INFUMORPH

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-When initiating therapy, begin with an immediate-release preparation and titrate to the appropriate analgesic dose and then convert the patient to an extended-release product.
-The use of extended-release morphine products is generally not recommended in pediatric patients and is not FDA-approved in this population. The use of these products should only be under the direct supervision of a clinician highly experienced in the use of potent opioids for the management of chronic pain in children.
-Storage: Store morphine securely in a location not accessible by others.
-Disposal: Flush unused morphine down the toilet when it is no longer needed if a drug take-back option is not readily available.
Oral Solid Formulations
Immediate-release Tablets
-Administer without regard to meals; may be given with food or milk to minimize gastrointestinal irritation.

Extended-release Tablets (e.g., MS Contin)
-Swallow whole; do not crush, break, dissolve, or chew.
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of therapy initiation or dose escalation.
-MS Contin 100 and 200 mg tablets or Morphabond 100 mg tablets are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Limit use of a single dose of extended-release tablets more than 60 mg or a total daily dose more than 120 mg to opioid-tolerant patients.

Oral Liquid Formulations
Oral Solution
-Carefully check dose prior to dispensing medication as many concentrations of morphine oral solution are available. Limit the use of the 20 mg/mL concentration to opioid-tolerant adult patients.
-Always use an appropriately calibrated measuring device (e.g., syringe, dosing cup) with metric units of measure.

Opium Tincture (0.4 mg/mL formulation; Paregoric, USP)
-Shake well before using.
-Dispense in unit-dose packaging.
-Protect from light and excessive heat. The product may deposit sediment if exposed to low temperatures. Filter if necessary.
-Serious overdosage may result if product selection is improper. Place poison labels on all containers of opium tincture as well as label the strength of morphine per mL. Include a warning regarding improper substitution of camphorated opium tincture (0.4 mg/mL) with deodorized opium tincture (10 mg/mL).

Extemporaneous Compounding-Oral
Extemporaneous 0.4 mg/mL Morphine Oral Solution Preparation
-Measure 10 mL (20 mg) of ethanol-free oral morphine 2 mg/mL solution (commercially-available from Roxane).
-Transfer to an appropriate-sized plastic amber bottle.
-Measure 40 mL of Sterile Water for Irrigation in a syringe or graduated cylinder.
-Transfer to the plastic amber bottle containing morphine.
-Shake to mix.
-Storage: The solution is stable for 60 days when stored in a light protected container at room temperature (20 to 25 degrees C).



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Resuscitative medications, including naloxone, and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.
Intravenous Administration
Intermittent IV Injection
-Inject directly into a vein or into the tubing of a freely flowing IV solution over 4 to 5 minutes. Rapid IV injection of morphine may result in an increased frequency of adverse effects.

Continuous IV Infusion
-Dilute in 5% Dextrose Injection, 10% Dextrose Injection, 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or Lactated Ringer's Injection.
-Common concentrations range from 0.5 to 1 mg/mL. Maximum concentrations of 5 mg/mL have been used.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 0.04 mg/mL, 0.5 mg/mL, or 1 mg/mL.
-Administer using a controlled-infusion device.
-Adjust dose and rate based on patient response.

Patient-Controlled Analgesia (PCA)
-A compatible patient-controlled infusion device must be used.
-Adjust dose and rate based on patient response. Consult the patient-controlled infusion device operator's manual for directions on administering the drug at the desired rate of infusion.

Intramuscular Administration
-Inject into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]).

Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.

Intrathecal Administration
-Use ONLY preservative-free injectable solutions.
-Intrathecal administration should only be used by specially trained healthcare professionals.
-Intrathecal dose is approximately one-tenth of the epidural dose.
-If the product is supplied in a glass vial, filter the drug through a 5 micron or smaller microfilter.

Intermittent Intrathecal Injection (morphine sulfate solution)
-After ensuring proper placement of the needle or catheter, inject appropriate dose intrathecally.
-Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose. Both early and late respiratory depression has occurred more frequently after intrathecal administration than epidural administration.

Other Injectable Administration
Epidural Administration
-Use ONLY preservative-free injectable solutions.
-Epidural administration should only be used by specially trained healthcare professionals.
-May be given as intermittent bolus, continuous infusion, or as patient-controlled epidural analgesia.
-If the product is supplied in a glass vial, filter the drug through a 5 micron or smaller microfilter.
-Storage: For single use only. Protect from light; discard any unused portion.

Intermittent Epidural Injection (morphine sulfate solution)
-After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space.
-Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose. Both early and late respiratory depression has occurred more frequently after intrathecal administration than epidural administration.

Continuous Epidural Infusion (morphine sulfate solution)
-A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Monitor patients in a fully equipped and staffed environment for several days after implantation of the device.
-If dilution of the injection is necessary, 0.9% Sodium Chloride Injection is recommended.
-Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdosage.
-To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, avoid depletion of the reservoir.



Rectal Administration
-Instruct patient or caregiver on proper use of suppository.
-Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

Pharmacologic tolerance to the analgesic effects of opiate agonists including morphine has been reported. Tolerance is the need for increasing opioid doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease, or psychological distress.

Although extremely rare, anaphylactoid reactions including cases of anaphylaxis have been reported. Evidence of histamine release such as urticaria, wheals, and local tissue irritation may occur with parenteral morphine administration. Skin rash (unspecified) has also been reported after rectal morphine administration. Other dermatologic or allergic adverse events that have been reported with extended-release morphine in adult patients include rash (unspecified) (< 3% to 10%), decubitus ulcer (< 3%), xerosis (< 5%), urticaria (< 5%), and edema (< 5%).

One of morphine's most noticeable side effects is sedation. Warn patients and their caregivers that activity requiring mental alertness can be affected because CNS depression, including drowsiness (2% to 19%), confusion (less than 10%), and dizziness (more than 5%) can occur. Tolerance to the CNS depression develops within a few days; however, if it does not resolve, excessive sedation may be managed with stimulants such as methylphenidate. High doses of morphine given intravenously are excitatory due to an increase in circulating catecholamine concentrations and may result in seizures. Other CNS-related adverse events reported with morphine therapy in adult patients include headache (4% or more), nervousness (less than 5%), sleep disturbances, dysphoria, euphoria (less than 5%), lightheadedness, alterations of mood (feelings of floating, disorientation, apprehension), anxiety (2% to 6%), restlessness, tremor (less than 5%), malaise (less than 3%), thinking disturbances/abnormal thinking (less than 5%), sedation, abnormal dreams (less than 3%), lethargy (1% to 9%), depression (less than 10%), loss of concentration (less than 3%), insomnia (less than 10%), amnesia (less than 5%), agitation (less than 5%), foot drop (less than 5%), ataxia (less than 5%), hypesthesia/hypoesthesia (less than 5%), slurred speech (less than 3%), apathy (less than 3%), obtunded feeling, nonarousable condition, unresponsiveness, abnormal gait (less than 5%), coma (less than 5%), delirium (less than 5%,) disorientation, weakness, uncoordinated muscle movements, increased intracranial pressure, and vertigo (less than 3%). Hallucinations (less than 3%) (especially of bugs and spiders) and seizures (less than 5%) have been reported in patients receiving extended-release morphine. Depending upon the individual patient tolerance, hallucinations may be reported in patients undergoing rapid dose escalation. Dysphoric reactions or toxic psychosis can occur after any dose. Flushing may also be reported in patients initiating morphine therapy.

The most significant adverse effects associated with opiate agonist use are respiratory depression, respiratory arrest, and apnea. This results from a decreased sensitivity to both carbon dioxide and electrical stimulation in the brainstem respiratory centers. Respiratory depression is more common in debilitated patients, after large initial doses in non-opioid tolerant patients, and when opioids are given with other CNS depressants. Respiratory depression is most significant after IV administration. The sensitivity of the respiratory center returns to normal within 2 to 3 hours of an IV dose; however, respiratory depression can occur up to 24 hours after an intrathecal or epidural dose. When oral morphine is 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 lung disease, decreased pulmonary reserve, cardiovascular disease, or those who are taking other CNS depressants. Bronchospasm has been reported infrequently in patients receiving extended-release morphine tablets ; such an event may pose an additive danger in patients with pre-existing elevations in airway resistance. Other respiratory adverse events reported in adults include decreased oxygen saturation (> 10%), hypoxia (5% to 10%), hypercapnia (2% to 5%), dyspnea (2% to 10%), hiccups (< 5%), hypoventilation (< 5%), voice alteration (< 5%), depressed cough reflex (< 3%), rhinitis (< 3%), atelectasis (< 3%), asthma (< 3%), and non-cardiogenic pulmonary edema (< 3%). Symptomatic respiratory depression should be treated cautiously with an opioid antagonist such as naloxone. Patients may also develop respiratory depression through sub-acute overdose of an opiate agonist in which sedation builds up slowly leading to a decreased respiratory rate and then respiratory failure. The risk of this is more common with methadone but may be seen with other long-acting opioid preparations or in patients with renal or hepatic impairment. This can be managed by holding 1 to 2 doses of the opioid and then restarting the opioid at 25% of the previous dose. Rarely, patients receiving epidural or intrathecal morphine may develop dose-dependent delayed respiratory depression. The incidence of respiratory depression is higher after intrathecal versus epidural administration. Delayed respiratory depression may be seen up to 24 hours after a single epidural dose of morphine. Early respiratory depression (within 1 to 2 hours) may be seen after epidural administration due to systemic uptake of morphine via spinal blood vessels. Most cases of respiratory depression during spinal administration of morphine occur in patients receiving concomitant parenteral opioids or sedatives. If naloxone is used to reverse respiratory depression from morphine, repeat doses may be needed. The duration of action of naloxone is considerably shorter than the duration of action of intrathecal or epidural morphine.

Morphine may cause a variety of effects on the GI system, most commonly nausea (7% to > 10%), vomiting (< 3% to > 10% depending on the patient population and formulation), and constipation (9% to > 10%). Nausea and vomiting is most commonly seen at the initiation of therapy or when switching agents. Opiate agonists affect the vestibular system and may cause more nausea/vomiting in ambulatory patients than bedridden patients. Scheduled treatment with an antiemetic during the first 1 to 2 days, then as needed during opiate therapy will usually control these symptoms until tolerance develops. If nausea/vomiting is associated with continuous infusion morphine, receipt of naloxone intravenously may be helpful. Constipation due to decreased GI motility and secretions is common during opiate agonist therapy. In some cases patients can develop ileus or GI obstruction. Ileus was reported in 2% to 5% of adult patients who received extended-release liposomal morphine injection (Depodur); the incidence for other formulations is unknown. Tolerance rarely develops to the constipating effect of morphine; therefore, patients require a bowel regimen consisting of a stool softener and mild stimulant throughout opioid therapy. Other GI adverse events reported with morphine in adults include anorexia (< 3% to 10%), dysphagia (< 5%), dyspepsia (< 3% to 5%), diarrhea (< 3% to 10%), abdominal pain (< 3% to 10%), stomach atony disorder (< 3%), gastroesophageal reflux (< 3%), delayed gastric emptying (< 3%), flatulence (5% to 10%), abdominal distention (2% to 5%), gastroenteritis (< 5%), abnormal liver function tests (< 5%), rectal disorder (< 5%), thirst (< 5%), dysgeusia (< 5%), weight loss (< 5%), laryngospasm, and abdominal cramps.

General adverse events reported with morphine use in adults include asthenia (< 3% to 10%), accidental injury (< 3% to 10%), fever (< 3% to > 10%), interference with thermal regulation, pain (< 3%), chest pain (unspecified) (< 3%), chills (< 3%), flu syndrome (< 3% to 10%), rigors (2% to 5%), and peripheral edema (< 3% to 10%).

Morphine is a controlled substance with a high potential for abuse and psychological dependence. Abuse and addiction are separate and distinct from physiological dependence and tolerance, which can develop during chronic opioid therapy. Tolerance is characterized by a reduced response to a drug after repeated administration. Physiological dependence develops as a result of repeated drug use. It manifests with a withdrawal syndrome after abrupt discontinuation or significant dose reduction, or administration of an agent with opioid antagonist activity (e.g., naloxone). Withdrawal is characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms include irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal. Neonatal opioid withdrawal syndrome may be life-threatening and requires management according to protocols developed by neonatology experts. It presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

Opiate analgesics can cause spasm of the sphincter of Oddi, with morphine producing greater effects than meperidine and meperidine producing greater effects than codeine. Hyperamylasemia, secondary to drug-induced spasm of the sphincter of Oddi, has been associated with various opiate agonists. While serum amylase and lipase concentrations can rise as a result of biliary obstruction or spasm, overt pancreatitis is rare with opiate analgesics. Gastritis and hepatotoxicity are also relatively rare with these agents. Biliary colic (< 3%), biliary pain (< 5%), and biliary tract spasm have been reported with the use of morphine in adults.

Morphine may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients as a result of peripheral vasodilation. Patients at risk include those whose ability to maintain blood pressure is already compromised by reduced blood volume or concurrent administration of certain central nervous system depressants (e.g., phenothiazines, general anesthetics); monitor these patients carefully. The most common events reported in pediatric patients are hypotension and bradycardia. Reactions reported in adults receiving morphine include sinus bradycardia (< 3% to 5%), sinus tachycardia (< 3% to 10% depending on the patient population), atrial fibrillation (< 3%), pallor (< 3%), facial flushing (< 3%), peripheral vasodilation (< 5%), palpitations (< 5%), hypertension (< 3% to 5%), hypotension (< 3% to > 10% depending on the patient population and formulation studied), orthostatic hypotension, diaphoresis (< 3%)/sweating (2% to 10%), faintness, and syncope (< 5%). In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur.

Morphine and other opiate agonists are known to cause pruritus (< 3% to > 10% depending on the formulation). A high incidence of pruritus is associated with a single dose of either epidurally or intrathecally administered morphine. The pruritus is dose-related and is not confined to the administration site. Occasionally, pruritus is also associated with continuous administration of epidural or intrathecal morphine; the cause is poorly understood. Pruritus tends to be a less frequent adverse effect of oral morphine products. Opiate agonist-induced pruritus is thought to be mediated through stimulation of central opiate receptors since opiate antagonists (i.e., nalmefene or naloxone) have been shown to ameliorate pruritus associated with cholestasis. If pruritus is associated with continuous administration of morphine, receipt of naloxone intravenously may lessen the adverse reaction. Alternatively, use of H1-blockers or changing to a different opioid may lessen the pruritus.

Some patients may experience anticholinergic side effects with morphine therapy. Adult patients have reported xerostomia (< 3% to 10%), blurred vision (< 3%), or urinary retention (< 5%) and urinary hesitancy (< 3%), which can cause oliguria (2% to 5%). After epidural or intrathecal administration of morphine, the incidence of urinary retention in adults is 40% to 100%. Urinary retention may last for 10 to 20 hours after a single epidural or intrathecal dose and for several days after initiation of a continuous infusion. While this may not be a problem for some post-operative patients who have an indwelling urinary catheter, ambulatory and chronic pain patients may have significant problems. Cholinomimetic medication may be advisable. If urinary retention is associated with continuous infusion morphine, receipt of naloxone intravenously may be helpful. Other urinary adverse events associated with morphine use in adults include urinary abnormality (< 3%), bladder spasm (2% to 5%), and dysuria (< 5%).

Morphine causes miosis infrequently at typical therapeutic doses; miosis may even occur in total darkness. Severe overdose can cause mydriasis once brain anoxia develops. Therapeutic doses can increase accommodation and sensitivity to light reflex and decrease intraocular tension in both normal and glaucomatous eyes. Other ocular adverse events reported with morphine use in adults include amblyopia (< 3%), conjunctivitis (< 3%), diplopia (< 3%), ocular pain (< 5%), nystagmus (< 3%), and visual disturbances.

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 hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression). Adolescent females may experience amenorrhea. Gynecomastia (< 3%) has also occurred in adults. 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. Morphine 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 can 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.

Unusual acceleration of neuraxial morphine requirements can occur in some persons, which may cause concern regarding systemic absorption and the hazards of large doses; these persons may benefit from hospitalization and detoxification. High doses of neuraxial morphine may produce myoclonia events. Myoclonic-like spasm of the lower extremities has been reported in 2 subjects receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some persons have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit during continuing treatment must be individualized.

Paresthesias (< 3% to 10%) have been reported with the use of morphine in adults. Non-infectious inflammatory masses, such as granulomas have surrounded catheter tips in patients that received continuous infusions of opioid analgesics by an intrathecal indwelling catheter. Symptoms that led to the discovery of an intraspinal mass included loss of analgesic drug effects, spinal cord or cauda equina compression, or a sudden neurologic deficit, such as paresthesias. Serious neurologic impairment, including paralysis, complete paraplegia or paresis has occurred. Some patients with masses that did not fill the spinal canal or cause neurological impairment have been treated by stopping or emptying the drug infusion pump or by refilling the pump with preservative-free normal saline. The action either caused mass stabilization or mass regression over several months. In contrast, despite prompt surgical intervention, permanent neurological impairment occurred in some patients with impending paraplegia from a mass that filled the spinal canal. Patients who receive continual morphine sulfate with or without preservatives by an indwelling intrathecal catheter need to be monitored for new neurologic signs and symptoms.

Musculoskeletal adverse events reported with the use of morphine in adults include back pain (< 3% to 10%), bone pain (< 3%), arthralgia (< 3%), skeletal muscle rigidity (< 5%), and decreased bone mineral density.

Hematologic adverse events that have been reported with morphine therapy in adults include anemia (< 5%), leukopenia (< 3%), thrombocytopenia (< 5%), and decreased hematocrit (2% to 5%).

Infection (unspecified) and urinary tract infection were reported in 5% to 10% of adult patients during morphine therapy; causality to the drug is unknown. Opioids have been shown to have a variety of effects on components of the immune system in both in vitro and animal models; however, the clinical significance of these findings is unknown. The effects of opioids appear to be modestly immunosuppressive.

Serotonin syndrome has been reported in patients taking opioids at recommended doses. Patients taking an opioid 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.

Cases of opioid-induced hyperalgesia (OIH) have been reported, both with short-term and longer-term use of opioids. OIH occurs when an opioid paradoxically causes an increase in pain or an increase in sensitivity to pain. Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Data suggests a strong biologic plausibility between opioids and OIH and allodynia. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching to a different opioid).

Hypoglycemia has been reported during opioid therapy. Most reports occurred in persons with at least 1 predisposing risk factor, such as diabetes.

Morphine use is contraindicated in patients with a history of hypersensitivity reactions to morphine. Further, do not use other opioid agonists of the phenanthrene subclass including oxycodone, codeine, and hydromorphone in such patients. If a hypersensitivity occurs, it may be possible to treat the patient with an opioid agonist from another subclass (e.g., phenylpiperidine, diphenylheptane, phenylpropylamine).

Morphine is contraindicated for use in patients with significant respiratory depression in unmonitored settings or in the absence of resuscitative equipment. Additionally, avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, low blood pressure, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation. Parenteral morphine is often used in surgical and critical care settings where some degree of respiratory depression is expected (e.g., patients on mechanical ventilation). When parenteral morphine is used in a non-intubated patient, careful monitoring of respiratory status must occur; patients with pre-existing pulmonary disease are at increased risk for respiratory adverse effects. All formulations of morphine, with the exception of opium tincture oral solution, are contraindicated in acute or severe bronchial asthma (i.e., status asthmaticus) in unmonitored settings or in the absence of resuscitative equipment. Receipt of moderate doses in these patients may significantly decrease pulmonary ventilation. Although opium tincture solution is not specifically contraindicated in patients with pre-existing respiratory depression or hypoxia, therapeutic doses may decrease respiratory drive to the point of apnea. In patients with pulmonary disease such as chronic lung disease (CLD), cor pulmonale, pulmonary hypertension, hypoxia, hypoxemia, hypercapnia, respiratory insufficiency, or pre-existing respiratory depression, it is recommended that except for in the most carefully monitored situations, non-opioid analgesics are considered as alternatives to morphine; even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), or paralysis of the phrenic nerve. Patients with debilitation or sleep apnea are at an increased risk for the development of respiratory depression. Use morphine with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in patients with CSA. Monitor patients who receive epidural or intrathecal morphine for a minimum of 24 hours after the dose due to the risk of delayed respiratory depression. Although the use of extended-release products is not common in the general pediatric population, these products are used off-label for certain patients with chronic pain and carry a serious risk of respiratory depression. Only healthcare professionals who are knowledgeable of the use of potent opioids for the management of chronic pain in children should prescribe morphine extended-release capsules and tablets. Proper dosing and titration are essential; monitor patients for respiratory depression, particularly for the first 24 to 72 hours after therapy initiation or dose escalation. Exercise caution when converting from a different opioid to morphine, as initial dose overestimation may lead to fatal overdose. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. A high level of vigilant monitoring is recommended.

Hypotension and bradycardia are 2 of the most common adverse effects of morphine in the pediatric population; use caution when administering morphine to any patient who is hemodynamically fragile. Morphine produces cholinergic side effects causing bradycardia and histamine release, which can result in peripheral vasodilation and hypotension. There is an increased risk in patients 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 these patients for signs of hypotension after initiating or titrating the opioid dosage. Avoid the use of morphine in patients with circulatory shock, as drug induced vasodilation may further reduce cardiac output and blood pressure. Morphine suppositories are contraindicated in patients with cardiac arrhythmias or heart failure secondary to chronic lung disease, as bradycardia, vasodilation, and respiratory depression may aggravate these conditions. Use morphine with caution in patients with atrial flutter, atrial fibrillation, or other supraventricular tachycardias, as vagolytic action may produce significant increases in ventricular response rate. Also use morphine cautiously in patients with cardiac disease, angina or pre-existing hypotension. Opiate agonists can induce vasovagal syncope or orthostatic hypotension; use caution in patients with preexisting orthostatic hypotension.

Morphine tablets, capsules, oral solution, and solution for injection are contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Use other morphine formulations with extreme caution in these conditions. Morphine causes decreased GI motility and delayed digestion; patients with pre-existing GI disease may be at increased risk for adverse events. In critically ill newborns and pediatric patients receiving morphine, monitor for abdominal distension and loss of bowel sounds. Use all forms of morphine cautiously in patients with ulcerative colitis, GI bleeding, or pre-existing constipation; avoid extended-release capsules and tablets in any type of GI obstruction. Patients with ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Morphine rectal suppositories are contraindicated for use in patients with known or suspected acute abdomen or surgical anastomosis; opiate agonists may obscure the diagnosis or clinical course in patients with an acute abdomen. Opium tincture solution is contraindicated for use in diarrhea caused by poisoning until the toxic material is eliminated from the GI tract.

In addition to the common parenteral routes of administration, preservative-free formulations of morphine solution for injection can be given intrathecally and epidurally. Several factors contraindicate the use of morphine via epidural administration or intrathecal administration. These include infection at the injection site, concomitant anticoagulant therapy, uncontrolled coagulapathy, and/or the presence of any other concomitant therapy or medical condition that would render epidural or intrathecal administration especially hazardous (e.g., sepsis, platelet abnormalities, thrombocytopenia, tumor at the injection site). Observe patients in a fully equipped and staffed environment for a minimum of 24 hours after the initial intrathecal or epidural dose and as appropriate for the first several days after catheter implantation for Infumorph administration, as severe adverse reactions may occur. Immediate availability of naloxone injection and resuscitative equipment is needed for the initial administration of intrathecal or epidural morphine and during Infumorph reservoir refilling or reservoir manipulation.

Although all forms of morphine have potential for overdose or poisoning, certain formulations are associated with specific risks. This includes morphine oral solutions due to possible concentration and/or dosing errors and long-acting and high-potency morphine products for the increased risk of life-threatening respiratory depression. Knowledge and care in product selection is advised. Serious adverse events and deaths have been reported in conjunction with accidental overdose of morphine 100 mg/5 mL oral solutions and other concentrations. Excessive doses may be a result of morphine oral solutions prescribed in milligrams and erroneously interchanged for milliliters of the product. Improper substitution of Infumorph injectable solution (10 mg/mL or 25 mg/mL) for Duramorph or Astramorph injectable solutions (0.5 mg/mL or 1 mg/mL) may cause serious overdosage. To reduce the risk of life-threatening adverse effects, several formulations of morphine are intended for opioid-tolerant patients only. Do not use the following in opioid-naive patients: 100 or 200 mg morphine extended-release tablets (MS Contin); 100 mg extended-release tablets (Morphabond); or 100 mg/5 mL morphine oral solution. Only use extended-release morphine (e.g., Arymo, MS Contin, and Morphabond) for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate; these formulations are not intended for as-needed analgesia. Morphine should be kept out of the reach of pediatric patients and others for whom it was not prescribed, as accidental exposure may cause a fatal overdose.

Do not abruptly discontinue methadone in patients who may be physically dependent on opioids. Abrupt discontinuation of methadone in physically opioid-dependent patients has resulted in serious withdrawal symptoms, uncontrolled pain, suicide, and drug-seeking behavior. Consider the opioid dose, duration of therapy, type of pain being treated, and physical and psychological attributes of the patient when decreasing the opioid dose or discontinuing therapy. Ensure ongoing care of the physically opioid-dependent patient, including a multimodal approach to pain management, and devise an appropriate tapering schedule and follow-up plan so that patient and provider goals are clear and realistic. When discontinuing therapy due to suspected substance abuse, evaluate and treat the patient or refer for evaluation and treatment of the substance abuse disorder. For physically opioid-dependent patients, decrease the methadone dose by no more than 10% to 25% of the total daily dose every 2 to 4 weeks. Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper. Reassess patients frequently to manage pain and withdrawal symptoms, if they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. If withdrawal symptoms arise, pause the taper or increase the opioid dose to the previous dose, then proceed with a slower taper. Monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. Avoid use of partial agonists (e.g., buprenorphine), mixed agonists/antagonists (e.g., nalbuphine), or pure antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the opioid antagonist. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial agonists or mixed agonist/antagonists in patients who have received or are receiving opioid agonist analgesia may reduce the analgesic effects of methadone.

Use morphine cautiously in patients with biliary tract disease or acute pancreatitis and monitor these patients for worsening symptoms. Morphine increases the tone of the biliary tract causing spasms (especially in the sphincter of Oddi) and increasing biliary tract pressure. Opioids may cause increases in serum amylase.

Use morphine with extreme caution in patients with head trauma, brain tumor, increased intracranial pressure (ICP), convulsive disorders (such as seizure disorders), or severe CNS depression; the use of morphine suppositories is specifically contraindicated in each of these conditions. Camphorated opium tincture is specifically contraindicated in convulsive states, such as those occurring in status epilepticus, tetanus, and strychnine toxicity. Opiate agonists can compromise the evaluation of neurologic parameters. Rapid administration of high-dose opiate agonists may transiently elevate intracranial pressure and reduce cerebral perfusion pressures. These events are associated with opiate-induced lowering of mean arterial pressure, which stimulates a regulatory response to increase cerebral blood flow leading to increased ICP. Opiate agonist-induced respiratory depression can produce cerebral hypoxia and raise CSF pressure, which is unrelated to but may exaggerate the injury. Use caution in patients with preexisting seizure disorder or cerebral arteriosclerosis. Opiate analgesics, especially in high doses, can precipitate seizures.

Morphine and other opiate agonists can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, urethral stricture, pelvic malignancy, or renal disease. Drug accumulation or prolonged duration of action can occur in patients with renal impairment or hepatic disease. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver or renal disease may require less frequent dosing intervals; titrate doses carefully and more slowly in patients with renal or hepatic impairment.

Advise any patient (or their caregiver) receiving an opiate agonist, such as morphine, about the possibility of sedation and to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle).

Improper use of various morphine dosage forms are associated with increased risks. As a general rule, controlled-release products should not be crushed, chewed, or dissolved. Some capsule formulations may be opened and sprinkled on food, but the contents must not be chewed. Refer to specific product information for details. All patients of an appropriate age should be warned to avoid ethanol ingestion while taking morphine; the combination can result in fatal respiratory depression. Use of an opioid agonist while under the influence of other CNS depressants or ethanol intoxication will increase risk of CNS and respiratory depressant effects. In addition, instruct patients who will take extended-release capsules (e.g., Avinza or Kadian) to avoid all ethanol, including use of any medication that contains alcohol; concurrent alcohol receipt may lead to rapid release and absorption of a potentially fatal morphine dose. Improper or erroneous substitution of Infumorph (10 mg/mL or 25 mg/mL) injection for Duramorph (0.5 mg/mL or 1 mg/mL) injection is likely to cause serious overdosage.

Use morphine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal 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 adrenal 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 adrenal insufficiency. It is unclear which, if any, opioids are more likely to cause adrenal insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

Morphine is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Use with caution in patients with a history of substance abuse or alcoholism; the use of morphine rectal suppositories is specifically contraindicated in patients with acute alcoholism or delirium tremens. Injectable morphine products have been associated with abuse and dependence among health care providers. Special measures to control the products within the hospital or clinic are recommended because of the limited indications, the overdosage risk, and the diversion/abuse risk. Specifically, rigid accounting, rigorous wastage control, and restricted access are recommended. Addiction may occur in patients who obtain morphine 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. The misuse of extended-release morphine products by crushing, chewing, snorting, or injecting the dissolved product will result in uncontrolled drug delivery which may produce fatal respiratory depression. To discourage abuse, the smallest appropriate quantity of morphine 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.

Neonates and infants younger than 6 months of age have highly variable clearance of opiate agonists. Therefore, infants younger than 6 months of age may be given opiate agonists but must be closely monitored for apnea until 24 hours after their last dose. Clinical practice guidelines suggest close monitoring of children up to 1 year of age. Premature neonates have significantly slower morphine clearance than other populations; careful monitoring and titration in small dosage increments is warranted. A multi-center randomized, placebo-controlled trial found morphine use to be associated with a delay in attaining full enteral feeds in premature infants; however, it was not associated with an increased risk of gastrointestinal pathology. The use of deodorized opium tincture (10 mg/mL) is contraindicated for use in neonates, infants, children, and adolescents; safety and efficacy are not established.

Use of morphine oral dosage forms, suppositories, and solution for injection is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. Manufacturers of other morphine dosage forms do not recommend the concurrent use of MAOIs or morphine use within 14 days of stopping such treatment. Additive CNS depression, drowsiness, dizziness, or hypotension may occur.

Prolonged in utero exposure to morphine may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. 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 opioids during labor or breast-feeding for signs of respiratory depression and excessive sedation. Withdrawal symptoms can occur in breast-fed infants when maternal administration of the opioid is stopped, or when breast-feeding is stopped.

Description: Morphine is a strong opioid analgesic used for the relief of moderate to severe acute and chronic pain due to various etiologies. Morphine is the strong opioid of choice for pain associated with cancer. Morphine is also used for the management of neonatal abstinence syndrome and as a continuous infusion as a component of sedation/analgesia regimens for critically ill patients. Many different formulations of morphine are available. Several of the injectable and oral formulations are available as multiple concentrations; caution is warranted when choosing a product to ensure the appropriate release formulation and concentration is being used. Two formulations of opium tincture, camphorated opium tincture and deodorized opium tincture, contain anhydrous morphine and have been used for the treatment of non-infectious diarrhea; however, deodorized opium tincture is not recommended for use in pediatric patients. Serious medication errors have resulted from confusion between the products, as the deodorized tincture is 25-times more concentrated than the camphorated tincture. Opium tinctures have not been found to be safe and effective by the FDA, and they are considered unapproved drugs. While many morphine products, including extended-release enteral formulations, are not FDA-approved for use in pediatric patients, some product labeling carries indications for patients as young as infants.

General Dosing Information:
-Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
-Individualize dosing for each patient; consider opioid-tolerance, the physical and medical status of the patient, the degree of analgesia desired, patient response, clinical environment, and risk factors for addiction, abuse, and misuse. Reduce initial doses in patients at risk for respiratory depression, including patients receiving other central nervous system (CNS) depressants.
-Higher than usual doses may be required when morphine is used in patients tolerant to opiate agonists. There is no maximum dose of morphine; however, careful titration of morphine in opioid-naive patients is required until tolerance develops to some of the side effects (i.e., drowsiness and respiratory depression).
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours after initiation and after dosage increases. Patients should be continually evaluated. If intolerable adverse effects occur, the dose and/or interval should be adjusted.
-For conversion between opiates, assessment of individual clinical response is necessary. Published tables vary in suggested equianalgesic doses. Because there is not complete cross-tolerance among these agents, it is recommended to lower the equianalgesic dosing when changing agents and then titrate to pain response. When converting to long-acting opioids, such as extended-release morphine products, it is safer to underestimate the patient's 24-hour morphine requirements and provide rescue medication as needed than to overestimate opioid requirements and manage adverse reactions. Refer to the Opioid Agonists Drug Class Overview for approximate equianalgesic doses.
-When discontinuing morphine therapy, slow withdrawal is recommended especially in patients receiving higher doses or long-term therapy.

For the treatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate:
Oral dosage (2 mg/mL or 4 mg/mL oral solution):
Infants and Children 6 to 23 months*: 0.15 to 0.3 mg/kg/dose (Max initial dose: 5 mg) PO every 3 to 6 hours as needed; titrate gradually to pain relief.
Children and Adolescents 2 to 17 years: 0.15 to 0.3 mg/kg/dose (Max initial dose: 10 to 20 mg) every 3 to 6 hours as needed; titrate gradually to pain relief.
Oral dosage (immediate-release tablets):
Children and Adolescents weighing less than 50 kg*: 0.15 to 0.3 mg/kg/dose (Max initial dose: 5 mg) PO every 3 to 6 hours as needed; titrate gradually to pain relief.
Children and Adolescents weighing 50 kg or more: 15 mg PO every 4 hours as needed (Max initial dose: 30 mg); titrate gradually to pain relief. General weight-based dosing for pediatric patients is 0.15 to 0.3 mg/kg/dose PO every 3 to 6 hours as needed.
Intermittent Intravenous, Intramuscular, or Subcutaneous dosage:
Neonates*: 0.05 to 0.1 mg/kg/dose IV/subcutaneously/IM every 3 to 4 hours as needed. Adjust dose as needed to achieve target pain assessment score.
Infants 1 to 5 months: 0.05 to 0.1 mg/kg/dose IV/subcutaneously/IM every 3 to 4 hours as needed. Adjust dose as needed to achieve target pain assessment score.
Infants, Children, and Adolescents 6 months to 17 years: 0.05 to 0.2 mg/kg/dose IV/subcutaneously/IM every 2 to 4 hours as needed; begin at lower end of dosage range and titrate to effect (usual max dose: 4 mg for children or 8 mg for adolescents; however dose must be individualized).
Continuous Intravenous Infusion dosage*:
NOTE: Continuous infusions should only be used in acute care settings (e.g., intensive care units) where trained personnel are continuously monitoring the patient and emergency medications and equipment are readily available.
Neonates: 0.01 to 0.03 mg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
Infants, Children, and Adolescents: A bolus of 0.05 to 0.2 mg/kg IV (or 5 to 10 mg IV for patients over 60 kg) followed by a continuous infusion. Initial infusion rates of 0.01 to 0.03 mg/kg/hour are common, but initial doses up to 0.06 mg/kg/hour IV may be appropriate for some patients. Alternatively, rates of 0.8 to 3 mg/hour IV may be used for patients over 60 kg. Higher maintenance infusion rates, up to 0.2 mg/kg/hour IV, have been used in patients with sickle cell disease. Titrate to pain relief.
Continuous Subcutaneous dosage*:
Infants, Children, and Adolescents: An initial infusion rate of 0.03 mg/kg/hour subcutaneously has been recommended; however, an initial dose of 0.01 mg/kg/hour is also reasonable. The mean infusion rate was 0.0175 mg/kg/hour over the first 24 hours after surgery in 60 patients (aged 7 months to 20 years) and decreased to 0.011 to 0.0133 mg/kg/hour over the next 48 hours. Higher infusion rates, ranging from 0.025 to 1.79 mg/kg/hour subcutaneously (median: 0.06 mg/kg/hour subcutaneously), were used in 17 patients (aged 22 months to 22 years) with terminal cancer. Titrate dose to pain relief.
Intravenous dosage (Patient Controlled Analgesia [PCA]):
Children and Adolescents 7 to 17 years: Various regimens have been reported. The following settings have been used in pediatric patients; titrate regimen to patient response.
Demand dose: 0.01 to 0.025 mg/kg IV (max: 1 mg/dose)
Lockout interval: 5 to 10 minutes
Doses per hour: 5
Basal rate (optional): 0.004 to 0.015 mg/kg/hour IV initially
4-hour limit (optional): 0.24 to 0.375 mg/kg
Epidural dosage* (preservative-free solution for injection):
Infants, Children, and Adolescents: Various regimens have been reported including single preoperative and postoperative doses of 0.03 to 0.1 mg/kg epidurally, postoperative doses of 0.02 to 0.03 mg/kg/dose epidurally every 8 hours, and postoperative continuous infusions of 0.004 to 0.01 mg/kg/hour. Use preservative-free formulations only.
Intrathecal dosage* (preservative-free solution for injection):
Infants, Children, and Adolescents: Single preoperative doses of 0.002 to 0.02 mg/kg intrathecally have been reported. Use preservative-free formulations only.
Rectal dosage*:
Infants, Children, and Adolescents: 0.2 mg/kg/dose rectally every 4 hours as needed or 0.3 mg/kg/dose rectally every 6 hours as needed has been recommended; do not exceed the usual adult dose of 10 to 20 mg/dose.
-for the treatment of persistent, severe pain* that requires an extended treatment period with a daily opioid and for which alternative treatments are inadequate:
NOTE: Extended-release morphine should be reserved for patients in whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would otherwise provide inadequate pain management. Discontinue all other around-the-clock opioid drugs when long-acting morphine is initiated.
NOTE: Although FDA-approved product labeling provides adult dosing for both opioid-naive and opioid-tolerant patients, it may be prudent to limit pediatric use to opioid-tolerant patients. There is substantial interpatient variability in the relative potency of different opioid drugs and products. FDA-approved labeling for extended-release morphine defines adult opioid-tolerant patients as those taking, for a minimum of 1 week, morphine 60 mg/day PO, oxycodone 30 mg/day PO, hydromorphone 8 mg/day PO, fentanyl 25 mcg/hour transdermally, or an equianalgesic dose of another opioid.
Oral dosage (extended-release tablets [e.g., MS Contin])*:
Children and Adolescents: Limited data are available, and there is wide variability in dosage needs. Doses of 0.2 to 2.3 mg/kg/dose PO every 12 hours have been used in patients with various types of cancer and sickle cell disease. Begin at the lower end of the dosage range, and titrate to pain relief. Do not exceed recommended adult doses; the initial adult dosage recommendation is 15 mg PO every 8 to 12 hours, with the longer interval used in opioid-naive patients. Many experts recommend beginning with an immediate-release product to titrate to an appropriate daily dose and then switch to an extended-release formulation and divide the patient's total daily dose into 2 or 3 equal doses. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. Extended-release morphine should not be used for as needed analgesia and is only appropriate for a select group of children; only clinicians highly experienced in pediatric pain management should prescribe extended-release formulations.

For analgesia/sedation during rapid-sequence intubation*:
Intravenous dosage:
Neonates: 0.05 to 0.2 mg/kg IV. Use the lower end of the range for opioid-naive neonates. Onset of action is typically 5 minutes. Use a preservative-free formulation.
Infants, Children, and Adolescents: 0.1 to 0.2 mg/kg IV. Onset of action is typically 2 to 5 minutes.

For the treatment of neonatal abstinence syndrome*:
Oral dosage:
Neonates: Initially, 0.03 to 0.1 mg/kg/dose PO every 3 to 4 hours. Increase by 20% of the initial dose every 8 hours until symptoms are controlled to a maximum of 0.2 mg/kg/dose. Once the patient is on a stable dose, individualize weaning based on the patient's symptoms. Reductions of 10% to 20% of the initial dose every 1 to 2 days have been suggested.

For the treatment of noninfectious diarrhea:
WARNING: Proper product selection is critical. Deodorized opium tincture 10 mg/mL solution is 25 times more concentrated than camphorated opium tincture 0.4 mg/mL solution. Serious patient harm may occur with incorrect product selection. Deodorized opium tincture 10 mg/mL solution is not recommended for use in pediatric patients.
Oral dosage (Camphorated Opium Tincture Solution [Paregoric, USP; contains 0.4 mg/mL anhydrous morphine]):
Children and Adolescents: 0.1 to 0.2 mg/kg/dose PO 1 to 4 times a day (max: 4 mg/dose). NOTE: Dosage is expressed in mg/kg dosing units of morphine. When using opium tincture 2 mg/5 mL concentration (Paregoric, USP), 0.1 to 0.2 mg/kg = 0.25 to 0.5 mL/kg.

For the treatment of dysautonomia* due to tetanus*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.02 to 0.05 mg/kg/hour continuous IV infusion.

For the treatment of hypercyanotic episodes associated with tetralogy of fallot (i.e. tetralogy spells*):
Intravenous or Intramuscular dosage:
Infants and Children: 0.05 to 0.1 mg/kg/dose IV or IM; may repeat dose as needed until desired response is achieved.

Maximum Dosage Limits:
-Neonates
Immediate-release formulations, injectable solution: With appropriate dosage titration, there is no maximum dose; other formulations not recommended.
-Infants
Immediate-release formulations, injectable solution: With appropriate dosage titration, there is no maximum dose; other formulations not recommended.
-Children
Immediate-release formulations, extended-release tablets, injectable solution: With appropriate dosage titration, there is no maximum dose.
Camphorated opium tincture (0.4 mg/mL concentration ONLY): 0.2 mg/kg/dose PO (Max: 4 mg/dose) and 0.8 mg/kg/day PO (Max: 16 mg/day).
-Adolescents
Immediate-release formulations, extended-release tablets, injectable solution: With appropriate dosage titration, there is no maximum dose.
Camphorated opium tincture (0.4 mg/mL concentration ONLY): 0.2 mg/kg/dose PO (Max: 4 mg/dose) and 0.8 mg/kg/day PO (Max: 16 mg/day).

Patients with Hepatic Impairment Dosing
Initiate morphine at a lower than usual dosage and titrate slowly in patients with cirrhosis; closely monitor for signs of respiratory depression, sedation, and hypotension.

Patients with Renal Impairment Dosing
Initiate morphine at a lower than usual dosage and titrate slowly in patients with renal failure; closely monitor for signs of respiratory depression, sedation, and hypotension. The following initial dosage adjustments have been recommended for pediatric patients :
GFR more than 50 mL/minute/1.73m2: No initial adjustment necessary; titrate carefully.
GFR 10 to 50 mL/minute/1.73m2: Reduce usual dose by 25%.
GFR less than 10 mL/minute/1.73m2: Reduce usual dose by 50%.

Intermittent hemodialysis and Peritoneal dialysis
Reduce the initial dose by 50% then titrate to desired clinical effect.

Continuous renal replacement therapy (CRRT)
Reduce the initial dose by 25% (assuming a dialysis dose of 2,000 mL/minute/1.73 m2) then titrate to desired clinical effect.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Morphine is a potent mu-opiate receptor agonist. Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C (PLC)-inositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2).

Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (mu2-, delta-, kappa-receptors) and higher levels in the CNS (mu1- and kappa3 receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (mu and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin, and glucagon.

The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms include differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

Clinically, stimulation of mu-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Respiratory depression is caused by direct action of opiate agonists on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention.

Several other clinical effects occur with opiate agonists including cough suppression, hypotension, and nausea/vomiting. The antitussive effects of opiate agonists are mediated through direct action on receptors in the cough center of the medulla. Cough suppression can be achieved at lower doses than those required to produce analgesia. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor center in the medulla. Induction of nausea and vomiting possibly occurs from direct stimulation of the vestibular system and/or the chemoreceptor trigger zone.

Pharmacokinetics: Morphine sulfate is administered orally, parenterally, intrathecally, epidurally, and rectally. There is no direct correlation between morphine serum concentrations and analgesic response; however, there is a minimum effective analgesia plasma concentration in each patient. This minimum effective concentration varies from patient to patient. Several factors may affect a patient's response to a given opiate agonist including age, prior opiate therapy, medical condition, and emotions. Also, there is not a direct correlation between morphine concentrations and incidence of adverse events, although higher concentrations are associated with more adverse events than lower concentrations.

Morphine has relatively low protein binding depending on patient age (approximately 35% in adults but less than 20% in premature neonates). Metabolism of morphine occurs primarily through conjugation in the liver. Morphine is also metabolized to a lesser extent by P-glycoprotein (P-gp) and cytochrome P450 3A4 enzymes. Morphine is conjugated with glucuronic acid through UDP-glucuronosyltransferases to form 3-glucuronide (50%), 6-glucuronide (5% to 15%), and 3,6-glucuronide and other minor metabolites. Morphine 3-glucuronide has a low affinity for opioid receptors, has no analgesic activity, and may cause hyperalgesia (hyperesthesia), myoclonus, and allodynia. In addition, the 3-glucuronide metabolite may be important in the development of tolerance to morphine. Morphine 3-glucuronide has been shown to stimulate respiration, but the mechanism (either direct stimulation or morphine and morphine-6-glucuronide antagonism) is unclear. Morphine 6-glucuronide has analgesic activity and may significantly contribute to morphine's activity. With chronic dosing of morphine, the systemic exposure of the glucuronide metabolites is greater than that of morphine. Morphine 6-glucuronide crosses the blood-brain barrier slowly. Thus, prolonged effects may be seen after morphine discontinuation or dialysis to remove morphine 6-glucuronide.

Excretion of morphine is largely in the urine and bile as the morphine- 3-glucuronide and 6-glucuronide metabolites. Smaller amounts are excreted as secondary conjugates and approximately 10% is eliminated as unchanged drug. Renal clearance of morphine and morphine- 6-glucuronide exceeds creatinine clearance, which suggests that both are actively secreted by the kidney. Within about 24 hours of the last dose, urinary elimination approximates 90%. Between 7% to 10% is excreted in the feces mainly via the bile. Typical morphine clearance in adults is approximately 15 to 20 mL/kg/minute. Clearance in pediatric patients is age-dependent, with clearance in neonates being significantly slower than that of adults to clearance in preschoolers being up to twice as fast as adult clearance.

Affected cytochrome P450 isoenzymes and drug transporters: P-gp
Morphine is a substrate for P-gp.


-Route-Specific Pharmacokinetics
Oral Route
Morphine is one-third to one-sixth as potent when administered orally as compared with intravenous administration. This is due to significant first-pass metabolism of morphine. The oral bioavailability of morphine is less than 40%. Oral absorption of the immediate release tablets can be increased by food. Peak analgesia is obtained about 60 minutes after oral administration. Oral sustained-release products have a slower onset of action and at steady state have a lower maximum serum concentration and higher minimum serum concentration when compared to immediate-release oral morphine.

Intravenous Route
Peak analgesia is obtained within 20 minutes after IV injection and the duration of analgesia is approximately 3 to 6 hours.

Intramuscular Route
Peak analgesia is obtained about 30 to 60 minutes after IM injections and the duration of analgesia is approximately 3 to 6 hours.

Subcutaneous Route
Peak analgesia is obtained about 50 to 90 minutes after subcutaneous injections and the duration of analgesia is approximately 3 to 6 hours.

Other Route(s)
Rectal Route
The approximate bioavailability of morphine after rectal administration is 30% (range 6% to 99%) in children. Peak serum concentrations are achieved within 30 minutes when morphine is dissolved in propylene glycol and within 60 to 90 minutes when an aqueous morphine solution is mixed with a dry starch hydrogel. The manufacturer of the rectal suppositories reports peak analgesia at 20 to 60 minutes after rectal administration.

Intrathecal Route
Lower doses of morphine (one-tenth of the dose) are required to produce similar analgesia when administered intrathecally versus epidurally because intrathecal administration circumvents the meningeal diffusion barriers. When morphine is injected into the intrathecal space, it slowly diffuses out into the systemic circulation. The slow rate of elimination accounts for the prolonged duration of action when used by this route. Morphine intrathecally may produce noticeable effects, both pain relief and adverse effects, for up to 24 hours.

Epidural Route
After epidural administration of morphine, the onset of analgesia is within 15 to 30 minutes with a duration of 4 to 24 hours. Unlike administration via the intrathecal route, morphine is rapidly absorbed systemically after epidural administration; the plasma-concentration profiles closely resemble those after IV or IM administration. The analgesia obtained from epidural morphine is not dependent upon systemic morphine concentrations, and the duration of analgesia continues beyond the time during which morphine may be detected in the plasma.


-Special Populations
Pediatrics
Neonates
In premature neonates, the estimated half-life and clearance of morphine are 9 hours and 2.2 mL/kg/minute, respectively; in term neonates, these estimated values are 6.5 hours and 8.1 mL/kg/minute, respectively. Preterm neonates are capable of glucuronidation, but this capability is influenced by gestational and postnatal age and birth weight leading to a lower metabolic capacity and lower elimination rate in preterm and term neonates compared to older pediatric patients.

Infants, Children, and Adolescents
Morphine's estimated half-life and clearance are 2 hours and 23.6 mL/kg/minute, respectively. The pharmacokinetics of morphine in pediatric patients appear to approach adult values around 2 to 6 months of age; however, there is large interpatient variability and a range of 2 weeks to 2.5 years of age has been reported. Some young children may exhibit clearance up to twice that of adults. In a population pharmacokinetic analysis of 66 patients 2 to 17 years, the geometric mean plasma half-life was up to 1.8 hours and the mean terminal elimination plasma half-life was 18.6 hours. The single dose mean Cmax of both the morphine 3-glucuronide and 6-glucuronide metabolite was not greater than in adults.

Hepatic Impairment
The half-life of morphine is significantly prolonged in patients with cirrhosis. 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 patients with severe hepatic impairment.

Renal Impairment
AUC is increased and clearance is decreased in patients with renal failure, potentially resulting in accumulation of the morphine-3 glucuronide and 6-glucuronide metabolites. Adequate studies of morphine pharmacokinetics have not been conducted in patients with severe renal impairment.

Gender Differences
Evidence of greater postoperative consumption of morphine in men vs. women is present in the literature; however, clinically significant differences in pharmacokinetic parameters and analgesic effects have not been consistently demonstrated.

Ethnic Differences
Pharmacokinetic differences may be associated with race. In 1 study, Chinese subjects given intravenous morphine had a higher clearance (1,852 mL/minute) compared to Caucasian subjects (1,485 mL/minute).