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PH3.9 | PH3.9 | Dependence-Producing Drugs and De-Addiction Management — SDL Guide — SDL Guide (Part 2)
Stimulants and Depressants — Mechanisms, Toxicity, and Dependence
Cocaine toxicology: acute cocaine toxicity reflects its sympathomimetic (NA reuptake inhibition) and dopaminergic (DAT blockade) effects: tachycardia, hypertension, hyperthermia, pupil dilation, euphoria. CNS: seizures (cocaine lowers seizure threshold via multiple mechanisms). Cardiac: cocaine-induced coronary vasospasm (NA-mediated) → myocardial infarction in young users without atherosclerosis — a classic emergency medicine presentation. 'Crack cocaine' (free-base, smoked) has more rapid, intense, shorter-lived effect than intranasal cocaine powder — higher addiction liability. Management of acute cocaine toxicity: BZDs (calming, anticonvulsant), cooling, IV fluids; avoid beta-blockers (unopposed alpha-adrenoceptor stimulation worsens coronary vasospasm and hypertension).
Amphetamine toxicology: similar sympathomimetic picture to cocaine. Methamphetamine causes selective destruction of DAergic and 5-HTergic terminals with chronic use (neurotoxicity). MDMA ('ecstasy') acute risk: hyperthermia, hyponatraemia (MDMA releases ADH + users drink excessive water at clubs), serotonin syndrome risk with SSRIs.
Cannabis: acute effects include relaxation, altered time perception, increased appetite (munchies — CB₁ agonism in hypothalamus), impaired short-term memory (hippocampal CB₁), and at high doses, anxiety and paranoia. Chronic heavy use: amotivational syndrome (reduced drive, apathy). Cannabinoid hyperemesis syndrome (paradoxical cyclic vomiting in heavy users — treated by hot showers, which stimulate TRPV1 receptors). No lethal overdose from cannabis alone.
Opioid dependence (covered in PH3.4 cross-reference): physical dependence is the defining feature — opioid withdrawal (dysphoria, lacrimation, rhinorrhoea, muscle cramps, diarrhoea, piloerection — 'goosebumps' = 'cold turkey') is intensely uncomfortable but not life-threatening in healthy adults (contrast with alcohol withdrawal which can be fatal).
Psychedelics and Drugs Used for Criminal Offences
LSD and classical psychedelics: LSD acts as a partial agonist at 5-HT₂A receptors in the thalamus and prefrontal cortex, disrupting the normal gating of sensory information and producing characteristic vivid visual and auditory hallucinations, ego dissolution, and altered time perception. Tolerance develops within 3-4 days of daily use (requiring dose escalation) but resolves within 7 days of abstinence. No physical dependence and no physiological withdrawal syndrome. LSD does not produce dopaminergic reward in the classic mesolimbic sense — explaining its lower addiction liability compared to opioids or stimulants.
GHB — mechanism and forensic significance: GHB (gamma-hydroxybutyrate) activates GABA-B receptors (pre- and post-synaptic) and specific GHB receptors — producing CNS depression, sedation, and euphoria at low doses, coma and respiratory depression at high doses. Its key properties that make it a DFSA drug: (1) colourless and nearly tasteless in solution — easily added to drinks undetected; (2) rapid onset (15-30 min after ingestion); (3) potent anterograde amnesia (the victim cannot recall events after ingestion); (4) short duration (2-4 hours before self-excretion); (5) very short detection window in urine (4-8 hours) — rapid forensic sampling is critical. GHB + alcohol is dangerous — synergistic CNS and respiratory depression.
Forensic response to suspected DFSA:
- Collect urine sample immediately (within 4-8 hours for GHB detection; longer window for flunitrazepam)
- Also collect blood sample (serum GHB detectable up to 6-8 hours)
- Preserve the drink container if available (for residue testing)
- Medical examination for injuries, STI prophylaxis
- Document victim's clinical state (level of consciousness, retrograde amnesia)
De-Addiction Pharmacotherapy — Opioids, Alcohol, and Tobacco
Opioid Use Disorder (OUD) — Pharmacotherapy options:
Buprenorphine/naloxone (Suboxone): sublingual combination tablet — buprenorphine (partial μ-agonist) prevents withdrawal and reduces craving; naloxone (opioid antagonist) is added as an abuse deterrent (inactive when taken sublingually as directed; precipitates withdrawal if injected — deters IV misuse). First-line for OUD in outpatient settings. Advantages: ceiling effect on respiratory depression (safer than methadone in overdose), widely available, can be prescribed by trained GPs.
Methadone: full μ-agonist, long half-life (15-60h). Oral once-daily supervised dispensing at a clinic (legally regulated). Suppresses cravings, prevents withdrawal, blocks euphoria from illicit opioids. Suitable for severe dependence requiring close supervision. Risk: QTc prolongation, drug interactions, lethal in unsupervised use — hence dispensing restrictions.
Naltrexone: pure μ-antagonist (oral or monthly depot injection). Used for relapse prevention AFTER complete detoxification — blocks opioid reward completely. Patient must be free of opioids for 7-10 days before starting (otherwise precipitates acute withdrawal). Poor compliance with oral formulation; long-acting injectable (naltrexone depot) improves adherence.
Tobacco (nicotine) use disorder:
- Nicotine replacement therapy (NRT): nicotine patches, gum, lozenges, inhaler, nasal spray. Replaces nicotine delivery without tobacco carcinogens; reduces withdrawal symptoms; facilitates gradual weaning.
- Varenicline (Champix/Chantix): partial agonist at α₄β₂ nicotinic acetylcholine receptors — provides partial stimulation (reduces withdrawal) while blocking the full reward from cigarettes. Most effective smoking cessation pharmacotherapy in trials. ADRs: nausea (most common), vivid dreams; monitor for neuropsychiatric symptoms (mood changes) in patients with psychiatric history.
- Bupropion (Zyban): NDRI antidepressant — mechanism of smoking cessation is partly via DA/NA reuptake inhibition in the reward circuit and partly via nicotinic receptor antagonism. Second-line; lowers seizure threshold.
Alcohol use disorder pharmacotherapy: disulfiram, naltrexone, acamprosate — covered in PH3.8; cross-reference.
| Substance | Drug | Mechanism | Role |
|---|---|---|---|
| Opioid | Buprenorphine/naloxone | Partial μ-agonist + antagonist deterrent | Maintenance (outpatient) |
| Opioid | Methadone | Full μ-agonist, long-acting | Maintenance (supervised) |
| Opioid | Naltrexone | μ-opioid antagonist | Relapse prevention (post-detox) |
| Tobacco | NRT (patch/gum) | Nicotine replacement | Withdrawal management |
| Tobacco | Varenicline | Partial α₄β₂ nAChR agonist | Cessation aid |
| Tobacco | Bupropion | NDRI + nAChR antagonist | Second-line cessation |
| Alcohol | Naltrexone | μ-opioid antagonist | Anti-craving |
| Alcohol | Disulfiram | ALDH inhibitor | Deterrent |
| Alcohol | Acamprosate | NMDA antagonist/GABA-B agonist | Withdrawal/craving |
SELF-CHECK
Cocaine's primary pharmacological mechanism of action in the reward pathway is:
A. Stimulating dopamine synthesis in the nucleus accumbens via tyrosine hydroxylase activation
B. Blocking the dopamine transporter (DAT) — and also the noradrenaline and serotonin transporters — preventing reuptake and increasing synaptic monoamine concentrations
C. Reversing the dopamine transporter to actively release dopamine into the synapse, like amphetamines
D. Activating D2 receptors directly in the nucleus accumbens
Reveal Answer
Answer: B. Blocking the dopamine transporter (DAT) — and also the noradrenaline and serotonin transporters — preventing reuptake and increasing synaptic monoamine concentrations
Cocaine is a reuptake inhibitor — it blocks the dopamine transporter (DAT), noradrenaline transporter (NET), and serotonin transporter (SERT) simultaneously, preventing monoamine reuptake from the synapse. Dopamine accumulation in the nucleus accumbens is the primary reward mechanism. Cocaine does NOT reverse the transporter (that is the amphetamine mechanism). Amphetamines actively release catecholamines; cocaine prevents their clearance. This mechanistic difference is clinically relevant — both produce euphoria, but the intensity and duration differ.
SELF-CHECK
A patient with opioid use disorder is assessed for buprenorphine/naloxone (Suboxone) therapy. His last heroin use was 12 hours ago and he is in moderate withdrawal. A colleague suggests giving naltrexone instead. What is the critical pharmacological reason NOT to give naltrexone at this point?
A. Naltrexone has the same mechanism as buprenorphine — both are partial agonists, making one redundant
B. Naltrexone is a pure opioid antagonist — administering it to a patient with active opioid dependence before full detoxification will precipitate severe acute withdrawal
C. Naltrexone causes QTc prolongation in combination with opioid-contaminated blood, producing arrhythmia
D. Naltrexone is only effective for alcohol use disorder, not opioid use disorder
Reveal Answer
Answer: B. Naltrexone is a pure opioid antagonist — administering it to a patient with active opioid dependence before full detoxification will precipitate severe acute withdrawal
Naltrexone is a pure competitive opioid receptor antagonist. In a patient with active physical opioid dependence (opioid receptors are occupied and chronically stimulated), administering naltrexone rapidly displaces opioids from all μ, κ, and δ receptors — immediately precipitating acute, severe opioid withdrawal (lacrimation, rhinorrhoea, severe muscle cramps, diarrhoea, agitation, hypertension). Naltrexone is for relapse PREVENTION — it must only be started after the patient has been fully detoxified and free of opioids for at least 7-10 days. Buprenorphine/naloxone can be started when withdrawal is already beginning (COWS score ≥8) — its partial agonism relieves, rather than precipitates, withdrawal.
SELF-CHECK
A young woman presents to the emergency department with retrograde amnesia for the past 6 hours and is distressed, reporting she may have been sexually assaulted after a party. You suspect drug-facilitated sexual assault using GHB. What is the most important IMMEDIATE forensic action, and why?
A. Ask the victim to wait for a psychiatric evaluation before any specimen collection
B. Collect urine and blood samples IMMEDIATELY — GHB's detection window in urine is only 4-8 hours; delay means the forensic evidence is permanently lost
C. Administer IV flumazenil — GHB is a benzodiazepine-like drug and flumazenil will reverse its effects
D. Order a urine drug screen using a standard hospital kit — GHB is detected by routine immunoassay
Reveal Answer
Answer: B. Collect urine and blood samples IMMEDIATELY — GHB's detection window in urine is only 4-8 hours; delay means the forensic evidence is permanently lost
GHB has an extremely short detection window — approximately 4-8 hours in urine and up to 6-8 hours in blood. Once the window closes, the evidence is permanently lost. Immediate urine and blood collection is the forensic imperative. Note: GHB is NOT detected by standard hospital urine immunoassay (which tests for opioids, BZDs, cannabis, cocaine, amphetamines) — specific GHB testing at a forensic laboratory is required. Flumazenil does NOT reverse GHB (GHB acts on GABA-B receptors, not GABA-A BZD-site). The correct antidote for GHB overdose is supportive care (airway); GABA-B antagonists are not clinically available.
CLINICAL PEARL
Buprenorphine timing in opioid withdrawal: buprenorphine must be started when the patient is already in mild-to-moderate withdrawal (COWS score ≥8) — not while they still have opioids on board. Because buprenorphine has very high μ-receptor affinity, administering it to a patient who is NOT yet in withdrawal will displace the full agonist from μ receptors — precipitating acute withdrawal ('precipitated withdrawal'). Wait for the first withdrawal symptoms before the first dose. This is the key clinical skill in OUD management and is frequently examined.