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Drug Intoxication and Withdrawal

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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 - PowerPoint PPT Presentation
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Drug Intoxication and Withdrawal Alexander Chyorny, MD November 2013

Drug Intoxication and Withdrawal

Drug Intoxication and WithdrawalAlexander Chyorny, MDNovember 2013Goals: to recognize and be able to treat acute intoxication and withdrawal from commonly abused substances (custody setting)1

12Pharmacological Treatment of Addiction

2 Age 24; oral cancer 1923-39; 1884 age 29 Uber Coca; Fleischl-Marxow morphine cocaine psychosis; quit 1896. Died: morphine 30 mg x 3. Halsted: started 1884, never completely quit, partially replaced by morphine; Howard Markel An Anatomy of Addiction.3Neurotransmitters-101Dopamine pathway learning, pleasureSerotonin pathway regulates moodOpioid pathway antinociceptiveCannabinoid appetite, pain, mood, memoryNoradrenergic alertness, decision-makingCholinergic memory, learning, arousalGlutamate excitation (NMDA, AMPA receptors)GABA inhibition

1-2 with next. N-Methyl-D-aspartate4

Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse.Cam J, Farr M. N Engl J Med 2003;349:975-986.5Figure 4. Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse.As shown in the rat brain, mesocorticolimbic dopamine (DA) systems originating in the ventral tegmental area include projections from cell bodies of the ventral tegmental area to the nucleus accumbens, amygdala, and prefrontal cortex; glutamatergic (GLU) projections from the prefrontal cortex to the nucleus accumbens and the ventral tegmental area; and projections from the -aminobutyric acid (GABA) neurons of the nucleus accumbens to the prefrontal cortex. Opioid interneurons modulate the GABA-inhibitory action on the ventral tegmental area and influence the firing of norepinephrine (NE) neurons in the locus ceruleus. Serotonergic (5-HT) projections from the raphe nucleus extend to the ventral tegmental area and the nucleus accumbens. The figure shows the proposed sites of action of the various drugs of abuse in these circuits.Brain Reward System:Mesocorticolimbic Dopamine Pathwaymodulates pleasure needed for survival: eating/drinking, sex, nurturing

1.6The Substance and the Brain:NeuroadaptationYin-Yang homeostasis (activating/inhibiting)Intoxication temporary dominanceTolerance activating opposition, down-regulating receptorsWithdrawal removing the drug; biological effects much longer-lasting (days to years)Tx of WD substance mimetics (long-acting, taper); antagonizing opposition

2 with next7Yin and Yang

Drug cravingIrritabilityDysphoriaAnxietyInsomnia+ specific Sx of whatever agonist/antagonist receptor systems involvedImmediate phase: starts w/i hours, lasts daysProtracted phase: 6-18 mo (malaise, cravings)

1 min. Knock the stuffing out of you, sweep the feet from under you, drive you into the ground. Decreased DA in NAc, increased cortisol/stress.9General Assessment PrinciplesPrimary substance type, route, frequency, amount, time of last useComplications of use and withdrawalHistory of medication-assisted detoxConcurrent substances use/co-morbiditiesVital signsMental statusPupilsAbility to ambulateUrine toxicology2 min10General Approach to O/D Coma cocktailThiamine 100 mg1 amp of D50Naloxone 2 mg

1 min. 11

Alcohol: the Most Common and LethalGABA-A vs. glutamate/NMDAIndirect release of -endorphins and dopamineIn and Out: consider Pruno, hand-sanitizersIntoxication: slurred speech, confusion, ataxia, HR; assess ability to protect airwayWithdrawalEarly symptoms 6-24 hrsSeizures 12-48 hrsIsolated hallucinosis 12-48 hrsDelirium Tremens 48-96 hrs

3 min. Activates GABA-A inhibit inhibitor (disinhibition); higher doses sedation. Hallucinosis due to increase DA from decreased GABA inhibition13

1 min.14Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)Most commonly used instrument, validatedMeasures 10 subscalesNausea/vomitingTactile disturbancesTremorAuditory disturbancesDiaphoresisVisual disturbancesAnxietyHeadacheAgitationOrientationMax score 67, prophylaxis if >8, hospitalization if >15-20, ICU if > 351 min15EtOH: Cornerstones of TreatmentMonitor CIWA-Ar, VS; close observationEtOH substitutes benzodiazepinesSupportive treatmentQuiet, protective environmentCorrect hypovolemia/electrolytesThiamine (before glucose), MVI, folate, MgSO4Adjunct treatmentBeta-blockers, antipsychoticsAnticonvulsants2 agonists, muscle relaxants 2-3 min. Haloperidol (QT prolongation); carbamazepine; lamotrigine/topiramate (NMDA blockers); clonidine; baclofen16EtOH substitute: BenzodiazepinesFixed ATC vs. Sx-triggered dosingChlordiazepoxide (Librium)Longest-acting, active metabolites, auto-taper50-75 mg PO q 4-6 hrs, addl doses hourly prnLorazepam (Ativan)Medium-to-short acting, no active metabolitesPreferable in patients with advanced cirrhosis or high risk for oversedation (elderly, co-morbidities)1-2 mg PO q 4-6 hrs, hourly prn

2 min. Long-term tx: acamprosate, disulfiram, naltrexone; other topiramate, baclofen17EtOH DependenceMedication is adjunct to -social interventionAcamprosateNMDA partial antagonist; 666 mg tidDisulfiramBlocks alcohol dehydrogenase; nausea/flushing/HR; 250-500 mg/dNaltrexoneBlocks -opioid receptorsOral (50 mg/d) or injectable (380 mg/mo)BaclofenGABA-B agonist; anxiolytic; 10-20 mg tidTopiramateGABA, glutamate; slow titration to 300 mg/d

1 min. Acamprosate: RR 0.86, NNT 1018

BenzodiazepinesMost abused: short-acting alprazolam (Xanax)Most common: clonazepam (Klonopin), Valium (Diazepam), lorazepam (Ativan)Intoxication: similar to EtOHWD: beware of much longer half-lifeTx: chlordiazepoxide or clonazepam taperCarbamazepine as an alternative for w/d Sx1 min. ED: flumazenil IV (as a diagnostic tool)Consider adjunct melatonin20

Gamma-HydroxybutyrateActs on specific GHB and GABA-B receptorsEuphoric, inhibition, amnesia, hypotonia, somnolence, HR, BP, clonus, resp. depressionShort-acting; acute intoxication best treated with observation if no respiratory compromiseWD: similar to BZD/EtOH, less autonomic, more CNS insomnia, tremor, anxiety; 1 wkTx: consider BZD taper, baclofen2 min. GBL gamma-butyrolactone, 1,4-butanediol. Low doses GHB receptors, release glutamate; higher doses GABA-B, inhibitoryXyrem for fibromyalgia22

Z-drugsZolpidem, zaleplone, (es)zopicloneGABA-A receptor; effects similar to BZDHigh doses euphoria, exaltation, anxiolysisDependence, withdrawal similar to BZD (from sympathetic O/D to Sz)Tx: consider diazepam or gabapentin taper1 min. Abusers more likely females (70%), 40-50s. Could be injected24

Carisoprodol (Soma)Metabolized into meprobamateActs on GABA-A; similar to barbiturates/BZDSedative, relaxant, euphoric; synergy w/ opiatesAbuse increasing; 2012 - schedule IVWD: anxiety, insomnia, HA, myalgia, tremors, hallucinations, paranoiaTx: consider BZD taper (if 12-25 tab/day)1 min.26

Gabapentin (Neurontin)Increased availability of endogenous GABA, +/- action on GABA-B, glutamate releaseIntranasal snorting: high similar to cocaineOral use: similar to EtOH, BZDWD: depression, anxiety, insomnia, depersonalization, paresthesias, deliriumTx: taper for doses >1800 mg/d2 min. Widespread abuse first reported in correctional medicine literature28Pregabalin (Lyrica)Similar to gabapentinHigher potency, quicker absorption, bioavailabilityEuphoric, dissociative effects; toleranceWD: agitation, tremor, HR, BPTx: 1-wk taper (for doses > 300 mg/d)1min29Topiramate (Topamax)Augments GABA actionAntagonizes AMPA/kainate glutamate receptorOften requested for wt loss propertiesEmerging usefulness in EtOH and stimulant dependenceLiterature indicates little potential for abuseSE somnolence, memory problems, paresthesias1-2 min. PubMed as well as web sites; EtOH good data; cocaine, MDMA smaller studies; may potentiate pleasurable effects from meth.30

Opiate Intoxication and ToleranceHeroin: fine china vs. black tar, , , receptorsAnalgesia, modulation of respiration, miosis, gut motility; trigger DA release in nucleus accumbens - euphoriaTolerance: receptor desensitization, ACh downregulation, cAMP upregulation2 min. Endogenous peptides endorphines, enkephalins, dynorphins; exogenous morphine is a prototype. Uncoupling from G-protein.

32Opiate OverdoseHeroin, morphine, oxycodone, hydrocodone, methadoneAMS, stupor, miosisBP, HR, slow shallow breaths, pulmonary edemaMotionless in a cold environment:temp, rhabdomyolysis, renal failureMeperidine (Demerol), propoxyphene (Darvon), tramadol (Ultram) mydriasis, SzAssess responsiveness, airway protectionLook for fentanyl patchesTx: naloxone (Narcan) 0.04-0.5-1-2-4-10 mg IV q 2 minWatch out for concurrent acetaminophen O/D (Norco, Percocet)3min serotonin release, MAOIEffects last hoursRelated stimulant: methylphenidate (Ritalin)

Euphoria, libido, appetite, concentrationSleeplessness, anxiety, paranoia, aggression2min 39

1min 40Classic Stimulants: IntoxicationAdrenergic stimulation (,), DA, serotonin (release, re-uptake)BP, HR, temp, mydriasisDry mucous membranes and diaphoresisAgitation, delirium, hypertonia, seizures Vasospasm (myocardial, cerebral), arrhythmiaRhabdomyolysis, renal/hepatic toxicityTx: lorazepam, haloperidol, labetalol for HTN; nitrates/CCB for chest pain; cooling

2min Excited (agitated) delirium41Stimulant O/D: Tx ConsiderationsAvoid 3PsPhysical restraintsPhenothiazines in escalating dosesPsychiatric wardUse ARTAcceptance (explanation, reassurance)Reduce stimuli (dark, quiet environment)Talkdown1min42Stimulant WithdrawalChronic use glutamate, DA, serotoninWD (tweaking) w/i 24 hrs of last doseCrash acute, 1wk; subacute 2-3 wksHyperarousal: craving, agitation, vivid dreamsReversed vegetative: hypersomnia, energy, appetiteAnxiety: dysphoria, anhedonia, paranoia, motor slowing

1min Depletes glutamate, downregulates glutamatergic transmission43Tx of Stimulant WD and DependenceNo proven tx, but a number of research avenuesModafinil: mild stimulant, glutamate; blocks euphoriaMay attenuate cocaine w/dNot effective for methamphetamine dependenceGABAergics for maintenanceVigabatrin, topiramateDisulfiramIncreases cocaine/DA levels, unpleasant anxietyCocaine and methamphetamine vaccinesStimulate production of Ab which prevent stimulants entrance into CNS

1min Amineptine atypical TCA, stimulant-like; effective, but removed from the market. Mirtazapine ineffective for cocaine w/d, may be effective for meth dependence. Propranolol for cocaine? NAC promising (glutamate) Dopamine agonists (amantidine) not effective. 44

Ecstasy/MDMA3,4-methylenedioxymethamphetamineSerotonin > DA/NE reuptake inhibitionOnset 30 min, last 4 hrsIntense sensual experiences, empathy, sociability, insomnia, appetiteTemp, BP, HR, mydriasis, diaphoresis, trismusSerotonin syndrome, hyponatremia, dehydrationNo medications for tx of mild intoxication or WDDependence rare, largely psychological2min 46

Bath SaltsCathinone (Khat plant) derivatives, stimulantsMephedrone, methylenedioxypyrovaleroneMephedrone: more stimulant, onset/action 30-60 minMDPV: more hallucinatory, onset 1 hr, lasts 2-3 hrsDA, serotonin, NE reuptake inhibitionEuphoria, hallucinations insomnia, paranoiaAgitation, twitches, HR, BP, temp, mydriasis, SzRhabdomyolysis, renal failure, MI, excited deliriumWD: very severe cravings, fatigue, irritability; 1-2 dTx: cooling, hydration, lorazepam, haloperidol

2min MDPV more hallucinations, mephedrone more stimulant. Plant food. Meph, MMC Hammer. Very caustic to veins. Extremely addictive.48AlbuterolStimulant-like (-adrenergic)Clenbuterol pill, abused by body-buildersFrequent canister exchange red flagSpray on paper, dry, inhale powderHR, BP, tremor, agitationTx: observation; consider propranolol1min Beta-2> beta 1. ED: IV propranolol, potassium


InhalantsVolatile solventsEnhance GABA-A, inhibit NMDA; DAEuphoria, drunkennessLethargy, confusion, HA, restlessness, incoordinationAlkyl nitritesSmooth muscle relaxants, libido, euphoriaNausea, BP, HA; hemolysis, methemoglobinemiaN2OEuphoria, distortion of sensation/time/space, anesthesiaOxidizes B12, resulting in deficiencyWD: craving; no physical signs; Tx: observation/support1min Whippets, toluene, poppers. Huffing, chroming.51

Bupropion (Wellbutrin)DA and NE reuptake inhibitor, nicotinic antagonistChemically similar to stimulantsAntidepressant, no wt gain or sexual dysfunctionAbused intranasally; high similar to cocaine, but less intenseSeizure with high doses (>600 mg/d)WD rare; anxiety, lethargy, irritabilityTx: gradual taper2min Removed from many correctional formularies53Selective Serotonin Reuptake InhibitorsIntoxication: serotonin syndrome (usually drug combinations)Flushing, fever, diaphoresisTrismus, tremor, irritabilityTx: lorazepam, consider cyproheptadineWD: anxiety, crying, dizziness, HA, nausea, insomnia, vivid dreams, tremor1min Under-recognized! Half-life dependent.54

Quetiapine (Seroquel)Antihistaminic and anticholinergic effectsSedative, anxiolytic; may amphetamine cravingblood methadone levels80% of opioid misusers exposed to quetiapineIntranasal and intravenous use describedWD: insomnia, anxietyTaper not needed for low dose ( 7mg/kg (metabolite dextrophan NMDA antagonist); serotomimeticStimulant, euphoriahallucinationssedation, disassociationBP, HR, respiratory depression, mydriasisUtox may cross-react with PCP assayEffects short-lived; no dependence/withdrawal2min Skittles, Robo, CCC, Dex. 9-10% abuse DM. Free-base extraction crystals. Serotonin syndrome. Naloxone for respiratory depression65

CaffeineMost widely used psychoactive drug worldwideStimulant; adenosine receptor antagonistNE and DA levels; alertness, coordinationIntoxication: HR, tremorWD: HA, fatigue, difficulty concentrating, depression, irritability, nausea, myalgiastart in 12-24 hrs, last 2-9 days1min 67

TobaccoActivation of nicotinic cholinergic receptorsDopamine release; also glutamate/GABAEnhanced performance, elevated mood, wtWD: anxiety, irritability, depression, insomniaNicotine substitutes: gum, patch, e-cigarette Partial agonists: cytisine, vareniclineBupropion SR: inhibits DA and NE reuptakeNortriptyline: similar effects, lesser abuse

1min Activation of GABA diminishes with time, while glutamate persists; lozenges, vaporizer, nasal spray; SE agonists nausea; clonidine. Hunger.Pre-release intent strong predictor of post-release quit rates. Quitline provision to releasees should be considered. Vaccine in development.69

Marijuana/CannabisMost widely used illicit drug worldwideHashish vs. sinsemilla (skunk): 9-THC/cannabidiol contentCannabis receptor, NE release, dopaminergic, anticholinergicIntoxication: euphoria, giggling, perceptual distortion, sedationLater: hunger, conjunctival injection, dry mouth, HR; panic, psychosisConsider propranolol for CV effects, lorazepam for anxietyWD: anxiety, insomnia, appetite, nausea, diarrhea, abdominal pain, anger, HA, chillsSx start w/i 24 hrs of cessation, last up to 28 dSmall studies of dronabinol, Li, buspirone, zolpidemNo medications currently recommended for tx of WD or dependence2min CWS cannabis withdrawal scale; correlates with impairment to ADLs; THC/cannabidiol content (3.4/3.4 vs. 12-18/1.5). Psychotic break: higher chance of using sinsemilla. 71

HallucinogensLysergic acid diethylamide, psilocybin, mescaline, DMT (dimethyltryptamine)Serotonin agonistsHallucinations, synesthesia, mild euphoria, time distortions, religious experiences, anxietyMydriasis, hyperthermiaTx: time, lorazepamWithdrawal: non-existent1min 5HT2A receptor. Ibogaine: a hallucinogen with anti-addictive properties73

Salvia DivinorumAgonist at opioid receptors; secondary effects cannabinoid, serotonin, DAOnset 30 sec, lasts 20-30 minVivid colors/shapes, hallucinations, synesthesiaOD: dysphoria, anxiety, psychosisWD: not well described; possible GI effects1min Sally D, Divine Sage, Magic Mint, Purple Sticky. Salvinorin A. Effects on other transmitters and receptor systems complex; may cause dysphoria by DA75