Transcript Drug Intoxication and Withdrawal - CA

Drug Intoxication and
Withdrawal
Alexander Chyorny, MD
November 2013
Pharmacological Treatment of
Addiction
Neurotransmitters-101
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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
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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
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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
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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
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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
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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)
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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)
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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
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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
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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
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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
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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)
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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)
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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
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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
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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
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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
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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
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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