PharmacologyTier 1Medical Sciences concept

Drug withdrawal/rebound phenomena (clonidine, beta-blockers, benzodiazepines)

Core concept

Chronic exposure causes receptor and pathway adaptation; abrupt removal leaves the adaptation unopposed
- Receptor upregulation after chronic antagonism -> rebound overshoot (beta-blockers, clonidine, H2 antagonists, PPIs)
- Receptor downregulation after chronic agonism -> withdrawal deficit (opioids, benzodiazepines, alcohol, corticosteroids)
Rebound = the original problem returns worse than baseline. Withdrawal = a new syndrome, often the mirror image of the drug's effect

Key detail

Drug	Syndrome	Timing	Prevention
Clonidine	Severe rebound hypertension - catecholamine surge from alpha-2 disinhibition; can mimic phaeochromocytoma	12-72 h	Taper over 2-4 days minimum; never stop abruptly
Beta-blockers	Rebound tachycardia, hypertension, angina, MI, arrhythmia (upregulated beta receptors)	Days	Taper over 1-2 weeks
Benzodiazepines	Anxiety, insomnia, tremor, seizures, delirium, perceptual disturbance	Short-acting 1-2 days, long-acting 3-7 days	Slow taper, convert to diazepam; taper by 10-25% every 1-2 weeks
Opioids	Yawning, lacrimation, mydriasis, piloerection, cramps, diarrhoea, myalgia - unpleasant, rarely fatal	6-12 h (short-acting)	Taper; clonidine, buprenorphine
Alcohol	Tremor, seizures 12-48 h, hallucinosis, delirium tremens 48-96 h - can be fatal	Hours-days	Symptom-triggered diazepam, thiamine
Corticosteroids	Adrenal insufficiency (HPA suppression) and disease flare	Days-weeks	Taper below physiological dose slowly; stress cover
PPI	Rebound acid hypersecretion (hypergastrinaemia)	2-4 weeks after >8 weeks use	Step down to H2 antagonist, or taper
Nitrates	Rebound angina/vasospasm	Hours	Nitrate-free interval to avoid tolerance in the first place
SSRIs	Discontinuation syndrome - dizziness, brain zaps, flu-like	Days; worst with paroxetine, venlafaxine	Taper; fluoxetine self-tapers
Baclofen (intrathecal)	Fever, rigidity, rhabdomyolysis - mimics NMS	24-72 h	Never interrupt the pump
Levodopa / dopamine agonist	Parkinsonism-hyperpyrexia syndrome (NMS-like)	Days	Never stop abruptly; use patch/NG if nil by mouth
Anticonvulsants	Status epilepticus	Days	Never stop abruptly
Denosumab	Rebound vertebral fractures	6-18 months	Follow with a bisphosphonate

A missed dose in hospital is the commonest cause - nil by mouth, medication reconciliation failure, transfer between wards

Clinical relevance

On every admission, ask what the patient normally takes and whether it has been given - unexplained hypertension, tachycardia, agitation, seizure, rigidity or fever is often a withheld drug
The drugs that must not be interrupted, including perioperatively and when nil by mouth: antiparkinsonian therapy, antiepileptics, clonidine, beta-blockers, corticosteroids, intrathecal baclofen, opioid agonist therapy, antiretrovirals, immunosuppressants
- Use NG, patch (rotigotine), or IV equivalents
Perioperative beta-blockers are continued, not withheld
Deprescribing needs a written taper and a monitoring plan - deprescribing is an active intervention, not just stopping
Distinguish rebound (physiological adaptation) from relapse (the underlying disease returning) and from dependence - only the last implies addiction

Correlations

Mechanisms of action of drugs of addiction/dependence
Antidepressant pharmacokinetics - discontinuation syndrome
Neuroleptic malignant syndrome; parkinsonism-hyperpyrexia
Corticosteroid potency; adrenal insufficiency
Proton pump inhibitor adverse effects; osteoporosis drug mechanisms

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