morphine (Rx)

>10%

Pruritus (≤80%)

Urinary retention (epidural/IT) (15-70%)

Vomiting (7-70%)

Constipation (>10%)

Headache (>10%)

Somnolence (>10%)

1-10%

Abdominal pain (5-10%)

Asthenia (5-10%)

Backache (5-10%)

Depression (5-10%)

Diarrhea (5-10%)

Dyspnea (5-10%)

Fever (5-10%)

Insomnia (5 -10% )

Loss of appetite (5-10%)

Nausea (5-10%)

Paresthesia (5-10%)

Peripheral edema (5-10%)

Rash (5-10%)

Sweating (5-10%)

Xerostomia (5-10%)

Respiratory depression (IT) (4-7%)

Anxiety (6%)

Dizziness (6%)

Abnormal liver function test results (<5%)

Amblyopia (<5%)

Hiccups (<5%)

Orthostatic hypotension (<5%)

Syncope (<5%)

Urinary retention (PO) (<5%)

<1%

Respiratory depression (epidural) (0.25-0.4% )

Frequency Not Defined

Anaphylaxis (rare )

Cardiac arrest

Circulatory depression

Finding of intracranial pressure

Ileus

Lightheadedness

Malaise

Miosis

Myoclonus

Shock

Thinking disturbances

Vertigo

Contraindications

Hypersensitivity

Paralytic ileus

Toxin-mediated diarrhea

Respiratory depression, acute or severe bronchial asthma, upper airway obstruction

Within 2 weeks of monoamine oxidase inhibitor (MAOI) therapy

GI obstruction (extended release)

Hypercarbia (immediate release tablets/solution)

Upper airway obstruction (epidural/intrathecal)

Heart failure due to chronic lung disease, head injuries, brain tumors, deliriums tremens, seizure disorders, during labor when premature birth anticipated (injectable formulation)

Cardiac arrhythmia, increased intracranial or cerebrospinal pressure, acute alcoholism, use after biliary tract surgery, surgical anastomosis (suppository formulcation)

Cautions

Use with caution in acute pancreatitis, Addison disease, benign prostatic hyperplasia, cardiac arrhythmias, central nervous system (CNS) depression, drug abuse or dependence, emotional lability, gallbladder disease, gastrointestinal (GI) disorder, morbidly obese patients, patients with urinary stricture, pseudomembranous colitis, GI surgery, head injury, hypothyroidism or untreated myxedema, intracranial hypertension, brain tumor, toxic psychosis, urethral stricture, urinary tract surgery, seizures, acute alcoholism, delirium tremens, shock, cor pulmonale, chronic pulmonary disease, emphysema, hypercapnia, kyphoscoliosis, severe obesity, renal or hepatic impairment, elderly or debilitated patients, neonates

May cause constipation; consider preventive measures (eg, stool softener, increased fiber) to reduce potential for constipation, especially in patients with unstable angina and patients with myocardial infarction

Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists

Use with caution in patients with adrenal insufficiency, including addison's disease; chronic opioid use may cause secondary hypogonadism, which may lead to mood disorders, osteoporosis, sexual dysfunction, and infertility

Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; use may cause constriction of sphincter of Oddi diminishing biliary and pancreatic secretion

Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

Some formulations may contain sodium benzoate/benzoic acid, which have been associated with potentially fatal toxicity (gasping syndrome) in neonates

Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages

While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of opioid

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients

Due to risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose

Monoamine oxidase inhibitors (MAOIs) may potentiate effects of opioid, opioid’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of initiating or stopping MAOIs

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

Products are designed for specific routes; use caution when prescribing, dispensing, or administering to use formulations only by intended routes

Some formulations contain sulfites, which may cause allergic reactions in sulfite sensitive patients

Kadian: Avoid concurrent consumption of alcohol or alcohol-containing foods or medications; co-ingestion results in increased plasma levels and potentially fatal overdose

May cause CNS depression and impair ability to operate heavy machinery

All formulations are capable of producing respiratory depression

Use with caution, particularly with IV administration, in patients with hypovolemia, cardiovascular disease, circulatory shock, or drugs that may exaggerate hypotensive effects, including general anesthetics and phenothiazines; may cause orthostatic hypotension and syncope in ambulatory patients

After chronic maternal exposure to opioids, neonatal withdrawal syndrome may occur in the newborn

Opioid pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages

Therapy may increase frequency of seizures in patients with seizure disorders and in other clinical settings associated with seizures; monitor patients for worsened seizure control during therapy

May obscure diagnosis or clinical course of patients with acute abdominal conditions

Long-acting opioids

• Schedule II opioid analgesics expose users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids due to the larger amount of active opioid present (see Black Box Warnings)
• Addiction, abuse, and misuse risks are increased in patients with a personal or family history of substance abuse or mental illness (eg, major depression); the potential for these risks should not, however, prevent the prescribing of proper pain management in any given patient; intensive monitoring is necessary (see Black Box Warnings)
• Serious, life-threatening, or fatal respiratory depression reported (see Black Box Warnings)
• Accidental exposure reported, including fatalities (see Black Box Warnings)
• Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black Box Warnings)
• Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; if concomitant use with benzodiazepine warranted, consider prescribing naloxone for emergency treatment of opioid overdose
• Not indicated for PRN use

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

• To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; Use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
• To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

Patient access to naloxone for emergency treatment of opioid overdose

• Assess potential need for naloxone; consider prescribing for emergency treatment of opioid overdose
• Consult on availability and ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines
• Educate patients regarding the signs and symptoms of respiratory depression and to call 911 or seek immediate emergency medical help in the event of a known or suspected overdose

Pregnancy

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

Labor and delivery

• Opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in neonate; drug is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions that temporarily reduce strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

Infertility

• Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible

Lactation

Morphine is present in breast milk; published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study; however, there is insufficient information to determine effects of morphine on breastfed infant and effects of morphine on milk production; no information is available on effects of drug on breastfed infant or effects of drug on milk production

The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Monitor infants exposed to therapy through breast milk for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Narcotic agonist-analgesic of opiate receptors; inhibits ascending pain pathways, thus altering response to pain; produces analgesia, respiratory depression, and sedation; suppresses cough by acting centrally in medulla

Absorption

Onset: PO, 15-30 min; IV, <5 min

Duration: 4 hr (immediate-release)

Peak plasma time: PO, <60 min; PR, 20-60 min; SC, 50-90 min; IM, 30-60 min; IV, 20 min

Peak plasma concentration: PO, 20-40 ng/mL

Distribution

Protein bound: IV, 36%

Vd: IV, 1-4.7 L/kg

Metabolism

Metabolized in liver via conjugation with glucuronic acid

Metabolites: 6-Glucuronide, 3,6-diglucuronide, 3-glucuronide

Elimination

Half-life: 2-4 hr (immediate release); 11-13 hr (Kadian)

Excretion: Urine (2-12%), feces (7-10%)

IV Incompatibilities

Additive: Aminophylline, amobarbital, chlorothiazide, floxacillin, fluorouracil, heparin, meperidine, midazolam(?), phenobarbital, phenytoin, sodium bicarbonate, thiopental

Syringe: Haloperidol, meperidine, pentobarbital(?), prochlorperazine(?), promethazine(?), thiopental

Y-site: Acyclovir (concentration-dependent?), alatrofloxacin, amphotericin B cholesteryl sulfate, azithromycin, cefepime, doxorubicin liposomal, furosemide(?), minocycline, phenytoin, propofol (concentration-dependent?), sargramostim, thiopental (concentration-dependent?)

IV Compatibilities

Solution: Most common solvents

Additive (partial list): Alteplase, atracurium, baclofen, dobutamine, fluconazole, furosemide, metoclopramide, ondansetron, succinylcholine, verapamil

Syringe (partial list): Atropine, chlorpromazine, cimetidine, clonidine, dimenhydrinate, diphenhydramine, fentanyl, glycopyrrolate, heparin(?), hydroxyzine, ketamine, metoclopramide, midazolam, milrinone, ondansetron, ranitidine

Y-site (partial list): Allopurinol, amikacin, amiodarone, ampicillin, atenolol, atracurium, atropine, aztreonam, calcium chloride, cefazolin, cisplatin, clindamycin, cytarabine, diazepam, diltiazem, diphenhydramine, dobutamine, dopamine, doxorubicin, erythromycin, esmolol, fentanyl, fluconazole, granisetron, haloperidol, heparin, hydroxyzine, labetalol, linezolid, lorazepam, magnesium sulfate, metoclopramide, metronidazole, midazolam, milrinone, nitroglycerin, penicillin G, phenobabital, potassium chloride, propranolol, sodium bicarbonate, sodium nitroprusside, tirofiban, tobramycin, trimethoprim-sulfamethoxazole, vancomycin, vecuronium, vitamins B and C, warfarin, zidovudine

IV Preparation

IV push: Dilute 2.5-15 mg in 4-5 mL of SWI

Infusion: Dilute in D5W to 0.1-1 mg/mL

Solution should be colorless; if it is discolored, do not administer

IV Administration

IV push: Administer over 4-5 minutes

Continuous infusion: Administer via controlled infusion device

Intrathecal & Epidural Administration

High-potency injectable solution (Infumorph): To be administered only IT or epidurally; not to be administered SC, IM, or IV, because of overdose risk; may require dilution before use, depending based on administration device and patient dose

Oral Administration

Extended-release tablet (MS Contin)

• Coingestion of alcohol with long-acting morphine products is known to disrupt slow-release delivery properties and lead to rapid release of drug, which may result in toxicity and potential overdose
• Swallow tablet whole; crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine

Extended-release capsule (Kadian)

• 100-, 130-, 150-, and 200-mg capsules are appropriate only for patients tolerant of comparably potent opioid
• Kadian is not bioequivalent to other ER morphine products, and same total daily doses may result in excess sedation or inadequate pain relief
• Consumption of alcohol or alcohol-containing medications should be avoided during use, in that coingestion of alcohol may result in increased levels of morphine and potentially fatal overdose
• Swallow capsule whole; dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine
• Alternatively, the contents of the Kadian capsules (pellets) may be sprinkled over applesauce and then swallowed; this method is appropriate only for patients able to reliably swallow the applesauce without chewing (rinse mouth following to be sure all pellets are swallowed)
• Do not administer through a nasogastric-tube

• Administered through a 16-Fr gastronomy-tube

  • Contents of the Kadian capsules (pellets) may be administered through a 16 French gastrostomy tube
  • Flush the gastrostomy tube with water to ensure that it is wet
  • Sprinkle the pellets into 10 mL of water
  • Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel
  • Rinse the beaker with a further 10 mL of water and pour this into the funnel
  • Repeat rinsing until no pellets remain in the beaker

Extended-release tablet, abuse deterrent (MorphaBond)

• 100-mg tablets, a single dose >60 mg, or a total daily dose >120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established
• Swallow tablet whole; crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine

Extended-release tablet, abuse deterrent (Arymo ER)

• A single dose >60 mg or a total daily dose >120 mg are only for use in patients who are opioid-tolerant
• Swallow tablet whole with sufficient water; do not crush, chew, or dissolve
• Do not lick or wet tablet prior to swallowing tablet

General principles for opioid administration

• Titration and maintenance

  • Breakthrough pain may be managed with PRN morphine sulfate IR
  • Subsequent dose increases may be made every 1-2 days combining morphine sulfate ER dose and morphine sulfate IR dose
  • Titrate dose according to response

• Discontinuation

  • Taper dose gradually by 25-50% every 2 to 4 days, monitoring for symptoms of withdrawal
  • If symptoms occur, increase dose to previous dose and titrate more slowly