Opioid Analgesics

Opioid analgesics act on mu, delta and kappa opioid receptors to relieve pain. They are the principal treatment for severe acute pain, cancer pain and palliative care, and are used for selected chronic pain. Their main harms are respiratory depression, sedation, constipation, tolerance, dependence and diversion, and their safe use depends on titration, monitoring and an explicit exit plan.

Mechanism. Mu-receptor agonism, in the brain, spinal cord and periphery, reduces nociceptive transmission and increases descending inhibition. Mu receptors also mediate respiratory depression, miosis, euphoria, nausea and reduced gut motility. Kappa agonism gives dysphoria and sedation.

Classification. Weak opioids (codeine, dihydrocodeine, tramadol); strong agonists (morphine, oxycodone, hydromorphone, fentanyl, methadone, pethidine, tapentadol); partial agonists (buprenorphine); mixed agonist-antagonists (nalbuphine, pentazocine); antagonists (naloxone, naltrexone).

Pharmacokinetics. Hepatic metabolism, mainly glucuronidation; active metabolites matter. Morphine forms morphine-6-glucuronide (active) and morphine-3-glucuronide (neuroexcitatory), both accumulating in renal impairment. Codeine and tramadol are prodrugs activated by CYP2D6.

Representative adult starting doses (opioid-naive).

• Morphine: 5 to 10 mg orally every 4 hours (2.5 to 5 mg if frail or renally impaired); intravenous titration 1 to 2 mg every 5 minutes.
• Oxycodone: 5 mg orally every 4 to 6 hours.
• Hydromorphone: 1 to 2 mg orally every 4 to 6 hours.
• Fentanyl: 25 to 50 micrograms intravenously, titrated.
• Codeine 30 to 60 mg every 4 hours (maximum 240 mg daily); tramadol 50 to 100 mg every 4 to 6 hours (maximum 400 mg daily).

Approximate oral morphine equivalence. Morphine 10 mg orally is about 5 mg subcutaneously or intravenously; oxycodone 10 mg orally is about 15 to 20 mg morphine; codeine and tramadol about one tenth of morphine; transdermal fentanyl 25 micrograms/hour is about 60 to 90 mg oral morphine daily. Reduce the calculated dose of a new opioid by 25 to 50% for incomplete cross-tolerance.

Pharmacological differences. Morphine suits most patients but accumulates in renal failure; oxycodone and hydromorphone are acceptable alternatives with caution; fentanyl and buprenorphine have little renally dependent accumulation; pethidine has a neurotoxic metabolite and is avoided; methadone has a long and variable half-life and prolongs QT.

• First-line. Severe acute pain unrelieved by nonopioids; cancer pain (oral morphine is the usual first strong opioid); postoperative pain; acute myocardial infarction pain.
• Alternative. Oxycodone or hydromorphone for intolerance or renal impairment; buprenorphine or fentanyl for renal failure or when oral intake is impossible.
• Specialist. Methadone for complex cancer and neuropathic pain, or opioid use disorder; intrathecal opioids.
• Emergency. Titrated intravenous morphine or fentanyl for severe trauma and acute coronary pain.

Principles. Use the lowest dose for the shortest time. Titrate to effect. Prescribe a laxative from the start. For chronic cancer pain, give breakthrough doses of one tenth to one sixth of the 24-hour dose. For chronic non-cancer pain, benefit is limited and harm rises over 50 mg oral morphine equivalent daily, so review at 3 months and aim to taper.

Contraindications. Respiratory depression without ventilatory support; acute severe asthma; paralytic ileus; raised intracranial pressure without airway control; concurrent monoamine oxidase inhibitor (pethidine, tramadol, methadone); hypersensitivity.

Serious adverse effects. Respiratory depression (boxed-warning-level, greatest with benzodiazepines and gabapentinoids); sedation; hypotension; constipation and ileus; nausea; urinary retention; delirium; hyperalgesia; dependence and addiction; neonatal opioid withdrawal; adrenal and hypogonadal effects with long use.

Major interactions. Benzodiazepines, alcohol, gabapentinoids and other sedatives (additive respiratory depression); serotonergic drugs with tramadol, pethidine and methadone (serotonin syndrome); CYP2D6 inhibitors (fluoxetine, paroxetine) reduce codeine and tramadol effect; CYP3A4 inhibitors raise fentanyl and oxycodone; QT-prolonging drugs with methadone.

Common prescribing errors.

• Starting doses too high in opioid-naive patients.
• Confusing mg with micrograms or mL.
• Modified-release preparations used for acute pain.
• No laxative.
• Incorrect conversion between opioids.
• Duplicate opioids.

Special groups.

• Pregnancy: use only when needed; prolonged use causes neonatal withdrawal, and naloxone in neonates of dependent mothers can provoke seizures.
• Breastfeeding: avoid codeine and tramadol; morphine at low doses is acceptable.
• Children: weight-based dosing; avoid codeine under 12 years and after tonsillectomy under 18.
• Older adults: start at 25 to 50% of the usual dose.
• Kidney: avoid morphine at eGFR under 30 mL/min.
• Liver: reduce dose and extend interval.
• East Africa: CYP2D6 ultrarapid metabolisers are more frequent in some East and North-East African populations, making codeine unpredictable; strong opioid availability and prescribing authority are limited in many facilities.

Monitoring. Sedation score and respiratory rate hourly after parenteral titration, then every 4 hours; oxygen saturation with continuous monitoring in high-risk patients; pain score; bowel function; renal function.

Referral and escalation. Respiratory rate under 8 breaths/minute, sedation unresponsive to voice, or oxygen saturation falling: give naloxone and call for senior help. Refer for specialist pain or palliative review when daily dose rises quickly, pain is neuropathic or opioid use disorder is suspected.

Comparison with alternative classes. Opioids work in severe pain where nonopioids fail, but carry respiratory, dependence and diversion risk, and are less effective in chronic non-cancer pain than in acute pain.