Drug Intoxication and Withdrawal

1. Drug Intoxication and Withdrawal Alexander Chyorny, MD November 2013

3. Pharmacological Treatment of Addiction

4. Neurotransmitters-101 • Dopamine pathway – learning, pleasure • Serotonin pathway – regulates mood • Opioid pathway – antinociceptive • Cannabinoid – appetite, pain, mood, memory • Noradrenergic – alertness, decision-making • Cholinergic – memory, learning, arousal • Glutamate – excitation (NMDA, AMPA receptors) • GABA – inhibition

5. Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse. Camí J, Farré M. N Engl J Med 2003;349:975-986.

6. Brain Reward System:Mesocorticolimbic Dopamine Pathway modulates pleasure needed for survival: eating/drinking, sex, nurturing

7. “The Substance” and the Brain:Neuroadaptation • Yin-Yang – homeostasis (activating/inhibiting) • Intoxication – temporary dominance • Tolerance – activating opposition, down-regulating receptors • Withdrawal – removing the drug; biological effects much longer-lasting (days to years) • Tx of WD – substance mimetics (long-acting, taper); antagonizing opposition

8. Yin and Yang

9. Drug craving Irritability Dysphoria Anxiety Insomnia + specific Sx of whatever agonist/antagonist receptor systems involved Immediate phase: starts w/i hours, lasts days Protracted phase: 6-18 mo (malaise, cravings)

10. General Assessment Principles • Primary substance • type, route, frequency, amount, time of last use • Complications of use and withdrawal • History of medication-assisted detox • Concurrent substances use/co-morbidities • Vital signs • Mental status • Pupils • Ability to ambulate • Urine toxicology

11. General Approach to O/D Coma cocktail • Thiamine 100 mg • 1 amp of D50 • Naloxone 2 mg

13. Alcohol: the Most Common and Lethal • GABA-A vs. glutamate/NMDA • Indirect release of β-endorphins and dopamine • In and Out: consider Pruno, hand-sanitizers • Intoxication: slurred speech, confusion, ataxia, ↓HR; assess ability to protect airway • Withdrawal • Early symptoms 6-24 hrs • Seizures 12-48 hrs • Isolated hallucinosis 12-48 hrs • Delirium Tremens 48-96 hrs

15. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) • Most commonly used instrument, validated • Measures 10 subscales • Nausea/vomiting Tactile disturbances • Tremor Auditory disturbances • Diaphoresis Visual disturbances • Anxiety Headache • Agitation Orientation • Max score 67, prophylaxis if >8, hospitalization if >15-20, ICU if > 35

16. EtOH: Cornerstones of Treatment • Monitor – CIWA-Ar, VS; close observation • EtOH substitutes – benzodiazepines • Supportive treatment • Quiet, protective environment • Correct hypovolemia/electrolytes • Thiamine (before glucose), MVI, folate, MgSO4 • Adjunct treatment • Beta-blockers, antipsychotics • Anticonvulsants • α2 agonists, muscle relaxants

17. EtOH substitute: Benzodiazepines • Fixed ATC vs. Sx-triggered dosing • Chlordiazepoxide (Librium) • Longest-acting, active metabolites, auto-taper • 50-75 mg PO q 4-6 hrs, add’ldoses hourly prn • Lorazepam (Ativan) • Medium-to-short acting, no active metabolites • Preferable in patients with advanced cirrhosis or high risk for oversedation (elderly, co-morbidities) • 1-2 mg PO q 4-6 hrs, hourly prn

18. EtOH Dependence • Medication is adjunct to ψ-social intervention • Acamprosate • NMDA partial antagonist; 666 mg tid • Disulfiram • Blocks alcohol dehydrogenase; nausea/flushing/↑HR; 250-500 mg/d • Naltrexone • Blocks μ-opioid receptors • Oral (50 mg/d) or injectable (380 mg/mo) • Baclofen • GABA-B agonist; anxiolytic; 10-20 mg tid • Topiramate • ↑GABA, ↓glutamate; slow titration to 300 mg/d

20. Benzodiazepines • Most abused: short-acting alprazolam (Xanax) • Most common: clonazepam (Klonopin), Valium (Diazepam), lorazepam (Ativan) • Intoxication: similar to EtOH • WD: beware of much longer half-life • Tx: chlordiazepoxide or clonazepam taper • Carbamazepine as an alternative for w/d Sx

22. Gamma-Hydroxybutyrate • Acts on specific GHB and GABA-B receptors • Euphoric, ↓inhibition, amnesia, hypotonia, somnolence, ↓HR, ↓BP, clonus, resp. depression • Short-acting; acute intoxication best treated with observation if no respiratory compromise • WD: similar to BZD/EtOH, less autonomic, more CNS – insomnia, tremor, anxiety; 1 wk • Tx: consider BZD taper, baclofen

24. Z-drugs • Zolpidem, zaleplone, (es)zopiclone • GABA-A receptor; effects similar to BZD • High doses – euphoria, exaltation, anxiolysis • Dependence, withdrawal – similar to BZD (from sympathetic O/D to Sz) • Tx: consider diazepam or gabapentin taper

26. Carisoprodol (Soma) • Metabolized into meprobamate • Acts on GABA-A; similar to barbiturates/BZD • Sedative, relaxant, euphoric; synergy w/ opiates • Abuse increasing; 2012 - schedule IV • WD: anxiety, insomnia, HA, myalgia, tremors, hallucinations, paranoia • Tx: consider BZD taper (if 12-25 tab/day)

28. Gabapentin (Neurontin) • Increased availability of endogenous GABA, +/- action on GABA-B, ↓ glutamate release • Intranasal snorting: high similar to cocaine • Oral use: similar to EtOH, BZD • WD: depression, anxiety, insomnia, depersonalization, paresthesias, delirium • Tx: taper for doses >1800 mg/d

29. Pregabalin (Lyrica) • Similar to gabapentin • Higher potency, quicker absorption, ↑ bioavailability • Euphoric, dissociative effects; tolerance • WD: agitation, tremor, ↑ HR, ↑ BP • Tx: 1-wk taper (for doses > 300 mg/d)

30. Topiramate (Topamax) • Augments GABA action • Antagonizes AMPA/kainate glutamate receptor • Often requested for wt loss properties • Emerging usefulness in EtOH and stimulant dependence • Literature indicates little potential for abuse • SE – somnolence, memory problems, paresthesias

32. Opiate Intoxication and Tolerance • Heroin: fine china vs. black tar • μ, δ, κ, σ receptors • Analgesia, modulation of respiration, miosis, gut motility; trigger DA release in nucleus accumbens - euphoria • Tolerance: receptor desensitization, AChdownregulation, cAMPupregulation

33. Opiate Overdose • Heroin, morphine, oxycodone, hydrocodone, methadone • AMS, stupor, miosis • ↓BP, ↓HR, slow shallow breaths, pulmonary edema • Motionless in a cold environment: • ↓temp, rhabdomyolysis, renal failure • Meperidine (Demerol), propoxyphene (Darvon), tramadol (Ultram) – mydriasis, Sz • Assess responsiveness, airway protection • Look for fentanyl patches • Tx: naloxone (Narcan) 0.04-0.5-1-2-4-10 mg IV q 2 min • Watch out for concurrent acetaminophen O/D (Norco, Percocet)

35. Opiate Withdrawal • Morphine, heroin – 6-12 hrs, methadone 36-48 hrs; last ≈ 2 wks • Activation of cholinergic and noradrenergic systems • Symptoms and signs – COWS • Nausea, diarrhea, cramping, lacrimation, rhinorrhea, diaphoresis, chills • Irritability, anxiety, insomnia, yawning, ↑HR, ↑BP • Opiate substitution • Methadone taper – daily, 20-30 d; most Sx at the end; few SE • Buprenorphine – few studies, varying doses/duration • Tramadol – limited literature, similar effectiveness to buprenorphine • α-2 agonists – modulate noradrenergic hyperactivity • Clonidine 0.1-0.3 mg tid x 2-4 days, taper over 7 days • Reduces WD Sx; increases # who completed WD (vs. placebo) • SE: drowsiness, dizziness, hypotension, dry mouth • Sxtx: acetaminophen, donnatal, loperamide, hydroxyzine, melatonin

36. Tx of Opiate Dependence • Substitute therapy • Methadone; 60-100 mg/d; QTc monitoring • Buprenorphine; 8-24 mg/d • Pure (Subutex) or combo with naloxone (Suboxone) • Antagonist therapy • Oral naltrexone; 50 mg/d • Injectable naltrexone; 380 mg/d

37. Stimulants

39. Classic Stimulants Cocaine Amphetamines Speed/crack/crystal meth, Rx (Adderall, Dexedrine) Besides transporter inhibition, ↑DA, NE>serotonin release, MAOI Effects last hours Related stimulant: methylphenidate (Ritalin) • Hydrochloride salt vs. free-base (crack) • DA, NE, serotonin uptake transporter inhibition • Lasts 30-60 min • Beware of combos: “speedball”, cocoethylene Euphoria, ↑ libido, ↓ appetite, ↑ concentration Sleeplessness, anxiety, paranoia, aggression

41. Classic Stimulants: Intoxication • Adrenergic stimulation (α,β), DA, serotonin (release, ↓re-uptake) • ↑BP, ↑HR, ↑temp, mydriasis • Dry mucous membranes and diaphoresis • Agitation, delirium, hypertonia, seizures • Vasospasm (myocardial, cerebral), arrhythmia • Rhabdomyolysis, renal/hepatic toxicity • Tx: lorazepam, haloperidol, labetalol for HTN; nitrates/CCB for chest pain; cooling

42. Stimulant O/D: Tx Considerations • Avoid 3Ps • Physical restraints • Phenothiazines in escalating doses • Psychiatric ward • Use ART • Acceptance (explanation, reassurance) • Reduce stimuli (dark, quiet environment) • Talkdown

43. Stimulant Withdrawal • Chronic use ↓ glutamate, DA, serotonin • WD (“tweaking”) w/i 24 hrs of last dose • “Crash” – acute, 1wk; subacute – 2-3 wks • Hyperarousal: craving, agitation, vivid dreams • Reversed vegetative: hypersomnia, ↓ energy, ↑appetite • Anxiety: dysphoria, anhedonia, paranoia, ψmotor slowing

44. Tx of Stimulant WD and Dependence • No proven tx, but a number of research avenues • Modafinil: mild stimulant, ↑ glutamate; blocks euphoria • May attenuate cocaine w/d • Not effective for methamphetamine dependence • GABAergics for maintenance • Vigabatrin, topiramate • Disulfiram • Increases cocaine/DA levels, unpleasant anxiety • Cocaine and methamphetamine vaccines • Stimulate production of Ab which prevent stimulants’ entrance into CNS

46. Ecstasy/MDMA • 3,4-methylenedioxymethamphetamine • Serotonin > DA/NE reuptake inhibition • Onset 30 min, last 4 hrs • Intense sensual experiences, empathy, sociability, insomnia, ↓appetite • ↑Temp, ↑BP, ↑HR, mydriasis, diaphoresis, trismus • Serotonin syndrome, hyponatremia, dehydration • No medications for tx of mild intoxication or WD • Dependence rare, largely psychological

48. Bath Salts • Cathinone (Khat plant) derivatives, stimulants • Mephedrone, methylenedioxypyrovalerone • Mephedrone: more stimulant, onset/action 30-60 min • MDPV: more hallucinatory, onset 1 hr, lasts 2-3 hrs • DA, serotonin, NE reuptake inhibition • Euphoria, hallucinations → insomnia, paranoia • Agitation, twitches, ↑HR, ↑BP, ↑ temp, mydriasis, Sz • Rhabdomyolysis, renal failure, MI, excited delirium • WD: very severe cravings, fatigue, irritability; 1-2 d • Tx: cooling, hydration, lorazepam, haloperidol

49. Albuterol • Stimulant-like (ᵦ-adrenergic) • Clenbuterol – pill, abused by body-builders • Frequent canister exchange – red flag • Spray on paper, dry, inhale powder • ↑HR, ↓BP, tremor, agitation • Tx: observation; consider propranolol