Morphine

Generic Name

Morphine sulfate

Brand Names

MS Contin

Kadian

Oramorph

Morphgesic

Sevredol

Duramorph

Avinza (discontinued)

Roxanol

DepoDur

Various injectable, oral, rectal, and epidural preparations exist globally

Drug Class

Opioid analgesic

Phenanthrene class

Mu-opioid receptor agonist (schedule II controlled substance in the US and similar regulatory status globally)

Mechanism of Action

Morphine acts primarily as a full agonist at the μ-opioid receptor in the central nervous system (CNS) and peripheral tissues

Binding to the μ-receptor inhibits ascending pain pathways, alters perception of and response to pain, and produces generalized CNS depression

It also has weak activity at kappa (κ) and delta (δ) opioid receptors

Activation of μ-receptors leads to analgesia, sedation, euphoria, respiratory depression, miosis, reduced gastrointestinal motility, and physical dependence

Indications

Approved Uses

Severe acute pain (postoperative, trauma, myocardial infarction)

Chronic pain (cancer, palliative care, end-of-life)

Pain associated with advanced disease or terminal illness

Pre-anesthetic medication or adjunct

Epidural and intrathecal analgesia for labor or surgical procedures

Control of dyspnea in advanced heart failure or cancer

Off-Label Uses

Refractory diarrhea (low-dose)

Management of persistent cough in palliative settings

Pulmonary edema (especially in acute left ventricular failure)

Sedation during mechanical ventilation (in ICU)

Dosage and Administration

Dosage Must Be Individualized Based on Prior Opioid Exposure

Oral Immediate Release (IR)

Initial: 5–30 mg every 4 hours as needed

Typical maintenance: 10–30 mg every 4–6 hours

Used in acute pain

Oral Extended Release (ER)

MS Contin, Kadian: 15–200 mg every 8–12 hours

Start with lowest possible dose in opioid-naïve patients

Do not crush, chew, or split ER tablets

Injectable (IV/IM/SC)

IV: 2–10 mg every 2–4 hours as needed

IM: 5–10 mg every 4 hours

SC: similar to IM dosing

IV bolus or continuous infusion for severe pain

Epidural/Intrathecal

Epidural: 2–5 mg once daily

Intrathecal: 0.2–1 mg single dose

Preservative-free formulations must be used for neuraxial routes

Rectal Suppositories

10–30 mg every 4 hours as needed

Pediatric Dosing

Based on weight and age

Oral: 0.2–0.5 mg/kg/dose every 4 hours (IR)

IV: 0.05–0.1 mg/kg/dose every 4 hours

Renal and Hepatic Impairment

Use lower initial doses and extend dosing intervals

Active metabolites (especially morphine-6-glucuronide) accumulate in renal failure

Administration Notes

Take oral morphine with food to minimize GI upset

Monitor for sedation and respiratory depression, especially after initial doses

Taper gradually after prolonged use to prevent withdrawal

Pharmacokinetics

Absorption

Well absorbed orally but significant first-pass metabolism

Oral bioavailability: ~20–40%

Distribution

Widely distributed

Crosses the blood-brain barrier, placenta, and into breast milk

Protein binding: 30–35%

Metabolism

Primarily in liver via conjugation with glucuronic acid

Major metabolites:

– Morphine-3-glucuronide (inactive)

– Morphine-6-glucuronide (active and potent)

Elimination

Renally excreted

Half-life: 2–4 hours (IR), up to 15–30 hours (ER)

Prolonged in renal failure

Contraindications

Significant respiratory depression

Acute or severe bronchial asthma

Paralytic ileus

Known hypersensitivity

Use of MAO inhibitors within 14 days

Coma or head injury (due to risk of intracranial pressure elevation)

Warnings and Precautions

Respiratory Depression

Dose-related and potentially fatal

Especially in elderly, opioid-naïve, and those with pulmonary disease

Use naloxone in emergencies

Addiction, Abuse, and Misuse

High potential for misuse

Risk increases with prolonged use

Prescribe minimum effective dose and quantity

Neonatal Opioid Withdrawal Syndrome (NOWS)

Prolonged use in pregnancy can cause physical dependence in the fetus

Newborns may experience withdrawal symptoms

Hypotension

May cause severe hypotension or syncope, especially in hypovolemia or with CNS depressants

Seizures

May lower seizure threshold

Use with caution in seizure disorders

Adrenal Insufficiency and Hypogonadism

Chronic use may suppress hypothalamic-pituitary axis

Monitor long-term users for hormonal changes

Use in Head Injury

May obscure clinical course due to sedation and miosis

Elevates intracranial pressure

Pregnancy and Lactation

Pregnancy Category C (US)

Avoid prolonged use unless absolutely necessary

Risk of neonatal withdrawal and respiratory depression

Lactation

Morphine is excreted in breast milk

Generally considered acceptable for short-term use

Monitor infants for sedation and feeding difficulty

Pediatric Use

Used under close monitoring in hospitalized settings

Dose carefully based on body weight

Avoid codeine-containing alternatives due to variable metabolism

Geriatric Use

Increased sensitivity to effects

Start at lower doses and monitor renal function

Adverse Effects

Very Common

Constipation

Nausea

Vomiting

Drowsiness

Miosis

Dry mouth

Sweating

Urinary retention

Common

Euphoria or dysphoria

Dizziness

Hypotension

Pruritus

Respiratory depression

Confusion

Serious

Severe respiratory depression

Apnea

Hypotension with syncope

Bradycardia

Seizures

Anaphylaxis (rare)

Addiction and overdose

Chronic Use

Physical dependence

Tolerance

Hormonal dysfunction

Cognitive impairment

Withdrawal Symptoms

Agitation

Anxiety

Lacrimation

Yawning

Muscle aches

Sweating

Insomnia

Diarrhea

Overdose

Symptoms

Pinpoint pupils

Severe respiratory depression

Hypotension

Bradycardia

Coma

Management

Supportive care

Airway protection

IV naloxone (0.4–2 mg every 2–3 minutes until reversal)

Continuous infusion may be needed due to shorter half-life of naloxone

Monitor for re-sedation

Drug Interactions

CNS Depressants

Benzodiazepines, alcohol, antihistamines

Additive sedation, respiratory depression

Use with extreme caution

MAO Inhibitors

Avoid use within 14 days

Risk of serotonin syndrome, hyperpyrexia, hypotension

Other Opioids

Additive effect or risk of overdose

Methadone and fentanyl combinations increase complexity

Serotonergic Drugs

SSRIs, SNRIs, triptans may increase risk of serotonin syndrome

Monitor for confusion, agitation, hyperreflexia

CYP3A4 and CYP2D6 Inhibitors

Can increase morphine plasma levels (although metabolism is mostly by conjugation)

Diuretics

Reduced diuretic efficacy due to renal vasoconstriction and sodium retention

Anticholinergics

Increased risk of constipation, urinary retention, paralytic ileus

Use in Special Populations

Renal Impairment

Active metabolites accumulate

Prefer alternative opioids (e.g. fentanyl, hydromorphone)

Hepatic Impairment

Reduced metabolism

Start at lower doses

Elderly

Use lowest effective dose

Greater sensitivity to sedative and hypotensive effects

Monitoring Parameters

Pain relief and functional improvement

Respiratory rate and sedation level

Bowel function (prevent constipation)

Signs of misuse or abuse

Renal and hepatic function

Endocrine function in chronic use

Formulations Available

Oral

IR tablets, capsules, and solution

ER tablets and capsules (12 or 24-hour release)

Injectables

IV, IM, SC (single and multi-dose vials)

PCA (patient-controlled analgesia) systems

Rectal Suppositories

10 mg, 20 mg, 30 mg (depending on brand)

Epidural and Intrathecal

Preservative-free formulations

Used in anesthesia and chronic pain

Comparative Pharmacology

Morphine vs Hydromorphone

Hydromorphone is 5–7 times more potent

Preferred in renal impairment due to fewer active metabolites

Morphine vs Fentanyl

Fentanyl is more potent and lipophilic

Preferred for rapid onset and in renal failure

Morphine vs Oxycodone

Oxycodone has better oral bioavailability

More commonly used in outpatient settings

Morphine vs Methadone

Methadone has NMDA receptor activity

Used for opioid dependence or severe neuropathic pain

Morphine vs Tramadol

Tramadol is weaker, has dual action (μ-agonist and SNRI)

Less risk of respiratory depression but risk of serotonin syndrome

Legal and Regulatory Status

Controlled substance (Schedule II in US)

Strict prescription and dispensing controls

Regulations vary by country but highly restricted universally