Weak Opioid Analgesics

Weak opioid analgesics are low-potency mu-receptor agonists used for mild to moderate pain that is not controlled by nonopioids. The class comprises codeine, dihydrocodeine and tramadol. Their analgesic ceiling is low, their variable metabolism makes response unpredictable, and in many settings they add harm without the benefit of a strong opioid at a low dose.

Mechanism. Codeine is a prodrug converted by CYP2D6 to morphine (about 5 to 10% of a dose). Dihydrocodeine has some intrinsic activity. Tramadol is a weak mu agonist whose active metabolite O-desmethyltramadol (CYP2D6) is much more potent, and it inhibits reuptake of serotonin and noradrenaline.

Pharmacogenetics. CYP2D6 poor metabolisers get little analgesia; ultrarapid metabolisers form excess morphine and risk respiratory depression. Ultrarapid genotypes are more frequent in some East African and North-East African populations than in northern Europeans.

Pharmacokinetics. Codeine half-life 3 hours, peak 1 hour. Tramadol half-life about 6 hours, peak 2 hours; onset 30 to 60 minutes.

Adjustments. Tramadol: eGFR under 30 mL/min, interval 12 hours and maximum 200 mg daily; cirrhosis, 50 mg every 12 hours. Reduce codeine in renal impairment because active metabolites accumulate.

Tapentadol. A strong opioid with noradrenaline reuptake inhibition, classed with strong opioids and not interchangeable with weak agents.

• First-line. None. Nonopioids come first.
• Alternative. Mild to moderate pain where paracetamol with an NSAID has failed or is contraindicated; short-term postoperative step-down.
• Specialist. Tramadol for neuropathic pain when other options fail.
• Emergency. Not used.

Selection rules.

• Both codeine and tramadol depend partly on CYP2D6, so response is unpredictable; avoid tramadol in epilepsy, with serotonergic drugs and in hyponatraemia.
• Lowest dose and shortest course (generally under 7 days).
• A weak opioid is not an alternative to a low dose of morphine in cancer pain; oral morphine 2.5 to 5 mg every 4 hours is often more effective.
• Add a laxative.

Contraindications.

• Codeine: children under 12 years for pain; tonsillectomy or adenoidectomy in children and adolescents under 18; breastfeeding; known CYP2D6 ultrarapid metabolism; acute respiratory depression.
• Tramadol: uncontrolled epilepsy; monoamine oxidase inhibitor use in the previous 14 days; acute intoxication with alcohol or opioids.
• Both: severe respiratory depression, paralytic ileus.

Serious adverse effects. Respiratory depression (especially ultrarapid codeine metabolism); constipation; nausea; dizziness; seizures; serotonin syndrome; hyponatraemia; hypoglycaemia; dependence; QT effects at high doses.

Major interactions.

• Fluoxetine and paroxetine (CYP2D6 inhibition): less analgesia.
• SSRIs, SNRIs, tricyclic antidepressants, linezolid: seizure and serotonin syndrome risk.
• Ondansetron may reduce tramadol effect.
• Benzodiazepines and alcohol: respiratory depression.
• Carbamazepine lowers tramadol levels.

Common prescribing errors.

• Codeine given to children and breastfeeding mothers.
• Total paracetamol exceeded through combination tablets.
• Tramadol at full dose in older adults or renal impairment.
• Continued without review.
• Assuming weak opioids are risk-free.

Special groups.

• Pregnancy: use only if necessary; neonatal withdrawal after prolonged use.
• Breastfeeding: avoid codeine and tramadol.
• Children: tramadol under 12 years is not generally licensed; codeine is avoided under 12 years and after tonsillectomy under 18.
• Older adults: start low, tramadol 50 mg.
• Kidney and liver: tramadol maximum 200 mg daily at CrCl under 30 mL/min and 50 mg every 12 hours in cirrhosis; reduce codeine in renal impairment.
• East Africa: genetic variation in CYP2D6 and wide over-the-counter paracetamol and codeine availability require caution.

Monitoring. Sedation and respiratory rate on initiation; sodium and glucose if tramadol continues in older adults; bowel function; review of ongoing need at 7 days.

Referral and escalation. Respiratory depression, seizure, serotonin syndrome, need for escalation to a strong opioid, or suspected misuse.

Comparison with alternative classes. Weak opioids add limited benefit over paracetamol and NSAIDs and carry more adverse effects. A low dose of a strong opioid is often more predictable than codeine.