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

1. Opioid receptors are Gi-coupled → ↓cAMP, ↑K⁺ efflux, ↓Ca²⁺ influx → neuronal inhibition.
2. Mu = analgesia, euphoria, respiratory depression, miosis, constipation, dependence; Kappa = spinal analgesia + dysphoria, less respiratory depression.
3. Morphine oral bioavailability ~25% (high first-pass); M6G active, M3G convulsant.
4. Respiratory depression is the killer in overdose; treat with naloxone (titrate, repeat/infuse).
5. Tolerance does NOT develop to miosis & constipation.
6. Pethidine → mydriasis, tachycardia, normeperidine seizures, MAOI interaction.
7. Tramadol & methadone are atypical: SNRI activity / NMDA antagonism respectively; both partially naloxone-resistant.
8. Codeine is a CYP2D6 prodrug; contraindicated post-tonsillectomy in children.
9. Buprenorphine = high-affinity partial μ-agonist, ceiling on respiratory depression, hard to reverse.
10. Pentazocine raises cardiac workload → avoid in MI; causes dysphoria.
11. Methylnaltrexone/naloxegol/alvimopan treat opioid-induced constipation peripherally.
12. Clonidine blunts the autonomic (locus coeruleus) features of opioid withdrawal; naltrexone for relapse prevention.