Opioid Analgesics
Pharmacology · CNS · lean revision notes
Opioid Analgesics
Opioids are the most powerful analgesics available, acting on G-protein coupled opioid receptors to relieve moderate-to-severe pain. NEET PG loves the receptor pharmacology, the active metabolites of morphine, partial-agonist quirks of buprenorphine, and the antidote naloxone — so master mechanisms, not just names.
Definitions & Terminology
- Opioid — any substance (natural, semi-synthetic or synthetic) acting on opioid receptors.
- Opiate — strictly the natural alkaloids of opium (morphine, codeine, thebaine, papaverine, noscapine). Papaverine and noscapine are not analgesic (papaverine = smooth-muscle relaxant; noscapine = antitussive).
- Narcotic — legal term for drugs producing stupor; loosely used for opioids.
High-yield: Opium contains ~10% morphine and ~0.5% codeine. Morphine is a phenanthrene derivative; papaverine is a benzylisoquinoline (no analgesia).
Opioid Receptors & Classification
Three classic G-protein coupled receptors (Gi/Go), all reduce neuronal excitability by closing voltage-gated Ca²⁺ channels (presynaptic) and opening K⁺ channels (postsynaptic, hyperpolarisation), plus inhibiting adenylyl cyclase → ↓cAMP.
| Receptor | Endogenous ligand | Key effects | Notes |
|---|---|---|---|
| Mu (μ / MOP) | Beta-endorphin | Supraspinal & spinal analgesia, euphoria, respiratory depression, miosis, constipation, physical dependence, bradycardia | Main therapeutic + abuse target |
| Kappa (κ / KOP) | Dynorphin | Spinal analgesia, dysphoria, sedation, miosis, less respiratory depression, diuresis | Target of pentazocine, nalbuphine |
| Delta (δ / DOP) | Enkephalins | Analgesia, mood modulation, may modulate μ activity | Less clinically exploited |
A fourth receptor, NOP (ORL-1, nociceptin/orphanin FQ), modulates pain but is not blocked by naloxone.
High-yield: Respiratory depression, euphoria, miosis, constipation and physical dependence are all mu-mediated. Dysphoria and hallucinations are kappa-mediated (explains pentazocine's psychotomimetic effect).
Classification by activity
| Class | Drugs |
|---|---|
| Strong agonists | Morphine, fentanyl, sufentanil, alfentanil, remifentanil, pethidine (meperidine), methadone, heroin |
| Moderate/weak agonists | Codeine, tramadol, dextropropoxyphene |
| Mixed agonist–antagonist | Pentazocine, nalbuphine, butorphanol (κ-agonist, μ-antagonist/partial) |
| Partial agonist | Buprenorphine (partial μ-agonist) |
| Antagonists | Naloxone, naltrexone, nalmefene, methylnaltrexone (peripheral) |
Morphine — The Prototype
Pharmacokinetics
- High first-pass metabolism → oral bioavailability only ~25% (oral:parenteral potency ratio ~1:6 for single dose, ~1:3 chronic).
- Glucuronidation in liver to two key metabolites:
- Morphine-3-glucuronide (M3G) — inactive analgesically, may cause neuroexcitation/seizures (the major metabolite quantitatively).
- Morphine-6-glucuronide (M6G) — MORE potent analgesic than morphine itself, accumulates in renal failure → prolonged effect/toxicity.
High-yield: In renal failure, M6G accumulates → avoid morphine; safer choices are fentanyl or methadone (no active metabolites of concern). M6G is the active one; M3G is the convulsant.
Pharmacological actions (mnemonic for morphine: "MORPHINES")
- Miosis (pinpoint pupils — Edinger-Westphal nucleus stimulation; no tolerance develops to miosis or constipation)
- Orthostatic hypotension (histamine release + vasodilation)
- Respiratory depression (↓ medullary responsiveness to CO₂ — commonest cause of death in overdose)
- Pain relief (analgesia + raised threshold, altered perception)
- Histamine release (urticaria, bronchospasm, itching — avoid in asthma)
- Infrequent urination / urinary retention (↑ detrusor + sphincter tone)
- Nausea & vomiting (CTZ — area postrema, D2 stimulation)
- Euphoria / sedation
- Sphincter of Oddi spasm + constipation (↓GI motility, ↑tone)
High-yield: Morphine causes biliary colic by spasm of the sphincter of Oddi → traditionally pethidine preferred in biliary/renal colic (though it also raises biliary pressure; the dogma persists in exams).
Individual Drugs — Exam Pearls
Fentanyl & congeners
- ~80–100× more potent than morphine; highly lipophilic → rapid onset, short duration (redistribution).
- Available as transdermal patch (chronic cancer pain), lozenges, IV.
- Truncal/chest-wall rigidity with rapid high-dose IV.
- Remifentanil — ultra-short acting, metabolised by plasma/tissue esterases (not pseudocholinesterase, unlike suxamethonium) → context-insensitive offset.
Pethidine (Meperidine)
- Anticholinergic (mydriasis, tachycardia — unlike morphine's miosis/bradycardia).
- Active metabolite normeperidine → CNS excitation, seizures (accumulates in renal failure).
- Avoid with MAO inhibitors → serotonergic crisis (excitatory: hyperthermia, rigidity, seizures, coma). Classic exam association.
Methadone
- Long t½, NMDA-receptor antagonist + μ-agonist → useful for opioid maintenance/de-addiction and neuropathic pain.
- Risk: QT prolongation / torsades.
Tramadol
- Weak μ-agonist + inhibits reuptake of serotonin & noradrenaline.
- Analgesia only partially reversed by naloxone.
- Risks: seizures (lowers threshold), serotonin syndrome (esp. with SSRIs/SNRIs). Less respiratory depression and dependence.
Codeine
- Prodrug → CYP2D6 converts ~10% to morphine (the analgesic step). Ultrarapid metabolisers → morphine toxicity in children (contraindicated post-tonsillectomy). Excellent antitussive; causes constipation.
Buprenorphine
- Partial μ-agonist, very high receptor affinity, slow dissociation.
- Ceiling effect on respiratory depression (safer) but the same property makes overdose poorly reversed by naloxone (needs high doses).
- Sublingual for chronic pain & de-addiction; combined with naloxone (Suboxone) to deter IV abuse.
Pentazocine / Nalbuphine / Butorphanol
- κ-agonist with μ-antagonist/partial activity → dysphoria, ↑ in patient already on pure agonist precipitates withdrawal.
- Pentazocine → ↑ cardiac workload, raises pulmonary artery/aortic pressure (avoid in MI), psychotomimetic effects.
Loperamide & Diphenoxylate
- Peripherally restricted μ-agonists → antidiarrhoeal; loperamide does not cross BBB at normal doses.
Therapeutic Uses
- Severe acute & chronic pain (post-op, cancer — WHO step 3).
- Acute left ventricular failure / acute pulmonary oedema — morphine IV.
- Myocardial infarction pain.
- Pre-anaesthetic medication, balanced anaesthesia (fentanyl).
- Cough (codeine, pholcodine), diarrhoea (loperamide).
- De-addiction/maintenance (methadone, buprenorphine).
High-yield: Morphine in acute pulmonary oedema works by — (1) venodilation → ↓preload, (2) ↓anxiety and air hunger, (3) ↓sympathetic drive and afterload, (4) reduced work of breathing. Tested repeatedly.
Constipation Mechanism (frequently asked)
Opioids bind μ-receptors in the myenteric (Auerbach's) and submucosal plexus of the gut → ↑ resting tone & non-propulsive segmental contractions → ↓ propulsive peristalsis → delayed transit → ↑ water absorption → hard stools. Tone of pyloric, ileocaecal and anal sphincters rises; no tolerance develops → chronic users always constipated.
High-yield: Treat opioid-induced constipation with peripherally-acting μ-antagonists — methylnaltrexone, naloxegol, alvimopan — which reverse gut effects without blocking central analgesia.
Tolerance, Dependence & Withdrawal
- Tolerance — develops to analgesia, euphoria, sedation, respiratory depression, nausea. NOT to miosis and constipation. Mechanism: receptor desensitisation, β-arrestin–mediated internalisation, upregulation of cAMP/adenylyl cyclase (compensatory).
- Physical dependence — abrupt stop or antagonist → withdrawal.
- Cross-tolerance among μ-agonists.
Withdrawal — clinical picture (opposite of opioid effects)
Lacrimation, rhinorrhoea, yawning, sweating → mydriasis, piloerection ("cold turkey"), gooseflesh → myalgia, abdominal cramps, diarrhoea, vomiting → tachycardia, hypertension, restlessness, "kicking the habit" (myoclonus). Distressing but rarely life-threatening (unlike alcohol/barbiturate withdrawal).
| Feature | Opioid intoxication | Opioid withdrawal |
|---|---|---|
| Pupils | Miosis (pinpoint) | Mydriasis |
| GI | Constipation | Diarrhoea, cramps |
| Secretions | Dry | Lacrimation, rhinorrhoea |
| Vitals | ↓RR, ↓HR, ↓BP | ↑HR, ↑BP, sweating |
| CNS | Sedation, coma | Restlessness, insomnia |
Withdrawal management
- Methadone or buprenorphine substitution then taper (long-acting → smooth detox).
- Clonidine / lofexidine (α2-agonists) → suppress autonomic (noradrenergic) symptoms.
- Symptomatic: loperamide (diarrhoea), NSAIDs, antiemetics.
- Naltrexone (oral) for relapse prevention after detox.
High-yield: Clonidine controls the autonomic/noradrenergic features of withdrawal because withdrawal involves locus coeruleus noradrenergic hyperactivity.
Acute Opioid Overdose & Reversal
Classic triad → pinpoint pupils + respiratory depression (↓RR) + coma. Also hypotension, hypothermia, cyanosis; death from respiratory failure.
Management flow: Airway/ventilate (100% O₂) → IV naloxone 0.4–2 mg, repeat every 2–3 min (titrate) → if no response by ~10 mg, reconsider diagnosis → because naloxone t½ (~30–60 min) is shorter than most opioids, use repeat doses or infusion to prevent re-narcotisation.
| Antagonist | Route/Use | Key point |
|---|---|---|
| Naloxone | IV, acute overdose | Pure antagonist; short t½; precipitates withdrawal in dependents |
| Naltrexone | Oral; alcohol & opioid de-addiction | Long acting; also reduces alcohol craving |
| Nalmefene | Longer-acting parenteral | Useful when re-narcotisation feared |
| Methylnaltrexone / Naloxegol / Alvimopan | Peripheral | Opioid-induced constipation, ileus — no central reversal |
High-yield: Naloxone given to an opioid-dependent person precipitates acute withdrawal. Buprenorphine overdose responds poorly to standard naloxone doses (high affinity, slow dissociation) — needs higher/continuous dosing.
Important Drug Interactions & Contraindications
- Pethidine + MAOI / SSRI → serotonin syndrome.
- Tramadol → seizures, serotonin syndrome.
- Morphine contraindicated/cautioned in: head injury/raised ICP (CO₂ retention → cerebral vasodilation; miosis masks pupillary signs), bronchial asthma/COPD (histamine, respiratory depression), hypotension/shock, biliary colic, hepatic failure, hypothyroidism/Addison's, pregnancy/labour (neonatal respiratory depression), elderly, BPH.
Complications / Adverse Effects (summary)
Respiratory depression (lethal), sedation, constipation, nausea/vomiting, urinary retention, pruritus & urticaria (histamine), biliary spasm, hypotension, miosis, tolerance & dependence, neonatal dependence, and (pethidine/tramadol) seizures.
Key Differentials & "Look-alike" Clinical Pictures
- Opioid vs clonidine/organophosphate poisoning — all cause miosis. OP poisoning adds cholinergic excess (SLUDGE, fasciculations); opioids give respiratory depression + coma responsive to naloxone.
- Opioid vs benzodiazepine overdose — BZD: pupils normal/mid-size, reversed by flumazenil; opioid: miosis, reversed by naloxone.
- Sympathomimetic/anticholinergic toxidrome — mydriasis, opposite picture.
Recently asked / exam angle
- Active analgesic metabolite of morphine? → Morphine-6-glucuronide (M6G); accumulates in renal failure.
- Which morphine metabolite causes seizures/neuroexcitation? → M3G.
- Opioid with NMDA antagonism used in de-addiction? → Methadone (also QT prolongation).
- Drug for opioid-induced constipation without losing analgesia? → Methylnaltrexone / naloxegol / alvimopan.
- Mechanism of morphine benefit in acute LVF/pulmonary oedema? → venodilation, ↓preload, ↓anxiety, ↓sympathetic tone.
- Receptor for dysphoria & hallucinations? → Kappa (pentazocine).
- Why does codeine vary between patients? → CYP2D6 polymorphism (prodrug → morphine).
- Pethidine + MAOI → serotonin/excitatory crisis.
- No tolerance develops to → miosis and constipation.
- Antidote with t½ shorter than opioid → risk of re-narcotisation → naloxone (use infusion).
- Buprenorphine — partial agonist, ceiling effect on respiratory depression, naloxone-resistant.
- Remifentanil metabolised by plasma esterases.
Rapid revision
- Opioid receptors are Gi-coupled → ↓cAMP, ↑K⁺ efflux, ↓Ca²⁺ influx → neuronal inhibition.
- Mu = analgesia, euphoria, respiratory depression, miosis, constipation, dependence; Kappa = spinal analgesia + dysphoria, less respiratory depression.
- Morphine oral bioavailability ~25% (high first-pass); M6G active, M3G convulsant.
- Respiratory depression is the killer in overdose; treat with naloxone (titrate, repeat/infuse).
- Tolerance does NOT develop to miosis & constipation.
- Pethidine → mydriasis, tachycardia, normeperidine seizures, MAOI interaction.
- Tramadol & methadone are atypical: SNRI activity / NMDA antagonism respectively; both partially naloxone-resistant.
- Codeine is a CYP2D6 prodrug; contraindicated post-tonsillectomy in children.
- Buprenorphine = high-affinity partial μ-agonist, ceiling on respiratory depression, hard to reverse.
- Pentazocine raises cardiac workload → avoid in MI; causes dysphoria.
- Methylnaltrexone/naloxegol/alvimopan treat opioid-induced constipation peripherally.
- Clonidine blunts the autonomic (locus coeruleus) features of opioid withdrawal; naltrexone for relapse prevention.