Opioid Withdrawal and Overdose

Introduction

Opioid withdrawal is the syndrome that follows cessation or reduction of opioids in a physically dependent person, or that is precipitated by giving an antagonist or partial agonist. It is characterised by profound noradrenergic overactivity and is subjectively one of the most distressing experiences in medicine - patients frequently describe fearing they will die, and the anticipation of withdrawal is itself a powerful driver of continued use.¹

Crucially, and in direct contrast with alcohol and benzodiazepine withdrawal, uncomplicated opioid withdrawal is not usually fatal in an otherwise healthy adult. The danger in opioid dependence lies overwhelmingly in overdose, and paradoxically the period immediately after successful withdrawal is the most lethal of all, because tolerance falls faster than habit.

Opioid-related deaths in the UK have risen substantially over the past decade, and the population involved is ageing, with increasing comorbidity. This article covers both withdrawal and acute overdose, since the two are inseparable in practice and both are core UKMLA content.

Pathophysiology

Opioids act principally at mu-opioid receptors, which are inhibitory G-protein coupled receptors. In the locus coeruleus - the brain's principal noradrenergic nucleus - mu agonism suppresses noradrenaline release.

Chronic exposure causes the locus coeruleus to compensate by upregulating its intrinsic activity so that normal noradrenergic output is maintained despite ongoing opioid suppression. When the opioid is removed, that compensation is unopposed and there is a surge of noradrenergic activity, producing the autonomic features of withdrawal: sweating, tachycardia, hypertension, piloerection, lacrimation, rhinorrhoea, mydriasis and gastrointestinal hyperactivity.

This mechanism explains the treatments directly. Substitution with a longer-acting opioid restores mu receptor occupancy and suppresses the surge. Alpha-2 agonists such as lofexidine or clonidine reduce noradrenaline release presynaptically and so blunt the autonomic features without providing opioid effect. Every symptomatic treatment used in withdrawal maps onto one of these two strategies.

Clinical features and timeline

Onset and duration depend on the half-life of the opioid involved, which is the key to predicting the course and to planning admission or detoxification.

Clinical features

• Early (6-12 hours): anxiety, craving, restlessness, yawning, lacrimation, rhinorrhoea, sweating
• Established: dilated pupils, piloerection ('gooseflesh' - the origin of the phrase 'cold turkey'), myalgia and arthralgia, abdominal cramps, nausea, vomiting and diarrhoea
• Autonomic: tachycardia, hypertension, hyperthermia or chills
• Neuropsychiatric: severe insomnia, dysphoria, irritability, intense craving
• Other: involuntary leg movements (the origin of 'kicking the habit'), hypersensitivity to pain
• Notably absent: confusion, seizures and hallucinations. If these are present, look for another cause - alcohol or benzodiazepine withdrawal, head injury, infection or metabolic derangement.

The COWS (Clinical Opiate Withdrawal Scale) provides an objective score across eleven domains including pulse, sweating, restlessness, pupil size, bone or joint aches, GI upset, tremor, yawning, anxiety, gooseflesh and rhinorrhoea. It is used both to grade severity and, critically, to determine when it is safe to start buprenorphine.

Acute opioid overdose

Overdose is the true emergency in opioid use, and death results from respiratory depression and consequent hypoxia.

• The classic triad: reduced conscious level, respiratory depression (slow rate, shallow, sometimes as low as 4-6 breaths per minute), and pinpoint pupils
• Additional features: cyanosis, hypotension, bradycardia, hypothermia, absent gag reflex, non-cardiogenic pulmonary oedema, and needle marks
• Risk is multiplied by co-ingestants - alcohol, benzodiazepines, gabapentinoids and other sedatives cause the majority of opioid deaths in combination rather than opioids alone

Management of overdose

1. A to E assessment with immediate attention to airway and ventilation - oxygenation and ventilation take priority over naloxone
2. Naloxone, a competitive mu antagonist, titrated intravenously in increments and repeated as needed; the intramuscular or intranasal route is used where IV access is unavailable, including in community take-home kits⁵
3. Titrate to adequate respiratory rate and oxygenation, not to full consciousness. Giving too much too fast precipitates acute, severe withdrawal - agitation, vomiting with aspiration risk, and in a patient with cardiac disease, catecholamine-driven harm. It also destroys any therapeutic relationship and makes the patient far less likely to accept help.
4. Anticipate re-sedation. Naloxone has a half-life of around 30-90 minutes, considerably shorter than heroin and much shorter than methadone. A patient who wakes up and self-discharges may re-sedate and die. Observe for an appropriate period and consider a naloxone infusion for long-acting opioids.
5. Look for complications - aspiration pneumonia, rhabdomyolysis and compartment syndrome from prolonged unconsciousness, and hypoxic brain injury
6. Use the presentation as an intervention opportunity - offer take-home naloxone, referral to drug services and a blood-borne virus screen before discharge

Investigations

• Capillary glucose - hypoglycaemia is an important differential for reduced consciousness
• Venous or arterial blood gas - to quantify respiratory depression and CO2 retention in overdose
• Urine drug screen - to confirm substances involved, remembering that synthetic opioids such as fentanyl analogues may not be detected on standard panels
• Paracetamol and salicylate levels - many opioid preparations are compound (co-codamol, co-dydramol), so paracetamol overdose frequently coexists and is easily missed
• U&Es and creatine kinase - rhabdomyolysis after prolonged unconsciousness
• FBC, CRP, chest radiograph - aspiration pneumonia is common
• Blood-borne virus screen - hepatitis B, hepatitis C and HIV for anyone who injects
• ECG - methadone prolongs the QTc interval, which matters when titrating maintenance doses
• Pregnancy test where relevant - management differs substantially

Management of withdrawal and dependence

Opioid substitution treatment

Substitution is the mainstay of treatment for opioid dependence, and the evidence for it is among the strongest in addiction medicine: it substantially reduces mortality, injecting, blood-borne virus transmission and offending.²

Symptomatic and adjunctive treatment

• Lofexidine - an alpha-2 agonist licensed in the UK for opioid withdrawal, reducing autonomic symptoms; monitor for hypotension and bradycardia⁴
• Loperamide for diarrhoea, metoclopramide or prochlorperazine for nausea, NSAIDs or paracetamol for myalgia, and short-term hypnotics for insomnia if genuinely needed
• Hydration and electrolyte replacement - vomiting and diarrhoea can cause significant losses
• Naltrexone for relapse prevention in motivated, fully detoxified patients - it blocks the effect of opioids, but requires complete abstinence first or it precipitates withdrawal

Detoxification

Detoxification means a planned, gradual reduction of the substitute opioid to zero. It should be offered where the person wants it, but it must be a considered choice rather than a default - retention in maintenance treatment reduces mortality more effectively than repeated cycles of detoxification and relapse. Rapid or ultra-rapid detoxification under sedation or anaesthesia is not recommended, carrying significant risk without improving long-term outcomes.

Special situations

• Pregnancy - do not attempt abrupt withdrawal. Withdrawal is associated with miscarriage and preterm labour; maintenance on methadone or buprenorphine is the standard of care, with obstetric and neonatal teams alerted to expect neonatal abstinence syndrome
• Acute pain in a patient on OST - continue the maintenance dose (it provides no analgesia) and add appropriate additional analgesia, often at higher doses because of tolerance. Never withhold analgesia on the grounds of dependence.
• Hospital admission - confirm the substitution dose with the prescribing service and the dispensing pharmacy before giving it. Never take the dose on the patient's word alone, and never assume a missed period of dosing has not reduced tolerance.

Complications

Fatal overdose is the dominant complication of opioid dependence, and is nearly always associated with co-ingested sedatives or with reduced tolerance. Injecting carries the risks of blood-borne virus transmission, injection-site abscess and cellulitis, infective endocarditis, deep vein thrombosis and, with inadvertent arterial injection, limb ischaemia.

Chronic use causes constipation, hypogonadism with associated osteoporosis, opioid-induced hyperalgesia, and dental disease. Neonatal abstinence syndrome affects infants born to dependent mothers and requires specialist neonatal management. Social consequences - homelessness, unemployment, criminal justice involvement and safeguarding concerns for dependent children - are common and require as much attention as the pharmacological management.

Red flags

Prognosis

Opioid dependence is a chronic, relapsing condition, and long-term outcomes are strongly determined by engagement with treatment rather than by any single episode of detoxification. Patients retained in opioid substitution treatment have a mortality several times lower than those out of treatment, and this benefit is maintained for as long as they remain engaged - which is the strongest argument for prioritising retention over rapid abstinence.³

Relapse after detoxification is common, and the associated loss of tolerance makes those relapses disproportionately dangerous. Better outcomes are associated with stable housing and employment, treatment of comorbid mental illness and chronic pain, social support, and access to take-home naloxone. Long-term recovery is entirely achievable and is achieved by many people, but is best understood as a process measured over years, with lapses managed as part of the course rather than treated as an endpoint.