Drug Intoxication and Withdrawal Alexander Chyorny, MD November 2013.
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Transcript of Drug Intoxication and Withdrawal Alexander Chyorny, MD November 2013.
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, 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
• 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
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 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
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
Classic Stimulants
Cocaine• Hydrochloride salt vs. free-base
(crack)• DA, NE, serotonin uptake
transporter inhibition• Lasts 30-60 min• Beware of combos:
“speedball”, cocoethylene
Amphetamines• 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, ↑ concentrationSleeplessness, 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