Opioid Use Disorder & Overdose

Opioids are among the most heavily tested substances in NEET PG psychiatry and pharmacology. This topic ties together the classic overdose triad, the dramatic but rarely fatal withdrawal syndrome, and a tightly examinable set of antidotes and maintenance drugs (naloxone, methadone, buprenorphine, clonidine). Master the timelines and the receptor pharmacology and most questions become single-line recalls.

Definition & Classification

Opioid Use Disorder (OUD) is a DSM-5 diagnosis: a problematic pattern of opioid use causing clinically significant impairment, with ≥2 of 11 criteria within a 12-month period. Severity is graded: mild (2–3 criteria), moderate (4–5), severe (≥6). Note that DSM-5 merged the older "abuse" and "dependence" into a single spectrum disorder and dropped legal problems as a criterion while adding craving.

Opioids are classified by origin and by receptor action:

Class	Examples	Note
Natural (opiates)	Morphine, codeine	From poppy Papaver somniferum
Semisynthetic	Heroin (diacetylmorphine), oxycodone, buprenorphine	Heroin crosses BBB faster than morphine → greater euphoria
Synthetic	Fentanyl, methadone, tramadol, pethidine	Fentanyl ~80–100× morphine potency
Endogenous	Endorphins, enkephalins, dynorphins	—

Receptor pharmacology is a favourite MCQ:

Drug	Receptor action	Clinical relevance
Morphine, heroin, methadone	Full µ (MOR) agonist	Full analgesia + full overdose risk
Buprenorphine	Partial µ agonist, κ antagonist	Ceiling effect on respiratory depression; high receptor affinity
Naloxone / naltrexone	Pure µ antagonist	Reverse overdose / maintain abstinence
Tramadol	Weak µ agonist + SNRI	Seizures, serotonin syndrome risk
Pentazocine	κ agonist, µ antagonist/partial	Can precipitate withdrawal in dependents

High-yield: Three opioid receptors — µ (MOR), κ (KOR), δ (DOR) — are all Gi-protein coupled, so activation decreases cyclic AMP, closes voltage-gated Ca²⁺ channels (less neurotransmitter release) and opens K⁺ channels (hyperpolarisation). µ mediates analgesia, euphoria, respiratory depression, miosis and constipation.

Etiology & Pathophysiology

Repeated µ-receptor stimulation produces tolerance and physical dependence via up-regulation of the cAMP pathway (adenylyl cyclase super-activation) and recruitment of the locus coeruleus noradrenergic system. When the opioid is withdrawn, the previously suppressed locus coeruleus fires excessively → noradrenergic storm, which explains nearly every withdrawal sign (sweating, tachycardia, hypertension, mydriasis, piloerection, GI hypermotility). This is precisely why clonidine, an α2-agonist that dampens locus coeruleus output, relieves the autonomic features of withdrawal.

High-yield: Opioid withdrawal is intensely unpleasant but rarely life-threatening (in contrast to alcohol and benzodiazepine withdrawal, which can kill via seizures/delirium). The exam loves this distinction.

Clinical Features

Acute Intoxication / Overdose — the Triad

High-yield: The opioid overdose triad = pinpoint pupils (miosis) + respiratory depression + CNS depression (coma). This is the single most repeated NEET PG fact in this topic.

• Miosis — "pinpoint pupils" due to µ-mediated parasympathetic stimulation of the Edinger-Westphal nucleus.
• Respiratory depression — the actual cause of death; ↓ brainstem chemoreceptor sensitivity to CO₂. Look for ↓ respiratory rate and bradypnoea.
• CNS depression — drowsiness → stupor → coma.
• Additional: hypotension, bradycardia, hypothermia, ↓ bowel sounds, needle track marks, non-cardiogenic pulmonary oedema (especially with heroin).

Exam trap: Pethidine (meperidine) and diphenoxylate can cause mydriasis (dilated pupils) rather than miosis, because of antimuscarinic/metabolite (normeperidine) effects. So "dilated pupils" does not exclude opioid overdose if pethidine is involved.

Withdrawal Syndrome

Opioid withdrawal mimics a severe flu plus sympathetic overdrive. There is lacrimation, rhinorrhoea, yawning, sweating, mydriasis, piloerection ("cold turkey"), myalgia, abdominal cramps, diarrhoea, nausea/vomiting, dilated pupils, tachycardia, hypertension, and intense drug craving. Importantly, consciousness is preserved and seizures do NOT occur (unlike alcohol/benzodiazepine withdrawal).

Withdrawal Timeline (very high-yield)

The timeline depends on the half-life of the drug used. Short-acting (heroin) → early, sharp; long-acting (methadone) → delayed, prolonged.

Drug	Onset	Peak	Duration
Heroin (short-acting)	6–12 hours	36–72 hours (1.5–3 days)	7–10 days
Morphine	8–16 hours	~48–72 hours	7–10 days
Methadone (long-acting)	24–48 hours (1–2 days)	72–96 hours+	14–21 days (up to weeks)

Flow of withdrawal severity: Last dose → 6–12 h: craving, anxiety, drug-seeking → 12–24 h: lacrimation, rhinorrhoea, yawning, sweating → 24–48 h: mydriasis, piloerection, myalgia, restlessness → 48–72 h (PEAK): abdominal cramps, vomiting, diarrhoea, tachycardia, hypertension → gradual resolution over 7–10 days.

High-yield: For heroin, remember the rule of thumb — onset ~8–12 h, peak at 2–3 days, resolution by 7–10 days. Methadone everything is roughly doubled/delayed.

High-yield: Neonatal abstinence syndrome (NAS) in babies of opioid-dependent mothers presents with high-pitched cry, irritability, tremors, sweating, poor feeding, diarrhoea; treated with oral morphine (or methadone). Use the Finnegan scoring system.

Diagnosis & Investigation of Choice

• Clinical diagnosis is primary — triad in overdose; flu-like autonomic picture in withdrawal.
• Urine immunoassay is the screening investigation of choice for opioids. Caveats: standard opiate immunoassays detect morphine/codeine but may miss synthetic opioids (fentanyl, methadone, oxycodone) — these need specific assays. Detection window for heroin/morphine in urine is ~1–3 days (longer with chronic use; methadone up to a week).
• Confirmatory test: Gas chromatography–mass spectrometry (GC-MS) — the gold standard.
• Standardised severity scale: COWS (Clinical Opiate Withdrawal Scale) — used to objectively grade withdrawal and decide induction timing for buprenorphine.

Exam angle: A diagnostic naloxone challenge that precipitates withdrawal confirms physical dependence — but be cautious, it can be unpleasant/dangerous.

Management

Acute Overdose — Drug of Choice

High-yield: Naloxone is the drug of choice for opioid overdose — a pure competitive µ-antagonist. Give IV (fastest), or IM/SC/intranasal if no access. Adult dose 0.4–2 mg, repeat every 2–3 minutes, titrating to adequate respiration (not full alertness).

Key naloxone facts:

• Short half-life (~30–90 min), much shorter than most opioids → risk of re-narcotisation/re-sedation; patient must be observed and may need a continuous infusion, especially with long-acting agents (methadone) or potent ones (fentanyl).
• In a dependent patient, naloxone precipitates acute withdrawal — titrate carefully.
• Naltrexone is the long-acting oral/depot antagonist used for relapse prevention/abstinence maintenance, NOT acute resuscitation.
• Airway, breathing, ventilation first — naloxone is adjunct to supportive ABC care.

Overdose flow: Suspect opioid (triad) → secure airway + bag-mask ventilation/O₂ → IV naloxone 0.4–2 mg, titrate to respiration → repeat / start infusion if long-acting opioid → observe 4–6 h (longer for methadone/fentanyl) for re-narcotisation.

Withdrawal Management

Two approaches: substitution (agonist) detox or non-opioid symptomatic control.

• Buprenorphine (often buprenorphine + naloxone, "Suboxone") — partial agonist; first-line for both detox and maintenance. Start only when patient is in mild–moderate withdrawal (COWS-guided) to avoid precipitated withdrawal due to its high receptor affinity displacing full agonists. The naloxone component is poorly absorbed sublingually but deters IV misuse.
• Methadone — long-acting full agonist; effective detox and maintenance; given as a single daily supervised dose. Watch QT prolongation and respiratory depression.
• Clonidine (α2-agonist) — non-opioid; controls autonomic/noradrenergic symptoms (sweating, tachycardia, hypertension, cramps). Does not relieve craving, insomnia or muscle aches well. Watch hypotension and sedation. Lofexidine is an FDA-approved α2-agonist alternative with less hypotension.
• Symptomatic: loperamide (diarrhoea), paracetamol/NSAIDs (myalgia), ondansetron/promethazine (nausea), hydroxyzine (anxiety).

Maintenance / Long-term (Medication-Assisted Treatment, MAT)

Drug	Mechanism	Pros	Cons
Methadone	Full µ agonist	Highly effective; supervised daily dose; reduces illicit use, crime, HIV spread	Overdose & QT risk; long detox; requires clinic
Buprenorphine ± naloxone	Partial µ agonist	Ceiling effect → safer in overdose; office-based; less diversion	Precipitated withdrawal if started too early
Naltrexone (oral / depot IM)	µ antagonist	No abuse/diversion potential; good for the motivated abstinent patient	Must be opioid-free 7–10 days first or precipitates withdrawal; poor compliance with oral form

High-yield: Buprenorphine has a ceiling effect on respiratory depression (partial agonist) making it safer than methadone in overdose — a repeatedly tested distinction. But buprenorphine has very high µ affinity, so it displaces full agonists and can precipitate withdrawal if given too soon.

High-yield: Methadone/buprenorphine maintenance is harm-reduction: it reduces mortality, criminal behaviour, needle-sharing and HIV/HCV transmission — the preferred public-health strategy over forced abstinence.

Complications

• Death from respiratory arrest (the leading cause of opioid mortality).
• Infectious: HIV, hepatitis B & C, infective endocarditis (right-sided, Staph aureus), septic emboli, abscesses, cellulitis from shared/dirty needles.
• Non-cardiogenic pulmonary oedema (classically heroin).
• Aspiration pneumonia, rhabdomyolysis with compartment syndrome and acute kidney injury after prolonged immobile coma.
• Constipation (chronic), hypogonadism, opioid-induced hyperalgesia.
• Seizures with tramadol and pethidine (normeperidine metabolite).
• Serotonin syndrome with tramadol/pethidine + SSRIs/MAOIs.
• Neonatal abstinence syndrome in newborns of dependent mothers.

Key Differentials

Feature	Opioid overdose	Clonidine/α2 OD	Pontine haemorrhage	Organophosphate poisoning
Pupils	Pinpoint	Pinpoint	Pinpoint	Pinpoint
Respiration	Depressed	Depressed	Variable	Bronchorrhoea, depressed
Distinguishing clue	Track marks, responds to naloxone	Bradycardia, prior rebound HTN	Quadriparesis, eye signs	SLUDGE, fasciculations, ↓RBC cholinesterase

Exam trap: All four causes of miosis above can confuse — the clincher for opioids is reversal with naloxone plus needle marks. Organophosphates add muscarinic SLUDGE (salivation, lacrimation, urination, defecation, GI, emesis) and respond to atropine + pralidoxime, not naloxone.

Other differentials: sedative-hypnotic (benzodiazepine) overdose — pupils usually normal/mid-size, reversed by flumazenil; alcohol intoxication; hypoglycaemia; CO poisoning; brainstem stroke.

Recently asked / exam angle

• Opioid overdose triad (miosis + respiratory depression + coma) — asked almost every cycle as a single-best-answer.
• Drug of choice for opioid overdose = naloxone; mechanism = pure µ antagonist; caution = short half-life → re-narcotisation.
• Onset/peak/duration of heroin withdrawal (onset 6–12 h, peak 2–3 days, duration 7–10 days) versus methadone (delayed and prolonged).
• Clonidine mechanism in withdrawal — α2-agonist reducing locus coeruleus noradrenergic outflow.
• Buprenorphine = partial agonist with ceiling effect; why it is started only in established withdrawal (precipitated withdrawal).
• Naltrexone for abstinence maintenance; must be opioid-free before starting.
• Pethidine/diphenoxylate cause mydriasis — exception to the "miosis" rule.
• Tramadol — seizures and serotonin syndrome.
• "Which withdrawal is NOT life-threatening?" → opioid (vs alcohol/benzodiazepine).
• Receptor type — µ/κ/δ all Gi-coupled, ↓cAMP.

Rapid revision

1. Overdose triad: miosis + respiratory depression + CNS depression/coma — respiratory failure kills.
2. Naloxone = DOC for overdose; pure µ antagonist; short t½ → watch for re-sedation, may need infusion.
3. Heroin withdrawal: onset 6–12 h, peak 48–72 h, resolves in 7–10 days.
4. Methadone withdrawal: delayed onset (1–2 days) and prolonged (2–3 weeks).
5. Opioid withdrawal is miserable but not fatal; no seizures (unlike alcohol/benzo).
6. Clonidine (α2-agonist) treats autonomic withdrawal symptoms via locus coeruleus suppression; lofexidine is the FDA-approved alternative.
7. Buprenorphine = partial µ agonist with a ceiling on respiratory depression; start only in mild-moderate withdrawal (COWS) to avoid precipitated withdrawal.
8. Methadone = long-acting full agonist; effective maintenance; risks QT prolongation + overdose.
9. Naltrexone = long-acting antagonist for abstinence; must be opioid-free 7–10 days first.
10. Pethidine/diphenoxylate → mydriasis, not miosis; pethidine/tramadol → seizures & serotonin syndrome.
11. Screening test = urine immunoassay (may miss synthetic opioids); confirmation = GC-MS.
12. IV drug use complications: HIV, HBV/HCV, right-sided infective endocarditis (S. aureus), non-cardiogenic pulmonary oedema, NAS in newborns.