Morphine - Drug Monograph

Introduction

Morphine is a naturally occurring opioid alkaloid derived from the opium poppy (Papaver somniferum) and represents the prototype opioid analgesic. As a Schedule II controlled substance, it remains a cornerstone in the management of moderate to severe acute and chronic pain. First isolated in 1804 by Friedrich Sertürner, morphine continues to be one of the most widely used and studied opioid medications worldwide.

Mechanism of Action

Morphine exerts its analgesic effects primarily through agonist activity at mu-opioid receptors in the central nervous system. It binds to opioid receptors in the brain, spinal cord, and peripheral tissues, resulting in:

• Inhibition of nociceptive neurotransmitter release
• Hyperpolarization of neurons through potassium channel activation
• Reduction in cyclic adenosine monophosphate (cAMP) production
• Modulation of both ascending pain pathways and descending inhibitory pathways

These mechanisms collectively result in altered pain perception, increased pain tolerance, and sedation.

Indications

FDA-approved indications:

• Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment
• Acute pain management when non-opioid analgesics are inadequate
• Preoperative analgesia and sedation
• Adjunct to anesthesia

Off-label uses (with appropriate clinical justification):

• Dyspnea in palliative care settings
• Myocardial infarction-related pain
• Pulmonary edema

Dosage and Administration

• Adults: 5-30 mg every 4 hours as needed
• Opioid-naïve patients: Start with 5-15 mg every 4 hours

• Administer every 8, 12, or 24 hours depending on product
• Must be swallowed whole; not for crushing, chewing, or dissolving

• Renal impairment: Reduce dose by 25-50% for CrCl <30 mL/min
• Hepatic impairment: Start with 50% of normal dose
• Elderly: Initiate with lower doses due to increased sensitivity
• Pediatrics: 0.2-0.5 mg/kg every 4-6 hours (careful monitoring required)

• Oral (tablets, solutions)
• Intravenous (2.5-15 mg every 4 hours)
• Intramuscular (5-20 mg every 4 hours)
• Subcutaneous (5-20 mg every 4 hours)
• Epidural (2-5 mg bolus)
• Intrathecal (0.1-0.3 mg bolus)

Pharmacokinetics

• Oral bioavailability: 15-50% (extensive first-pass metabolism)
• Tmax: 1 hour (immediate-release), 7-8 hours (extended-release)
• Food may delay but not significantly reduce absorption

• Vd: 3-5 L/kg
• Protein binding: 30-35%
• Crosses placenta and blood-brain barrier

• Primarily hepatic via glucuronidation
• Major metabolites: morphine-3-glucuronide (inactive), morphine-6-glucuronide (active)
• CYP450 metabolism minimal (<10%)

• Half-life: 2-4 hours
• Clearance: 15-30 mL/min/kg
• Excretion: Primarily renal (90%), with 10% fecal elimination

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma in unmonitored settings
• Known or suspected gastrointestinal obstruction
• Hypersensitivity to morphine
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days
• Paralytic ileus

Warnings and Precautions

• Risk of respiratory depression, especially during initiation and dose escalation
• Risk of misuse, abuse, and addiction
• Risk of neonatal opioid withdrawal syndrome with prolonged use during pregnancy
• Cytochrome P450 3A4 interaction risk

• Increased intracranial pressure
• Seizure disorders
• Bradyarrhythmias
• Acute abdominal conditions
• Hypotension
• Hepatic and renal impairment
• Elderly and debilitated patients
• Risk of adrenal insufficiency with long-term use
• Risk of decreased sex hormone levels with long-term use

Drug Interactions

• CNS depressants (benzodiazepines, alcohol, sedatives): Additive CNS depression
• MAOIs: Risk of serotonin syndrome and exaggerated opioid effects
• Mixed agonist/antagonist opioids (pentazocine, butorphanol): May reduce analgesic effect
• CYP3A4 inhibitors (azole antifungals, macrolides): May increase morphine levels
• Anticholinergics: Increased risk of constipation and urinary retention

• Diuretics: Morphine may reduce efficacy
• Antihypertensives: Enhanced hypotensive effects

Adverse Effects

• Constipation (require prophylactic management)
• Nausea and vomiting
• Sedation/drowsiness
• Pruritus
• Sweating
• Xerostomia

• Respiratory depression
• Hypotension
• Bradycardia
• Dependency and addiction
• Adrenal insufficiency
• Seizures (with high doses)
• Serotonin syndrome (when combined with serotonergic drugs)
• QT prolongation (with high doses)

Monitoring Parameters

• Pain intensity and relief scores (using standardized scales)
• Respiratory rate and depth (especially during initiation)
• Oxygen saturation (consider continuous monitoring in high-risk patients)
• Blood pressure and heart rate
• Bowel function (implement constipation management protocol)
• Mental status and sedation scores
• Signs of misuse or addiction
• Renal and hepatic function (periodically with long-term use)
• Adrenal function (with chronic therapy)

Patient Education

• Proper dosing schedule and strict adherence to prescribed regimen
• Never share medication with others
• Storage in secure location to prevent diversion
• Recognition of overdose symptoms (extreme drowsiness, slow breathing)
• Management of constipation with increased fluids, fiber, and laxatives
• Avoidance of alcohol and other CNS depressants
• Caution when operating machinery or driving
• Importance of not abruptly stopping medication
• Proper disposal of unused medication
• Pregnancy and breastfeeding considerations
• Development of tolerance and physical dependence

• Do not crush or chew extended-release tablets
• Report any signs of allergic reaction
• Inform all healthcare providers of morphine use
• Use caution with other medications that may cause drowsiness

References

1. American Pain Society. (2016). Guidelines on the management of postoperative pain. The Journal of Pain, 17(2), 131-157. 2. FDA Prescribing Information: Morphine Sulfate. (2022). Accessdata.fda.gov. 3. Inturrisi, C. E. (2002). Clinical pharmacology of opioids for pain. The Clinical Journal of Pain, 18(4), S3-S13. 4. Trescot, A. M., et al. (2008). Opioid guidelines in the management of chronic non-cancer pain. Pain Physician, 11(2S), S5-S62. 5. World Health Organization. (2018). WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organization. 6. Dowell, D., et al. (2016). CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recommendations and Reports, 65(1), 1-49. 7. Lexicomp Online. (2023). Morphine monograph. Wolters Kluwer Clinical Drug Information. 8. Micromedex Solutions. (2023). Morphine drug information. IBM Watson Health.