduced blood volume or concurrent administration of certain medications (e.g., phenothiazines, general anesthetics). Atropine has been reported to lead to a wide array of cardiac conduction abnormalities. In doses of 0.4 to 0.6 mg, atropine causes slight sinus bradycardia due to vagal stimulation. In larger doses (1 to 2 mg), it causes sinus tachycardia secondary to inhibition of vagal control of the SA node in the heart.
Pruritus and urticaria may occasionally occur with belladonna; opium. Opioid agonist-induced pruritus is thought to be mediated through stimulation of central opioid receptors since opioid antagonists have been shown to ameliorate pruritus associated with cholestasis.
Urinary retention can occur with belladonna; opium suppository administration. The active constituents of belladonna and opium are atropine and morphine, respectively. Atropine can cause urinary retention secondary to decreased tone and amplitude of contractions of the ureters and bladder. Some patients may experience anticholinergic side effects with morphine therapy, and urinary retention has been reported. Urinary incontinence and urinary urgency have also been reported with atropine, and urinary hesitancy, which can cause oliguria, has been reported with morphine.
Xerostomia can occur with belladonna; opium suppository administration. The active constituents of belladonna and opium are atropine and morphine, respectively. Xerostomia is a common reaction to atropine caused by inhibition of acetylcholine activity in the salivary glands. Some patients may experience anticholinergic side effects with morphine therapy, and xerostomia has been reported. Nasal dryness is also common with atropine; rarely hypersalivation, laryngitis, laryngospasm, and oral ulceration have also been reported.
Serotonin syndrome has been reported in patients taking opioids at recommended doses. Patients taking opioids concomitantly with a serotonergic medication should seek immediate medical attention if they develop symptoms such as agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Symptoms generally present within hours to days of taking an opioid with another serotonergic agent, but may also occur later, particularly after a dosage increase. If serotonin syndrome is suspected, either the opioid and/or the other agent should be discontinued.
Opioid agonists can interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH), and by stimulating secretion of prolactin, growth hormone (GH), insulin, and glucagon. Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression). Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence (erectile dysfunction), amenorrhea, or infertility. Other various medical, physical, lifestyle, and psychological stressors may influence gonadal hormone concentrations; these stressors have not been adequately controlled for in clinical studies with opioids. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation. Opioid agonists can inhibit the release of thyrotropin, leading to a decrease in thyroid hormone. Morphine and related compounds can stimulate the release of vasopressin (ADH). Hyponatremia can occur as a result of SIADH.
Opioids may interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH) and cortisol. Rarely, adrenocortical insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency.
As with other opioid agonists, belladonna; opium presents the potential for abuse or psychological dependence. Accidental and non-accidental overdose of this medication may occur. Physiological dependence, as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug, has been reported and may occur in any patient during chronic opioid therapy. Symptoms of withdrawal include nausea, diarrhea, coughing, lacrimation, yawning, sneezing, rhinorrhea, profuse sweating, twitching muscles, abdominal and muscle pain/cramps, hot and cold flashes, and piloerection. Elevations in body temperature, respiratory rate, heart rate, and blood pressure may also occur. Routine use of opioid agonists, such as morphine, by an expectant mother can lead to depressed respiration in the newborn and a neonatal opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome is estimated to occur in up to 50% of neonates born to opioid-dependent mothers. Withdrawal symptoms may include irritability, hyperactivity, abnormal sleep pattern, tremor, high-pitched crying, vomiting, diarrhea, poor feeding, failure to gain weight, rigidity, and seizures. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Monitor neonates exposed to morphine closely as neonatal opioid withdrawal can be life-threatening if not recognized and treated. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal.
As with other opioid agonists, the most significant adverse effect associated with opium is respiratory depression. Respiratory depression is more common in elderly or debilitated patients, after therapy initiation or dosage increase, or when opioids are given with other agents that cause CNS depression. When opioids are appropriately titrated, the risk of respiratory depression is generally small as tolerance rapidly develops to this effect. Caution needs to be employed in patients with chronic obstructive pulmonary disease or decreased pulmonary reserve, cardiovascular disease, or who are taking other CNS depressants. Treat severe, symptomatic respiratory depression cautiously with an opioid antagonist such as naloxone; acute abstinence syndrome may be precipitated after use of an antagonist in patients who are physically dependent.
Opioid agonists can cause spasm of the sphincter of Oddi. Hyperamylasemia, secondary to drug-induced spasm of the sphincter of Oddi, has been associated with various opioid agonists. While serum amylase and lipase concentrations can rise as a result of biliary obstruction or spasm, overt pancreatitis is rare with opioid analgesics.
Although true opioid agonist hypersensitivity is rare, the use of belladonna; opium is contraindicated in patients with opium hypersensitivity or narcotic idiosyncrasies. Use is also contraindicated in patients with belladonna hypersensitivity.
Belladonna; opium is contraindicated in patients with acute alcoholism and delirium tremens. Consumption of ethanol will result in additive CNS depressant effects. Advise patients to avoid ethanol ingestion and ethanol intoxication, including the ingestion of alcohol contained in prescription or non-prescription medications, during therapy. Patients with alcoholism should be advised of this serious risk, or an alternative medication should be used.
Opium is an opioid agonist and therefore has abuse potential and risk of fatal overdose from depressed respiration. Addiction may occur in patients who obtain opium illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. To discourage abuse, the smallest appropriate quantity of belladonna; opium should be dispensed, and proper disposal instructions for unused drug should be given to patients. Discuss the availability of naloxone with all patients and consider prescribing it in patients who are at increased risk of opioid overdose, such as patients who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental ingestion or opioid overdose.
Belladonna; opium is contraindicated in persons with significant respiratory depression and those with acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment. Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in persons for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor closely for signs or symptoms of respiratory depression and sedation. Persons with chronic obstructive pulmonary disease (COPD), cor pulmonale, respiratory insufficiency, hypoxemia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive even at recommended doses. Persons with advanced age, cachexia, or debilitation are also at an increased risk for opioid-induced respiratory depression. Monitor such persons closely, particularly when initiating and titrating the opioid; consider the use of non-opioid analgesics. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in persons with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Management of respiratory depression may include observation, necessary supportive measures, and opioid antagonist use when indicated.
Belladonna; opium is contraindicated in persons with known or suspected GI obstruction, including paralytic ileus. Opium may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor persons with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Belladonna; opium is contraindicated in persons with severe renal disease.
Use belladonna; opium rectal suppositories with caution in geriatric or debilitated adults, as these patients are more susceptible to adverse reactions from opioids, especially sedation and respiratory depression, probably as a result of the altered distribution of the drug or decreased elimination. Belladonna has significant anticholinergic effects, particularly in the older adult. Carefully monitor and take into account analgesic effects, adverse reactions, and concomitant drugs that may depress respiration. According to the Beers Criteria, opioid agonists are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures; avoid use, except in the setting of severe acute pain, since opioids can produce ataxia, impaired psychomotor function, syncope, and additional falls. If belladonna; opium must be used, consider reducing use of other CNS-active medications and implement strategies to reduce fall risk. In patients receiving palliative care, the balance of benefits and harms of medication management may differ from those of the general population of older adults.
Avoid abrupt discontinuation of belladonna; opium in a physically-dependent patient. When a patient who has been taking opioids regularly and may be physically dependent no longer requires therapy with belladonna; opium, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Consider tapering to reduced opioid dosage, or tapering and discontinuing long-term opioid therapy, when pain improves; the patient requests dosage reduction or discontinuation; pain and function are not meaningfully improved; the patient is receiving higher opioid doses without evidence of benefit from the higher dose; the patient has current evidence of opioid misuse; the patient experiences side effects that diminish quality of life or impair function; the patient experiences an overdose or other serious event (e.g., hospitalization, injury) or has warning signs for an impending event such as confusion, sedation, or slurred speech; the patient is receiving medications (e.g., benzodiazepines) or has medical conditions (e.g., lung disease, sleep apnea, liver disease, kidney disease, fall risk, advanced age) that increase risk for adverse outcomes; or the patient has been treated with opioids for a prolonged period and current benefit-harm balance is unclear. If the patient has a serious mental illness, is at high suicide risk, or has suicidal ideation, offer or arrange for consultation with a behavioral health provider before initiating a taper. In patients with opioid use disorder, offer or arrange for medication-assisted treatment. Individualize opioid tapering schedules. The longer the duration of previous opioid therapy, the longer the taper may take. Common tapers involve dose reduction of 5% to 20% every 4 weeks; a faster taper may be appropriate for some patients. Significant opioid withdrawal symptoms may indicate the need to pause or slow the taper. Opioids may be stopped, if appropriate, when taken less often than once daily. Advise patients that there is an increased risk for overdose on abrupt return to a previously prescribed higher dose; provide opioid overdose education, and consider offering naloxone. Monitor patients closely for anxiety, depression, suicidal ideation, and opioid use disorder, and offer support and referral as needed.
Avoid belladonna; opium use in persons with CNS depression, impaired consciousness, or coma; opioids may obscure the clinical course in a person with a head trauma injury. Monitor persons who may be susceptible to the intracranial effect of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure, brain tumor, or intracranial mass) for signs of sedation and respiratory depression, particularly when initiating belladonna; opium therapy. Opium may reduce respiratory drive and resultant carbon dioxide retention can further increase intracranial pressure.
Belladonna; opium may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery. Advise patients not to drive or operate machinery unless they are tolerant to the effects of belladonna; opium and know how they will react to the medication.
Opium may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory persons. There is an increased risk in persons whose ability to maintain blood pressure has already been compromised by hypovolemia or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines, general anesthetics). Monitor for signs of hypotension after initiating or titrating the opioid dosage. Avoid the use of oxycodone in persons with circulatory shock; it may cause vasodilation that can further reduce cardiac output and blood pressure.
Belladonna; opium is contraindicated in patients with convulsive disorders, which may include seizure disorder. Seizures can be precipitated by opioid agonists in patients with a preexisting seizure disorder, and belladonna; opium may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during belladonna; opium therapy.
Belladonna; opium is contraindicated in patients with severe hepatic disease.
Like all opioid analgesics, opium is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Belladonna; opium should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure may cause respiratory failure and a fatal overdose.
Belladonna; opium is contraindicated for use in patients with glaucoma.
Use of belladonna; opium is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. MAOIs may potentiate the effects of opioids, including respiratory depression, coma, and confusion.
There are no available data with belladonna; opium use in human pregnancy to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects. Results for a population-based prospective cohort, including 448 women exposed to morphine at any time during pregnancy and 70 women exposed during the first trimester of pregnancy, indicate no increased risk for congenital malformations; however, risk cannot be excluded due to study methodological limitations. Neural tube defects (i.e., exencephaly and cranioschisis) have been noted when morphine was given subcutaneously to hamsters and mice at 5 and 16 times a human daily dose of 60 mg based on body surface area. Lower fetal body weight and increased abortion incidence were observed at 0.4 times the human daily dose in rabbits, growth retardation at 6 times the human daily dose in rats, and axial skeletal fusion and cryptorchidism at 16 times the human daily dose in mice. Doses of 3 to 4 times the human daily dose given during organogenesis and throughout lactation have produced cyanosis, hypothermia, decreased brain weight or body weight, adverse effects on reproductive tissues, and death in rats. Some long-term neurochemical changes in the brains of rat offspring which correlate with altered behavioral responses that persist through adulthood have been observed with exposures comparable to and less than the human daily dose. Belladonna refers to plant alkaloids that contain anticholinergic agents such as atropine. Atropine used in human pregnancies has not been associated with birth defects or adverse fetal effects, although the drug readily crosses the placenta. Use during pregnancy may increase risk of respiratory abnormalities, hypospadias, and eye or ear malformations, but a causal relationship is unclear. The Collaborative Perinatal Project found no relationship between first trimester use of atropine and birth defects in the offspring but found an increase in birth defects in general in the offspring of pregnancies where the mother had taken belladonna. There was no relationship to any particular syndrome of anomalies. A statistically significant, although weak, association was discovered between congenital anomalies and maternal use of belladonna. A study was conducted based on the infants of 554 women who took belladonna during the first 4 months of pregnancy. The study was conducted in the Collaborative Perinatal Project and showed that belladonna is unlikely to cause minor congenital abnormalities. The estimated maximum risk is most likely less than 3% if maternal belladonna is used early in pregnancy. Belladonna; opium is contraindicated for use in women who are in premature labor. Belladonna; opium is not recommended for use during and immediately before labor when other analgesic techniques are more appropriate. Opioids can prolong labor and obstetric delivery by temporarily reducing the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. An opioid antagonist (e.g., naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate. Further, prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for NOWS, and how long-term opioid use may affect care during a future pregnancy. In women undergoing uncomplicated normal spontaneous vaginal birth, consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, use in combination with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. Use immediate-release opioids instead of extended-release or long-acting opioids; order the lowest effective dosage and prescribe no greater quantity of opioids than needed for the expected duration of such pain severe enough to require opioids. For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Opioid agonist pharmacotherapy (e.g., methadone or buprenorphine) is preferable to medically supervised withdrawal in pregnant women with opioid use disorder.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for belladonna; opium and any potential adverse effects on the breast-fed infant from belladonna; opium or from the underlying maternal condition. Monitor infants exposed to belladonna; opium through breast milk for sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. The major active constituent of opium is morphine. Morphine is excreted in the maternal milk, and the milk to plasma morphine AUC ratio is about 2.5:1. Previous American Academy of Pediatrics recommendations considered morphine usually compatible with breast-feeding, particularly in short-term post-partum use, due to a lack of data regarding symptoms in exposed infants.
Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Monitor patients for symptoms of opioid-induced endocrinopathy. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.
General dosing information
-Individualize dosing for each patient; consider severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse. Use the lowest effective dose for the shortest duration consistent with individual treatment goals.
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours after initiation and dose escalation, and adjust the dosage accordingly. Continually reevaluate patients to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to monitor for the development of addiction, abuse, or misuse. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the opioid dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
-There is substantial interpatient variability in the relative potency of different opioid drugs and products. When adjusting belladonna; opium dosages or converting from another opioid agonist, it is better to underestimate the patient's daily dose requirements and give rescue doses than to risk an adverse event. If an adverse event occurs, the next dose may be reduced. Refer to the Opioid Agonists Drug Class Overview for approximate equianalgesic doses.
-When discontinuing belladonna; opium therapy in patients who are opioid-dependent, taper the dose gradually by 10% to 25% every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
For the treatment ureteral spasm (bladder spasm) severe pain requiring an opioid analgesic and for which alternative treatments are inadequate:
Rectal dosage:
Adults: 1 suppository rectally once or twice daily, not to exceed 4 doses/day.
Adolescents: 1 suppository rectally once or twice daily, not to exceed 4 doses/day.
Maximum Dosage Limits:
-Adults
4 suppositories/day PR.
-Geriatric
4 suppositories/day PR.
-Adolescents
4 suppositories/day PR.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Belladonna; opium is contraindicated in patients who have severe hepatic disease. Specific guidelines for dosage adjustments in lesser degrees of hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Belladonna; opium is contraindicated in patients who have severe renal disease. Specific guidelines for dosage adjustments in lesser degrees of renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
AbobotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Acetaminophen; Aspirin; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when dihydrocodeine is used concomitantly with an anticholinergic drug. The concomitant use of dihydrocodeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Codeine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant oxycodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Acetylcholine Chloride: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Aclidinium: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufacturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Aclidinium; Formoterol: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufacturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Alfentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when alfentanil is used concomitantly with an anticholinergic drug. The concomitant use of alfentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Alosetron: (Major) Concomitant use of alosetron and anticholinergics, which can decrease GI motility, may seriously worsen constipation, leading to events such as GI obstuction, impaction, or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid anticholinergics in patients taking alosetron. (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Aluminum Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Amobarbital: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Amoxapine: (Major) Concomitant use of opioid agonists with amoxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with amoxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when amoxapine is used concomitantly with other anticholinergic agents. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when these drugs are combined with amoxapine.
Antacids: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opium is used concomitantly with an anticholinergic drug. The concomitant use of opium and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Apomorphine: (Major) Concomitant use of opioid agonists with apomorphine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with apomorphine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like apomorphine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
Aripiprazole: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Asenapine: (Moderate) Concomitant use of opioid agonists with asenapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with asenapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of opoid agonists with orphenadrine may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opoid agonists with carisoprodol may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant oxycodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atenolol; Chlorthalidone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth mucle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to antimuscarinic agents, such as the belladonna alkaloids. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
Azelastine: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Azelastine; Fluticasone: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Azilsartan; Chlorthalidone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Baclofen: (Major) Concomitant use of opioid agonists with baclofen may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with baclofen to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose.
Barbiturates: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with benzhydrocodone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of benzhydrocodone with opioid agonists to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking opium, reduce initial dosage and titrate to clinical response. If opium is prescribed in a patient taking benzhydrocodone, use a lower initial dose of opium and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and opium because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when benzhydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of benzhydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bethanechol: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa. (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Botulinum Toxins: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brexpiprazole: (Major) Concomitant use of opioid agonists with brexpiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brexpiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brompheniramine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Brompheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Bumetanide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when loop diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Meloxicam: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Buprenorphine: (Major) Avoid the concomitant use of buprenorphine and opiate agonists, such as opium. Mixed opiate agonist/antagonists may block the effects of opiate agonists and reduce analgesic effects. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use can also cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Buprenorphine; Naloxone: (Major) Avoid the concomitant use of buprenorphine and opiate agonists, such as opium. Mixed opiate agonist/antagonists may block the effects of opiate agonists and reduce analgesic effects. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use can also cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Buspirone: (Moderate) Concomitant use of CNS depressants, such as buspirone, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If concurrent use of codeine and buspirone is imperative, reduce the dose of one or both drugs.
Butalbital; Acetaminophen: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Butorphanol: (Major) Butorphanol may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists. Butorphanol may also be used concurrently with some opiate agonists and cause additive CNS, respiratory, and hypotensive effects. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when butorphanol is used concomitantly with an anticholinergic drug. The concomitant use of butorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Calcium Carbonate: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Magnesium Hydroxide: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Simethicone: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Calcium; Vitamin D: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and belladonna. CNS depressants can potentiate the effects of cannabidiol.
Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of opioid agonists and metaxalone increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Carbidopa; Levodopa: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Carbidopa; Levodopa; Entacapone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Cariprazine: (Moderate) Concomitant use of opioid agonists like opium with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Carisoprodol: (Major) Concomitant use of opoid agonists with carisoprodol may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Celecoxib; Tramadol: (Major) Concomitant use of tramadol with opium may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cenobamate: (Moderate) Concomitant use of opium with cenobamate may cause excessive sedation and somnolence. Limit the use of opium with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Cetirizine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant cetirizine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Cetirizine; Pseudoephedrine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant cetirizine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Cevimeline: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorcyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chloroprocaine: (Minor) Due to the CNS depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
Chlorothiazide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpromazine: (Major) Concomitant use of opioid agonists with chlorpromazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpromazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including chlorpromazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Chlorthalidone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Chlorzoxazone: (Major) Concomitant use of opioid agonists with chlorzoxazone may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with chlorzoxazone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Cholinergic agonists: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Citalopram: (Moderate) Citalopram impairs metabolism via the CYP2D6 pathway at therapeutic doses. This can result in increased concentrations of drugs metabolized via the same pathway, including some opiate agonists.
Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clomipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Clopidogrel: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration. (Moderate) Coadministration of opioid agonists, such as opium, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clozapine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Pain medications such as opiate agonists, should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Codeine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Codeine; Guaifenesin: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant promethazine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant codeine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant promethazine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
COMT inhibitors: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and antimuscarinics are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as antimuscarinics, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration. (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
Cyclobenzaprine: (Major) Concomitant use of opioid agonists with cyclobenzaprine may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with cyclobenzaprine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of opioid agonists and cyclobenzaprine increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant cyclobenzaprine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dantrolene: (Major) Concomitant use of opoid agonists with dantrolene may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Daridorexant: (Moderate) Concomitant use of opium with daridorexant may cause excessive sedation and somnolence. Limit the use of opium with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Dasiglucagon: (Major) The concomitant use of intravenous glucagon and anticholinergics increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Concomitant use is not recommended.
DaxibotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Delavirdine: (Major) Delavirdine is a potent inhibitor of CYP3A4 and an inhibitor (in vitro) of CYP2D6, CYP2C9, and CYP2C19. Therefore, delavirdine may alter the response to various opiate agonists. Increased concentrations of the CYP substrates alfentanil, fentanyl, hydrocodone, morphine, sufentanil, and oxycodone may be noted. Due the potential for increased formation of neurotoxic metabolites, concurrent use of delavirdine and meperidine or propoxyphene is not recommended. Delavirdine may decrease the efficacy of codeine-containing analgesics by inhibiting the conversion of codeine to morphine via CYP2D6. Delavirdine may also inhibit the metabolism of methadone, requiring a decrease in methadone doses.
Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as belladonna, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dexchlorpheniramine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dexmedetomidine: (Moderate) Concomitant use of opioid agonists with dexmedetomidine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with dexmedetomidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Difelikefalin: (Major) Avoid concomitant use of opioids and other CNS depressants, such as difelikefalin. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Dimenhydrinate: (Moderate) Concomitant use of opioid agonists with dimenhydrinate may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dimenhydrinate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diphenhydramine; Ibuprofen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diphenhydramine; Naproxen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth mucle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to antimuscarinic agents, such as the belladonna alkaloids. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
Disopyramide: (Moderate) In addition to its electrophysiologic effects, disopyramide exhibits clinically significant anticholinergic properties. These can be additive with other anticholinergics. Clinicians should be aware that urinary retention, particularly in males, and aggravation of glaucoma are realistic possibilities of using disopyramide with other anticholinergic agents.
Donepezil: (Moderate) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
Donepezil; Memantine: (Moderate) The adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy. (Moderate) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
Doxepin: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Doxylamine; Pyridoxine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Dronabinol: (Moderate) Concomitant use of opioid agonists with dronabinol may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dronabinol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Use caution if coadministration of dronabinol with anticholinergics is necessary. Concurrent use of dronabinol, THC with anticholinergics may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity.
Droperidol: (Major) Concomitant use of opioid agonists with droperidol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with droperidol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days. (Major) Avoid use of eluxadoline with medications that may cause constipation, such as opium. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Entacapone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Escitalopram: (Moderate) Escitalopram modestly inhibits metabolism via the CYP2D6 pathway. Theoretically, this can result in increased concentrations of drugs metabolized via the same pathway, including opium.
Esketamine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Eszopiclone: (Major) Concomitant use of opioid agonists with eszopiclone may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with eszopiclone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
Ethacrynic Acid: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when loop diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking opioids. Alcohol consumption may result in additive CNS depression and may increase the risk for opioid overdose. Consider the patient's use of alcohol when prescribing opioid medications. If the patient is unlikely to be compliant with avoiding alcohol, consider prescribing naloxone especially if additional risk factors for opioid overdose are present.
Ethotoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Etomidate: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fenfluramine: (Moderate) Concomitant use of opioid agonists with fenfluramine may cause excessive sedation and somnolence. Limit the use of opioid agonists with fenfluramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fentanyl: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Flibanserin: (Moderate) Concomitant use of opioid agonists with flibanserin may cause excessive sedation and somnolence. Limit the use of opioid pain medication with flibanserin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Fluoxetine: (Major) Fluoxetine may inhibit the metabolism of opium. Clinicians should be alert for an exaggerated opiate response if opium is given with fluoxetine.
Fluphenazine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Fosphenytoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Furosemide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when loop diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Gabapentin: (Major) Concomitant use of opioid agonists with gabapentin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications with gabapentin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Galantamine: (Moderate) The therapeutic benefits of galantamine, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
General anesthetics: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Glucagon: (Major) The concomitant use of intravenous glucagon and anticholinergics increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Concomitant use is not recommended.
Glycopyrronium: (Moderate) Although glycopyrronium is minimally absorbed into the systemic circulation after topical application, there is the potential for glycopyrronium to have additive anticholinergic effects when administered with other antimuscarinics. Per the manufaturer, avoid concomitant administration of glycopyrronium with other anticholinergic medications.
Guanfacine: (Moderate) Concomitant use of opioid agonists with guanfacine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with guanfacine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Guanidine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants, such as opiate agonists, Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydantoins: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydromorphone is used concomitantly with an anticholinergic drug. The concomitant use of hydromorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydroxyzine: (Major) Concomitant use of opioid agonists with hydroxyzine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with hydroxyzine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Ibritumomab Tiuxetan: (Moderate) Use anticholinergics, such as belladonna, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant oxycodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Imipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
IncobotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Indapamide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when indapamide is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Ipratropium: (Moderate) Although ipratropium is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinic or anticholinergic medications. Per the manufacturer, avoid coadministration.
Ipratropium; Albuterol: (Moderate) Although ipratropium is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinic or anticholinergic medications. Per the manufacturer, avoid coadministration.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Isocarboxazid: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
Isoflurane: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Itraconazole: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Ketamine: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lasmiditan: (Moderate) Concomitant use of opium with lasmiditan may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of opium with lasmiditan to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Lemborexant: (Moderate) Concomitant use of opium with lemborexant may cause excessive sedation and somnolence. Limit the use of opium with lemborexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Levocetirizine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant cetirizine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Levodopa: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Levorphanol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when levorphanol is used concomitantly with an anticholinergic drug. The concomitant use of levorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lidocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lidocaine; Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Linaclotide: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and belladonna. Lofexidine can potentiate the effects of CNS depressants. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and opium. Lofexidine can potentiate the effects of CNS depressants.
Loop diuretics: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when loop diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Lopinavir; Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered.
Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Loxapine: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
Lubiprostone: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain. (Moderate) Opium can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone.
Lumateperone: (Moderate) Concomitant use of opioid agonists like opium with lumateperone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lumateperone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Lurasidone: (Moderate) Antipsychotic agents may disrupt core temperature regulation; therefore, caution is recommended during concurrent use of lurasidone and medications with anticholinergic activity such as antimuscarinics. Concurrent use of lurasidone and medications with anticholinergic activity may contribute to heat-related disorders. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if lurasidone is used with antimuscarinics. (Moderate) Concomitant use of opioid agonists like opium with lurasidone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lurasidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Macimorelin: (Major) Avoid use of macimorelin with drugs that may blunt the growth hormone response to macimorelin, such as antimuscarinic anticholinergic agents. Healthcare providers are advised to discontinue anticholinergics at least 1 week before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
Magnesium Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Magnesium Salts: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Maprotiline: (Major) Concomitant use of opioid agonists with maprotiline may cause excessive sedation and somnolence. Limit the use of opioid pain medications with maprotiline to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Meclizine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Melatonin: (Moderate) Concomitant use of opioid agonists with melatonin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with melatonin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Memantine: (Moderate) The adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy.
Meperidine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when meperidine is used concomitantly with an anticholinergic drug. The concomitant use of meperidine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Meprobamate: (Moderate) Concomitant use of meprobamate and opium can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If used together, a reduction in the dose of one or both drugs may be needed.
Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of opioid agonists and metaxalone increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Methadone: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract; severe constipation or paralytic ileus is possible, especially with chronic use. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when methadone is used concomitantly with an anticholinergic drug. The concomitant use of methadone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Methocarbamol: (Major) Concomitant use of opioid agonists with methocarbamol may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with methocarbamol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Methohexital: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Metoclopramide: (Moderate) Drugs with significant antimuscarinic activity, such as anticholinergics and antimuscarinics, may slow GI motility and thus may reduce the prokinetic actions of metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur as well. The clinical significance is uncertain. (Moderate) The effects of metoclopramide on gastrointestinal motility are antagonized by narcotic analgesics. Concomitant use of opioid agonists with metoclopramide may also cause excessive sedation and somnolence. Limit the use of opioid pain medications with metoclopramide to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Metolazone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with mirtazapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Molindone: (Moderate) Antipsychotics are associated with anticholinergic effects; therefore, additive effects may be seen during concurrent use of molindone and other drugs having anticholinergic activity such as antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur. (Moderate) Concomitant use of opioid agonists like opium with molindone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with molindone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Monoamine oxidase inhibitors: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
Morphine: (Major) Concomitant use of morphine with opium can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or opium is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant morphine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Morphine; Naltrexone: (Major) Concomitant use of morphine with opium can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or opium is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant morphine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Nabilone: (Major) Avoid coadministration of opioid agonists with nabilone due to the risk of additive CNS depression. (Moderate) Concurrent use of nabilone with anticholinergics may result in pronounced tachycardia and drowsiness.
Nalbuphine: (Major) Nalbuphine concurrently used with some opiate agonists can cause additive CNS, respiratory, and hypotensive effects. If a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced. Due to opioid antagonistic properties, nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
Nirmatrelvir; Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
Nortriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Olanzapine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Olanzapine; Fluoxetine: (Major) Fluoxetine may inhibit the metabolism of opium. Clinicians should be alert for an exaggerated opiate response if opium is given with fluoxetine. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Olanzapine; Samidorphan: (Contraindicated) Salmidorphan is contraindicated in patients who are using opiate agonists or undergoing acute opioid withdrawal. Salmidorphan increases the risk of precipitating acute opioid withdrawal in patients dependent on opioids. Before initiating salmidorphan, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations, if a salmidorphan-treated patient requires opiates for anesthesia or analgesia, discontinue salmidorphan. The opiate agonist should be administered by properly trained individual(s), and the patient properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation. In non-emergency situations, if a salmidorphan-treated patient requires opiate agonist treatment (e.g., for analgesia) discontinue salmidorphan at least 5 days before opioid treatment. Salmidorphan, as an opioid antagonist, may cause opioid treatment to be less effective or ineffective shortly after salmidorphan discontinuation. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Oliceridine: (Major) Concomitant use of oliceridine with opium may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of oliceridine with opium to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oliceridine is used with belladonna. Use of anticholinergics may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
OnabotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Opicapone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Orphenadrine: (Major) Concomitant use of opoid agonists with orphenadrine may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Oxazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant oxycodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Oxymorphone: (Major) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Severe constipation, paralytic ileus, respiratory depression, hypotension, profound sedation, or coma may result from combination therapy. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Prior to concurrent use of oxymorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxymorphone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxymorphone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Slowly titrate the dose as necessary for adequate pain relief and monitor for sedation or respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone is used concomitantly with an anticholinergic drug. The concomitant use of oxymorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Ozanimod: (Contraindicated) Do not use opium in patients taking MAOIs or within 14 days of stopping them. An active metabolite of ozanimod inhibits MAO-B. MAO inhibitor interactions with opium may manifest as serotonin syndrome, hypertensive crisis, or opioid toxicity (e.g., respiratory depression, coma). Although a small number of patients treated with ozanimod were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from coadministration.
Paroxetine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Pegvisomant: (Moderate) In clinical trials, patients taking opiate agonists often required higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opiate agonists. The mechanism of this interaction is unknown.
Pentazocine; Naloxone: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as opium. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when pentazocine is used concomitantly with an anticholinergic drug. The concomitant use of pentazocine and anticholinergic medications may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Pentobarbital: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Perampanel: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Perphenazine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including perphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with perphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Perphenazine; Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including perphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with perphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perphenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Phenelzine: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
Phenobarbital: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Phentermine; Topiramate: (Moderate) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia.
Phenytoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Pilocarpine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including opiate agonists.
Potassium Bicarbonate: (Moderate) Use anticholinergics, such as belladonna, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Potassium Chloride: (Moderate) Use anticholinergics, such as belladonna, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Pralidoxime: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Pramipexole: (Major) Concomitant use of opioid agonists with pramipexole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pramipexole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like pramipexole have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as opiate agonists, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose. (Major) Pramlintide therapy should not be considered in patients taking medications that alter gastric motility, such as anticholinergics. Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications that have depressive effects on GI could potentiate the actions of pramlintide.
Prasugrel: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Pregabalin: (Major) Concomitant use of opioid agonists with pregabalin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Prilocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Primidone: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Procainamide: (Moderate) The anticholinergic effects of procainamide may be significant and may be enhanced when combined with anticholinergics. Anticholinergic agents administered concurrently with procainamide may produce additive antivagal effects on AV nodal conduction, although this is not as well documented for procainamide as for quinidine.
Procarbazine: (Moderate) Opiate agonists may cause additive sedation or other CNS effects when given in combination with procarbazine.
Prochlorperazine: (Major) Concomitant use of opioid agonists with prochlorperazine may cause excessive sedation and somnolence. Concurrent administration of prochlorperazine is contraindicated in patients receiving large doses of opiate agonists. Limit the use of opioid pain medications with prochlorperazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including prochlorperazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant promethazine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Promethazine; Dextromethorphan: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant promethazine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Promethazine; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant promethazine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Propofol: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Protriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Pseudoephedrine; Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Quazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Quetiapine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant quetiapine and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Ramelteon: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Rasagiline: (Moderate) MAOIs exhibit secondary anticholinergic actions. Additive anticholinergic effects may be seen when MAOIs are used concomitantly with antimuscarinics. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with MAOIs. (Moderate) Opiate agonists (e.g., alfentanil, codeine, hydrocodone, morphine, sufentanil, etc.) may cause additive CNS depression, drowsiness, dizziness or hypotension, so use with MAOIs should be cautious; lower initial dosages of the opiate are recommended followed by careful titration.
Remifentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Remimazolam: (Major) Concomitant use of opioid agonists with remimazolam may cause respiratory depression, hypotension, profound sedation, and death. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Revefenacin: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
RimabotulinumtoxinB: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Risperidone: (Moderate) Additive CNS depression may occur if opiate agonists are used concomitantly with risperidone. The dose of one or both drugs should be reduced.
Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered.
Rivastigmine: (Moderate) The therapeutic benefits of rivastigmine, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
Ropinirole: (Major) Concomitant use of opioid agonists with ropinirole may cause excessive sedation and somnolence. Limit the use of opioid pain medication with ropinirole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ropivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Rotigotine: (Major) Concomitant use of opioid agonists with rotigotine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with rotigotine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like rotigotine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Safinamide: (Contraindicated) Concomitant use of safinamide with opioids is contraindicated due to the risk of serotonin syndrome. Allow at least 14 days between discontinuation of safinamide and initiation of treatment with opioids.
Secobarbital: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Secretin: (Major) Discontinue anticholinergic medications at least 5 half-lives before administering secretin. Patients who are receiving anticholinergics at the time of stimulation testing may be hyporesponsive to secretin stimulation and produce a false result. Consider additional testing and clinical assessments for aid in diagnosis.
Sedating H1-blockers: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Selegiline: (Moderate) Concomitant use of opioid agonists with selegiline may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of opium with selegiline to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sevoflurane: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by anticholinergics. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
Sodium Oxybate: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Use anticholinergics, such as belladonna, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Solifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with other antimuscarinics. Blurred vision and dry mouth would be common effects. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opium is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of opium and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Spironolactone: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Stiripentol: (Moderate) Concomitant use of opioid agonists with stiripentol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with stiripentol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and belladona. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when sufentanil is used concomitantly with an anticholinergic drug. The concomitant use of sufentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Suvorexant: (Moderate) Concomitant use of opioid agonists with suvorexant may cause excessive sedation and somnolence. Limit the use of opioid pain medications with suvorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Tapentadol: (Major) Concomitant use of tapentadol with opium may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of tapentadol with opium to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Tapentadol should be used cautiously with anticholinergic medications since additive depressive effects on GI motility or bladder function may occur. Monitor patients for signs of urinary retention or reduced gastric motility. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Additive CNS effects like drowsiness or dizziness may also occur.
Tasimelteon: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Tegaserod: (Major) Drugs that exert significant anticholinergic properties such as antimuscarinics may pharmacodynamically oppose the effects of prokinetic agents such as tegaserod. Avoid administering antimuscarinics along with tegaserod under most circumstances. Inhaled respiratory antimuscarinics, such as ipratropium, are unlikely to interact with tegaserod. Ophthalmic anticholinergics may interact if sufficient systemic absorption of the eye medication occurs.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Temazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tenapanor: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
Tetrabenazine: (Moderate) Additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression. Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as opiate agonists, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Tetracaine: (Major) Due to the central nervous system depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists. Excitation or depression of the CNS may be the first manifestation of CNS toxicity. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of CNS toxicity. After each local anesthetic injection, careful and constant monitoring of ventilation adequacy, cardiovascular vital signs, and the patient's state of consciousness is advised.
Thalidomide: (Major) Avoid coadministration of opioid agonists with thalidomide due to the risk of additive CNS depression.
Thiazide diuretics: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Thioridazine: (Major) Concomitant use of opioid agonists with thioridazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with thioridazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like thioridazine are used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Thiothixene: (Moderate) Anticholinergics may have additive effects with thiothixene, an antipsychotic with the potential for anticholinergic activity. Monitor for anticholinergic-related adverse effects such as xerostomia, blurred vision, constipation, and urinary retention during concurrent use. (Moderate) Concomitant use of opioid agonists like opium with thiothixene may cause excessive sedation and somnolence. Limit the use of opioid pain medication with thiothixene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Ticagrelor: (Moderate) Coadministration of opioid agonists, such as opium, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
Tiotropium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Tiotropium; Olodaterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Tizanidine: (Major) Concomitant use of opioid agonists with tizanidine may cause respiratory depression, profound sedation, and death. Limit the use of opioid agonists with tizanidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose.
Tolcapone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tolterodine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opium is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of opium and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Topiramate: (Moderate) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia.
Torsemide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when loop diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Tramadol: (Major) Concomitant use of tramadol with opium may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Tramadol; Acetaminophen: (Major) Concomitant use of tramadol with opium may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Tranylcypromine: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
Trazodone: (Moderate) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Triamterene: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when triamterene is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when triamterene is administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Triazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tricyclic antidepressants: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Trifluoperazine: (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including trifluoperazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. (Moderate) Concomitant use of opioid agonists with trifluoperazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with trifluoperazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like opiate agonists, may potentiate the effects of either trimethobenzamide or the opiate agonist. (Moderate) Trimethobenzamide has CNS depressant effects and may cause drowsiness. The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the anticholinergics, may potentiate the effects of either trimethobenzamide or the anticholinergic.
Trimipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Trospium: (Moderate) Additive anticholinergic effects may be seen when trospium is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined with trospium. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when trospium, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Umeclidinium: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
Umeclidinium; Vilanterol: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
Valerian, Valeriana officinalis: (Moderate) Concomitant use of opioid agonists with valerian may cause excessive sedation and somnolence. Limit the use of opioid pain medication with valerian to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Valproic Acid, Divalproex Sodium: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when thiazide diuretics are administered with opium. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Vibegron: (Moderate) Vibegron should be administered with caution in patients taking anticholinergics because of potential for an increased risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with opiate agonists.
Vilazodone: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering opium with vilazodone. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Zaleplon: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including opium.
Zolpidem: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
Zonisamide: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
Zuranolone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Belladonna; opium a combination opioid analgesic and antispasmodic agent. The belladonna extract component provides the active alkaloids atropine and scopolamine, while the opium component provides primarily morphine. Opium contains more than 20 alkaloids, principally morphine (10%), narcotine (6%), papaverine (1%), and codeine (0.5%). Of these, only morphine is the major pharmacologically active constituent. The atropine alkaloid is parasympatholytic, exerting antispasmodic activity by relaxation of smooth muscle that is stimulated by the parasympathetic nervous system. The atropine alkaloid is also the dl isomer of l-hyoscyamine and exerts the same pharmacologic activity; however, it exerts about one-half the activity peripherally as l-hyoscyamine. Atropine activity also counteracts morphine-induced smooth muscle spasm without affecting the analgesia. The morphine alkaloid of opium exerts analgesic activity by increasing the pain threshold and decreasing the sensitivity to pain. The oxidative dealkylated normetabolites of morphine begin the analgesic process. Additionally, the side effect of euphoria may contribute to a sense of pain relief.
Belladonna; opium is administered rectally.
-Belladonna: Through its parasympatholytic action, atropine (belladonna) relaxes smooth muscle resulting from parasympathetic stimulation. It is the dl isomer of l-hyoscyamine and therefore exhibits the same clinical effects. It is approximately one-half as active peripherally as l-hyoscyamine, the latter being the major active plant alkaloid. The dl isomer atropine is formed during the process of isolation of the belladonna extract. The atropine effect of the belladonna extract serves to eliminate morphine induced smooth muscle spasm without affecting the sedative analgesic action of powdered opium.
-Opium: The active component of opium is morphine. Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Although the primary site of action is the central nervous system, only small quantities cross the blood-brain barrier. The Vd of morphine is approximately 1 to 6 L/kg, and morphine is 20% to 35% reversibly bound to plasma proteins. The major pathway of morphine metabolism is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine is demethylated, virtually all morphine is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity. Most of a dose of morphine is excreted in urine as M3G and M6G, with elimination of morphine occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling, and 7% to 10% of the administered morphine is excreted in the feces. The mean adult plasma clearance is approximately 20 to 30 mL/minute/kg.
Affected cytochrome P450 isoenzymes: P-gp
Morphine is a substrate for P-glycoprotein (P-gp).
-Route-Specific Pharmacokinetics
Other Route(s)
Rectal Route
Peak analgesia is achieved about 20 to 60 minutes after rectal administration.
-Special Populations
Hepatic Impairment
The half-life of morphine is significantly prolonged and clearance is decreased in persons with cirrhosis or hepatic disease. The morphine-3 glucuronide and 6-glucuronide to morphine plasma AUC ratios are also decreased, indicating diminished metabolic activity. Adequate studies of morphine pharmacokinetics have not been conducted in persons with severe hepatic impairment.
Renal Impairment
In persons with renal dysfunction, morphine AUC is increased and clearance is decreased. The metabolites, morphine-3 glucuronide and morphine-6 glucuronide, may accumulate to much higher plasma concentrations in persons with renal failure. Adequate studies of morphine pharmacokinetics have not been conducted in persons with severe renal impairment.