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Drug Intoxication and Withdrawal Alexander Chyorny, MD November 2013 Pharmacological Treatment of Addiction 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 Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse. Camí J, Farré M. N Engl J Med 2003;349:975-986. Brain Reward System: Mesocorticolimbic Dopamine Pathway modulates pleasure needed for survival: eating/drinking, sex, nurturing “The Substance” and the Brain: Neuroadaptation • Yin-Yang – homeostasis (activating/inhibiting) • Intoxication – temporary dominance • Tolerance – activating opposition, downregulating receptors • Withdrawal – removing the drug; biological effects much longer-lasting (days to years) • Tx of WD – substance mimetics (long-acting, taper); antagonizing opposition Yin and Yang • • • • • • 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) 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 General Approach to O/D Coma cocktail – Thiamine 100 mg – 1 amp of D50 – Naloxone 2 mg 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 Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) • Most commonly used instrument, validated • Measures 10 subscales – Nausea/vomiting – Tremor – Diaphoresis – Anxiety – Agitation Tactile disturbances Auditory disturbances Visual disturbances Headache Orientation • Max score 67, prophylaxis if >8, hospitalization if >15-20, ICU if > 35 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 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’l doses 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 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 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 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 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 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) 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 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) 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 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, ACh downregulation, cAMP upregulation 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) 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 • Sx tx: acetaminophen, donnatal, loperamide, hydroxyzine, melatonin 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 Stimulants Classic Stimulants Cocaine Amphetamines • Hydrochloride salt vs. freebase (crack) • DA, NE, serotonin uptake transporter inhibition • Lasts 30-60 min • Beware of combos: “speedball”, cocoethylene • Speed/crack/crystal meth, Rx (Adderall, Dexedrine) • Besides transporter inhibition, ↑DA, NE>serotonin release, MAOI • Effects last hours • Related stimulant: methylphenidate (Ritalin) Euphoria, ↑ libido, ↓ appetite, ↑ concentration Sleeplessness, anxiety, paranoia, aggression 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 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 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 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 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 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 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 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 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 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 Quetiapine (Seroquel) • • • • • • • Antihistaminic and anticholinergic effects Sedative, anxiolytic; may ↓amphetamine craving ↑blood methadone levels 80% of opioid misusers exposed to quetiapine Intranasal and intravenous use described WD: insomnia, anxiety Taper not needed for low dose (<200 mg/d) 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 Antihistamines • Promethazine (Phenergan),diphenhydramine (Benadryl), TCAs, baclofen • Potentiate opiates; high dose – hallucinations • Anticholinergic properties: “Hot as a hare, dry as a bone, red as a beet, mad as a hatter” • Mydriasis, ↑HR, ↑BP, urinary retention, Sz • QT prolongation • Tx: tincture of time 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 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 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 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 Tobacco • • • • • • • • Activation of nicotinic cholinergic receptors Dopamine 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 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 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 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