Drug Intoxication and Withdrawal

1. Drug Intoxication and Withdrawal Alexander Chyorny, MD alexander.chyorny@hhs.sccgov.org November 2013

2. Neurotransmitters-101 • Dopamine pathway – learning, pleasure • Serotonin pathway – regulates mood • Opioid pathway – antinociceptive • Noradrenergic – alertness, decision-making • Glutamate – excitation • GABA, acetylcholine – inhibition

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

4. “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

5. Universal Withdrawal Symptoms • 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)

6. 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

7. General Approach to O/D • Airway • Breathing • Circulation Coma cocktail • Thiamine 100 mg • 1 amp of D50 • Naloxone 2 mg

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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)

17. 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

18. 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)

19. 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

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

21. 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 • Consider concurrent acetaminophen O/D (Norco, Percocet)

22. 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

23. 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 • Injectablenaltrexone; 380 mg/d

24. Stimulants

25. Classic Stimulants Cocaine Amphetamines Speed/crack/crystal meth, Rx (Adderal, 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Bath Salts • Mephedrone, methylenedioxypyrovalerone • Mephedrone: more stimulant, onset/action 30-60 min • MDPV: more hallucinatory, onset 1 hr, lasts 2-3 hrs • Cathinone (Khat plant) derivatives, stimulants • 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

32. 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

33. Bupropion (Wellbutrin) • DA and NE reuptake inhibitor, nicotinic antagonist • Chemically similar to stimulants • Antidepressant, no wt gain or sexual dysfunction • Abused intranasally; high similar to cocaine, but less intense • Seizure with high doses (>600 mg/d) • WD rare; anxiety, lethargy, irritability • Tx: gradual taper

34. Selective Serotonin Reuptake Inhibitors • Intoxication: serotonin syndrome (usually drug combinations) • Flushing, fever, diaphoresis • Trismus, tremor, irritability • Tx: lorazepam, consider cyproheptadine • WD: anxiety, crying, dizziness, HA, nausea, insomnia, vivid dreams, tremor

35. Quetiapine (Seroquel) • Antihistaminic and anticholinergic effects • Sedative, anxiolytic; may ↓amphetamine craving • ↑blood methadone levels • 80% of opioidmisusers exposed to quetiapine • Intranasal and intravenous use described • WD: insomnia, anxiety • Taper not needed for low dose (<200 mg/d)

36. Steroids • Anabolic-androgenic; testosterone derivatives • Androstenedione, DHEA – OTC precursors • Frequent co-dependence with opioids • ↑Muscle mass, ↑strength, ↓fat; appearance, performance, sense of well-being • Excessive dose – mania, psychosis, hepatotoxic • WD: hypogonadism, fatigue, HA, myalgia, insomnia, depression • Tx (rarely needed): gradual tapering of injectable testosterone, guided by trough levels

37. Antihistamines • Promethazine (Phenergan),diphenhydramine (Benadryl), TCAs, baclofen • Potentiate opiates; high dose – hallucinations • Anticholinergic properties: “Hot as hare, dry as a bone, red as beet, mad as hatter” • Mydriasis, ↑HR, ↑BP, urinary retention, Sz • QT prolongation • Tx: tincture of time

38. Dissociatives - PCP • Phencyclidine (PCP, angel dust) • NMDA agonist, anticholinergic, opioid agonist, α-adrenergic, dopaminergic • Intoxication: violent agitation, bizarre behavior, lethargy – fluctuating delirium • Tx: lorazepam and haloperidol

39. Dissociatives - Ketamine • Onset – 5-30 min, lasts up to 3 hrs • Antagonist at NMDA, agonist at μ–opioid receptor • Anticholinergic, potentiates GABA, releases DA • Hallucinations, distortions of time/space • Dissociation, depersonalization – “K-hole” • OD: non-lethal; prone to accidents; abdominal pain, dizziness, lower urinary tract Sx; ↑ HR • WD: anxiety, craving, +/- tremor, diaphoresis • Methoxetamine – slower onset, longer duration

40. Dextromethorphan • OTC component of cough syrup or tablet • Synthetic analog of codeine; σ-opioid receptor • Dissociative in doses > 7mg/kg (metabolite dextrophan – NMDA antagonist); serotomimetic • Stimulant, euphoria→hallucinations→sedation, disassociation • ↑BP, ↑HR, respiratory depression, mydriasis • Utox – may cross-react with PCP assay • Effects short-lived; no dependence/withdrawal

41. Caffeine • Most widely used psychoactive drug worldwide • Stimulant; adenosine receptor antagonist • ↑NE and DA levels; ↑ alertness, coordination • Intoxication: ↑HR, tremor • WD: HA, fatigue, difficulty concentrating, depression, irritability, nausea, myalgia • start in 12-24 hrs, last 2-9 days

42. Tobacco • Activation of nicotinic cholinergic receptors • DA release; also glutamate/GABA • Enhanced performance, elevated mood, ↓ wt • WD: anxiety, irritability, depression, insomnia • Nicotine substitutes: gum, patch, e-cigarette • Partial agonists: cytisine, varenicline • Bupropion SR: inhibits DA and NE reuptake • Nortriptyline: similar effects, lesser abuse

43. Marijuana/Cannabis • Most widely used illicit drug worldwide • Hashish vs. sinsemilla (skunk): Δ9-THC/cannabidiol content • Cannabis receptor, NE release, dopaminergic, anticholinergic • Intoxication: euphoria, giggling, perceptual distortion, sedation • Later: hunger, conjunctival injection, dry mouth, ↑HR; panic, psychosis • Consider propranolol for CV effects, lorazepam for anxiety • WD: anxiety, insomnia, ↓appetite, nausea, diarrhea, abdominal pain, anger, HA, chills • Sx start w/i 24 hrs of cessation, last up to 28 d • Small studies of dronabinol, Li, buspirone, zolpidem • No medications currently recommended for tx of WD or dependence

44. Hallucinogens • Lysergic acid diethylamide, psilocybin, mescaline, DMT (dimethyltryptamine) • Serotonin agonists • Hallucinations, synesthesia, mild euphoria, time distortions, religious experiences, anxiety • Mydriasis, hyperthermia • Tx: time, lorazepam • Withdrawal: non-existent

45. Salvia Divinorum • Agonist at κ–opioid receptors; secondary effects – cannabinoid, serotonin, DA • Onset 30 sec, lasts 20-30 min • Vivid colors/shapes, hallucinations, synesthesia • OD: dysphoria, anxiety, psychosis • WD: not well described; possible GI effects

46. Inhalants • Volatile solvents • Enhance GABA-A, inhibit NMDA; ↑DA • Euphoria, “drunkenness” • Lethargy, confusion, HA, restlessness, incoordination • Alkyl nitrites • Smooth muscle relaxants, ↑libido, euphoria • Nausea, ↓BP, HA; hemolysis, methemoglobinemia • N2O • Euphoria, distortion of sensation/time/space, anesthesia • Oxidizes B12, resulting in deficiency • WD: craving; no physical signs; Tx: observation/support

47. References • Cami J, Farre M. Drug addiction. NEJM 2003; 349:975-86 • Mokhesi B. et al. Adult toxicology in critical care. Chest 2003; 123:577-92, 897-921 • Kosten T, O’Connor, P. Management of drug and alcohol withdrawal. NEJM 2003; 348:1786-95 • Lingford-Hughes AR, et al. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity. J Psychopharmacology 2012; 26:899–952 • Amato L. et al. Efficacy and safety of pharmacological interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Library 2011, Issue 6 • Loperz-Munoz F. The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines. J Anxiety Disord 2011; 25:554–62 • Parr JM et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction 2008; 104:13–24 • Dell’osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? European Psychiatry 2013; 28:7–20 • Reeves R. Benzodiazepines and low-dose quetiapine in prison: guideline, education, and peer comparison to reduce prescriptions. J Correct Health Care 2012; 18:45-52 • Snead O, Gibson K. γ-Hydroxybutyric acid. NEJM 2005; 352:2721-32 • Wojtowitz JM et al. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone. CJEM 2008;10:69-74

48. Recoppa L., et al. Gabapentin abuse in inmates with prior history of cocaine dependence. American J on Addictions 2004; 13:321-3 • Gabapentin and pregabalin: abuse and addiction. Rev Prescrire 2012; 340:116-8 • Gahr M et al. Concerns about pregabalin: further experience with its potential of causing addictive behaviors. J Addict Med 2013;7:147–9 • Reeves RR et al. Carisoprodol: update on abuse potential and legal status. Southern Medical Journal 2012; 105:619-23 • Victorri-Vigneau C et al. Pharmacoepidemiologicalcharacterisation of zolpidem and zopiclone usage. Eur J ClinPharmacol 2013; epub • Sporer, K. Acute heroin overdose. Ann Int Med 1999; 130:584-90 • Boyer E. Management of opioid analgesic overdose. NEJM 2012; 367:146-55 • Threlkeld M et al. Tramadol versus buprenorphine for the management of acute heroin withdrawal. American J on Addictions, 2006; 15:186–91 • Gowing L et al. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochraine Library 2009, Issue 3 • Lobmaier P et al. The pharmacological treatment of opioid addiction. Eur J Clin Pharmacol 2010; 66:537–45 • Fareed A et al. Heroin anticraving medications. American J Drug and Alcohol Abuse, 2010; 36:332–341

49. Lee MR. The history of ephedra (ma huang). R Coll Physicians Edinb 2011; 41:78–84 • Snelders S, Pieters T. Speed in the Third Reich: metamphetamine (Pervitin) use and a drug history from below. Soc History Med 2011; 24:686–99 • Panenka WJ et al. Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug and Alcohol Dependence 2013; 129:167–79 • Freye, E. Pharmacology and abuse of cocaine, amphetamines, ecstasy, and related designer drugs. Springer Science 2009. • Shoptaw SJ, Kao U,Heinzerling K, Ling W. Treatment for amphetamine withdrawal. Cochrane Library 2009, Issue 2 • Kampman KM. What’s new in the treatment of cocaine addiction? Curr Psychiatry Rep 2010; 12:441–7 • Winder GS et al. Are “Bath Salts” the next generation of stimulant abuse? J Subst Abuse Treat 2013; 44:42–45 • Zawilska JB, Wojcieszak J. Designer cathinones—an emerging class of novel recreational drugs. Forensic Science Internat 2013; 231:42–53 • Boucher A. et al. Salbutamol misuse or abuse with fatal outcome: A case-report. Hum Exp Toxicol 2011 30: 1869-71

50. Yoon G, Westermeyer J. Intranasal bupropion abuse: case report. American J on Addictions 2013; 22:180 • Reeves RR, Ladner ME. Additional evidence of the abuse potential of bupropion. J Clinical Psychopharmacology 2013; 33:584-5 • Nielsen M et al. What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction 2011; 107:900–8 • McLarnon ME et al. Characteristics of quetiapine misuse among clients of a community-based methadone maintenance program. J Clin Psychopharmacology 2012; 32:721-3 • Tamburello AC et al. Successful removal of quetiapine from a correctional formulary. J Am Acad Psychiatry Law 2012; 40:502–8 • Kanayama G et al. Anabolic–androgenic steroid dependence: an emerging disorder. Addiction 2009; 104:1966–78 • Shapiro B et al. Promethazine misuse among methadone maintenance patients and community-based injection drug users. J Addict Med 2013;7:96–101 • Corazza O et al. From “Special K” to “Special M”: the evolution of the recreational use of ketamine and methoxetamine. CNS Neuroscience & Therapeutics 2013; 19:454–60 • Romanelli F, Smith KM. Dextromethorphan abuse: clinical effects and management. J Am Pharm Assoc. 2009; 49:e20–7