Infections of the upper respiratory tract. Clinical syndromes.
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Acute Withdrawal Syndromes K. Scott Whitlow, DO, FAAEM Medical Toxicology/Emergency Medicine Clinical Professor - Emergency Medicine – TUCOM Director – Academic Affairs and DIO St. Joseph’s Medical Center - Stockton
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Acute Withdrawal Syndromes
K. Scott Whitlow, DO, FAAEMMedical Toxicology/Emergency Medicine
Clinical Professor -
Emergency Medicine – TUCOM
Director –
Academic Affairs and DIOSt. Joseph’s Medical Center -
Stockton
Objectives
•
Define physical and psychological dependence•
Define and recognize withdrawal
•
Review associated morbidity and mortality•
Understand that there are different withdrawal syndromes
•
Understand patho-physiology•
Gain confidence in treatment and management
Dependence
•
Physical•
Altered physiologic state resulting from continued administration of a xenobiotic
•
Psychological•
Overwhelming drive to continue administration of a substance for pleasure or to prevent withdrawal
Withdrawal
•
Defined•
Physical and emotional signs and symptoms precipitated by an abrupt cessation of a drug
•
Characteristics•
Pre-existing physiologic adaptation
•
Rapidly decreasing concentrations
Etiology
•
Sedative Hypnotic•
GHB, alcohol (#1 abuse drug in world), benzodiazepines, barbiturates
•
Opiate•
Stimulants
•
Amphetamines, cocaine, methamphetamine
•
SSRI•
Clonidine
•
Caffeine/Nicotine
Goals of Treatment
•
Relieve symptoms
•
Prevent complications•
Pharmacotherapy, Precautions
•
Evaluate and treat underlying psychiatric illness
•
Rehabilitation
Alcohol / Sedative Hypnotic Withdrawal
Epidemiology of ETOH Withdrawal in Healthcare Setting
•
8% all admitted pts •
16% post-op pts•
31% trauma pts•
Typically male•
3rd
or 4th
decades•
Beware of trying to characterize pts•
Severity does not change with age or gender
•
Australian study (etoh only)
•
Foy A, Kay J: The Incidence of alcohol -related problems and the risk of alcohol withdrawal in a general hospital population.Drug Alcohol Rev 1995;14:49-54
Pathophysiology
•
Chronic alcoholism effects balance between neurotransmitters
–
γ-aminobutyric acid (GABA) receptors desensitized resulting in reduce inhibitory effect
–
Alcohol inhibits N-methyl-D-aspartate (NMDA); receptors are up regulated resulting in excitation upon cessation of alcohol use
–
Alcohol also results in the release of endogenous opioids
Clinical Picture
•
Withdrawal is a CONTINUUM of progressive s/s•
S/S begin 6-12h post cessation•
Tremulousness•
Hallucinosis•
Misinterpretation of stimuli (illusions)•
Frank hallucinations
•
Abstinence seizures -
5-15%•
90% occur within 7-48h post cessation•
Only 5% with status epilepticus•
MAJOR Withdrawal•
DELERIUM TREMENS•
If cessation > 5 days, 5% will develop DT’s•
AMS, autonomic instability, diaphoresis•
50% have onset w/i 24-96h post cessation
Stages of ETOH Withdrawal
•
Stage 1: 6-8 hours following last drink
–
Tremor–
Anxiety
–
Hyper-reflexia–
Hypertension
–
Tachycardia–
Diaphoresis
–
Hyperthermia–
Nausea/vomiting
–
Insomnia–
Craving
Stage 2Stage 2 occurs within 12occurs within 12--24 hours with 24 hours with duration 1duration 1--3 days3 days
––Same as stage 1 Same as stage 1 plus plus audio/visual hallucinationsaudio/visual hallucinations
––Same as stage 1Same as stage 1--3 3 plusplus seizures*seizures*
Stage 3: occurs 12Stage 3: occurs 12--48 hours after last drink of alcohol48 hours after last drink of alcohol
Stage 4: occurs 3Stage 4: occurs 3--5 days 5 days after last drink of alcoholafter last drink of alcohol
––Delirium tremensDelirium tremens
*have been reported in as little as 2 hours after last drink
Gerard Clancy, M.D.
“Kindling Effect”
Repeated incidents of alcohol withdrawal increase in severity
•
Successively higher doses of benzodiazepines required upon repeated admissions
Associated Conditions
•
CNS trauma•
Liver dz•
Coagulopathy, hypoglycemia, hyperamonemia
•
Malnourishment•
Electrolyte abnormalities•
Vitamin deficiencies•
W/K syndrome•
Malnutrition
•
Rare today in setting of etoh abuse (1-3%)
•
Infectious processes•
AKA•
Dehydration
GHB Withdrawal
GammaGamma--OHOH
Somatomax Somatomax PM PM
AlcoverAlcover
Gamma HydrateGamma HydrateXyremXyrem
Natural Sleep 500Natural Sleep 500
GHB
GBL
BD
Blue Nitro 2.5gm/ozInvigorate 3.5gm/ozGH Gold 34gm/ozRenewTrient 1.98gm/6
Zen 4gm/oz Rejoov 3gm/ozInner G 2.25gm/oz
Introduction
•
Used as anesthetic agent –
1960•
Nutritional supplement
•
DOA•
Sexual enhancer
•
Incapacitator•
Narcolepsy
•
xyrem•
Treatment of withdrawal
•
GBL, 1-4 BTD•
Met to GHB
GHB and Analogs/Precursors GHB and Analogs/Precursors Gamma Butyrolactone (GBL) & 1,4Gamma Butyrolactone (GBL) & 1,4--
Butanediol (BD) Butanediol (BD)
NaOH + H2 Oin vitro
in vivoLactonase
Alcoholdehydrogenase
Aldehydedehydrogenase
gamma hydroxybutyrate, GHBGBL
GHB
Pathophysiology
•
Rapidly absorbed and eliminated•
Exerts effect at GHB receptors
•
Close resemblance to GABA•
Modulates both GABA a & b receptors
•
Down regulates inhibitory receptors
•
Releases excitatory neurotransmitter inhibition
•
Clinically similar to other sedative hypnotic / withdrawal syndromes
Clinical Picture
•
Withdrawal may begin w/i hours•
Can be VERY SEVERE
•
S/S:•
Early (1-24h):
•
Anxiety, restlessness, insomnia, n/v•
Progressive (1-6d):
•
Anxiety, restlessness, confusion, delirium, hallucinations, autonomic instability, diaphoresis
•
Episodic (7-14d)•
Anxiety, restlessness, confusion, hallucinations
•
May last up to 15d
Complications
•
Fluid and electrolyte imbalances•
Hyperpyrexia
•
Rhabdomyolysis•
Amnesia
•
Long Term cessation symptoms•
Anxiety, depression, insomnia
•
Mortality•
Etoh = 5-15%
•
Benzodiazepines 1%
•
GHB ?
Other Agents
•
Benzodiazepines•
Short acting
•
Onset w/i 24h
•
Long acting
•
Onset w/i 3-7d
•
Barbiturates•
Onset 8-36h
•
Seizures (common) w/i 2-8d
Management of Acute Withdrawal
•
Sedation
•
Liberal and aggressive use of benzodiazepines•
Diazepam
•
Lorazepam
•
Propofol, pentobarbital
•
Clonidine
•
? Anticonvulsants•
Carbamazepine
•
? Acamprosate –
no role in acute alcohol withdrawal•
Naltrexone
•
Endogenous opioid modulation –
decreases relapse from over 50% to 25%
•
Intubation, paralysis, general anesthesia
•
Cooling measures, S/S care•
IVF•
Studies: cbc, bmp, ck,VpH, cxr, ecg, CT, ?LP•
Rule out and/or treat other conditions
Drugs to AVOID in Acute Withdrawal
•
PO meds•
Difficult to administer
•
Prolonged onset of therapeutic effect•
Less effective
•
Phenothiazines•
Hypotension
•
Dystonia
•
Agitation
•
Butyrophenones•
Lower seizures threshold
Disposition
•
Admission•
Persistent seizures•
AMS•
Hallucinations
•
Delusions
•
Autonomic instability•
Despite adequate therapy
•
Co morbidities•
Psychosocial issues
•
Discharge•
Mild Moderate s/s•
s/s relieved with ED tx•
Good social support and controlled env.
Opiate/Opioid Withdrawal
Pathophysiology•
Opioids bind to specific receptors
•
µ,
,•
Agonist (1,2, )•
Agonist-antagonist •
(
agonist,
antagonist)
•
Antagonist •
(1, 2,
antagonist)
•
Partial agonist •
(1, 2 agonist,
antagonist)
•
Mostly inhibitory effects•
Inhibit cAMP
•
Abuse/tolerance•
Alters # or configuration of receptors•
Down regulates endogenous opioids
Opioid Withdrawal Syndrome
•
Cause:•
Antagonists or lack of access
•
Onset:•
Heroin: typically 12h after last dose•
Last up to 10d
•
Methadone: > 30h•
Last up to 14d
•
Clinically:•
mydriasis, piloerection, yawning, rhinorrhea, abdominal cramps, vomiting, agitation, altered vital signs
•
may resemble a severe viral syndrome
Management•
S/S care
•
Buprenorphine
•
More effective, stay in treatment longer, more likely to complete
•
SAMSHA Protocol –
must show s/s of physiologic withdrawal
•
Use clinical opiate withdrawal scale –
must score in 13 –
24 range to start
•
Needs DEA License
•
Induction Needs to be directly observed
•
Antiemetics
•
Metoclopramide
•
Ondansetron
•
Clonidine
•
Alpha-2 agonist
•
Decrease sympathetic outflow
•
Dose q6h
•
Opioids
•
Methadone ?
•
Blocks euphoria
•
T1/2 up to 50h
Select initial Suboxone®
or Subutex®
doseNote: The dosing of Suboxone® or Subutex® depends on the patient’s existing dose of long-acting opioid(labeled as the methadone-equivalent dose in the following table).METHADONE-EQUIVALENT DOSELast long-acting opioid dose ≤10 mg 10–40 mg 40–60 mgFirst day buprenorphine target dose 2-4 mg 4-8 mg 4-8 mgOptional supplementary dose Dose review Dose review Dose review(2–4 hours after first dose) not required not required required2-4 mg additionalif neededSecond day buprenorphine target dose 4 mg 8 mg (4-8 mg) 8 mg (6-10 mg)Third day buprenorphine target dose 6 mg (6-8 mg) 12 mg (8-12 mg) 12 mg (10-16 mg)See: National Clinical Guidelines on the Use of Buprenorphine in
the Management of Heroin Dependence. Canberra:National Drug Strategy, Commonwealth of Australia. 2001. Lintzeris N, Clark NC, et al.
Dose adjustment/stabilization following inductionYou should aim to have reached a suitable maintenance dose of Suboxone®
or Subutex®
within1-2 weeks.It takes from 3-7 days for steady-state blood levels to be achieved.After the patient is stabilized (2-3 days), once-a-day dosing should be possible.Doses should be titrated according to regular review of the following clinical signs/symptoms:-
Intoxication, withdrawal, and cravings over the past 24 hours-
Additional drug use and the patient’s reason for use of illicit street drugs or prescription opioids-
Side effects or other adverse events-
Adherence to dosing regimen-
Patient’s expressed satisfaction
Adjustments to the Suboxone®
(buprenorphine HCl/naloxone HCI dihydrate) or Subutex®
(buprenorphineHCl) sublingual tablets dose should be made:-
At 3-
to 7-day intervals-
In 2-
to 4-mg increases or 2-mg decreases if the patient experiences intoxication (notwithdrawal effects)
Stimulant Withdrawal
Cocaine and Amphetamines
•
Effect:•
norepinepherine, dopamine, serotonin•
Increases release/blocks reuptake in acute intoxication
•
Depletes from long term use
•
Block monoamine transporter proteins•
Therefore inhibiting re-uptake of and increasing levels of synaptic monamines
•
Reduces post-synaptic DA receptors
•
Withdrawal:•
Lasts 8-48h•
Minimal s/s may last up to 14d
•
S/S = dysphoria, sleep disturbances, appetite changes, motor disturbances•
May look like depressive state
Management
•
S/S care
•
NO meds reduce severity of s/s
•
Propranolol may improve Tx retention
•
Possibly antidepressants after withdrawal
THC Withdrawal•
Withdrawal -
controversial
•
Irritability, insomnia, depression, anxiety, anorexia, craving
•
1-2 days after cessation
•
Resolves w/in 10 days
•
? Related to increased adenylyl cyclase activity and Protein Kinase A in the cerebellum
•
? treatments
•
Cannabis dependence is growing•
Is becoming clinically significant
•
Abuse disorder
•
Cyclical vomiting
Clonidine Withdrawal
Pathophysiology
•
Central and peripheral alpha-2 agonist•
Blocks sympathetic outflow
•
Elimination t1/2 of 14h
•
24h post discontinuation•
efferent sympathetic activity
•
NE
Clonidine Withdrawal Syndrome
•
S/S:HA, flushing, sweating, hallucinations, anxiety, tremor, palpitations, vomiting
•
May resemble pheochromocytoma crisis•
May mimic opiate withdrawal•
Encephalopathy reported•
W/I 24-48h BP at or higher than pretx•
May occur after 1 dose•
May occur even with gradual discontinuation•
May be fatal•
Worse if on long term high dose tx
•
Concurrent B-blocker use will worsen s/s
Management
•
Tx:•
S/S care
•
Reinstitute clonidine
•
B-blockers ABSOLUTELY CONTRAINDICATED
•
May worsen rebound hypertension
Includes
•
TCA
•
MAOI
•
SSRI/SSNRI
Pathophysiology
•
SSRI’s selectively inhibit presynaptic reuptake of serotonin
•
Withdrawal•
? From serotonin receptor down regulation
•
Alterations in serotonergic activity
•
Interactions with other neurotransmitters
•
Indiv. Biologic/cognitive sensitivity
Syndrome
•
Pt on SSRI for 1 month or more•
S/S of withdrawal occur w/i 1-7d
•
May last up to 21d•
Must have 2 or more of:•
Dizziness/lightheadedness, paraesthesias, anxiety, diarrhea, fatigue, ataxia, HA, insomnia,irritability, n/v, tremor, visual disturbances,dysphoria
•
Above must cause:•
Functional impairment
•
Other causes excluded
•
Not life threatening •
Does not occur with taper
•
Venlafaxine most common
Management
•
S/S care
•
Rapidly resolves with reinstatement
Caffeine/Nicotine Withdrawal
Caffeine
•
Antagonizes inhibitory effects of adenosine•
Occupies adenosine receptors•
receptor affinity for adenosine•
Exposure = HR, RR, GI motility, gastric acid secretion, and motor actv•
Chronic exposure = tolerance
•
Withdrawal causes strong adenosine effect•
HA, fatigue, hypersomnia, anxiety, depression, •
Peak 24-48h•
Lasts 1 week
•
Tx•
S/S
Nicotine
•
Affects nicotinic receptors•
Excitatory and inhibitory effects
•
Autonomic ganglia, adrenal medulla, CNS, spinal cord, neuromuscular junction, carotid and aortic bodies
•
Usual cause is smoking cessation•
Withdrawal
•
Cigarette craving and subjective dysphoria•
Irritability, restlessness, HR, BP•
Usually resolves over 3-4 weeks•
Craving may last for months
Management
•
S/S care
•
Nicotine replacement•
Gum
•
Patch
•
Buproprion
•
Varenicline
•
A4b2 nicotinic acetylcholine receptor partial agonist
•
Inhibits dopamine activation
•
Mood disturbances
Summary•
ALWAYS consider withdrawal in diff dx!!!
•
chronic drug administration•
Physical dependent patient
•
Abrupt cessation•
Antagonists or lack of access
•
S/S (signs and symptoms) tend to be opposite of intended therapeutic effects
•
Clinically see: ie: OPIATES:•
mydriasis, piloerection, yawning, rhinorrhea, abdominal cramps,
vomiting, diarrhea, agitation, altered vital signs
References
•
Goldfrank’s Toxicologic Emergencies, 7th
Ed. Chapters 59 and 72.
•
Dyer, JE, et al.Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001;37(2):147-53.
•
Kosten, TR, et al.Management of drug and alcohol withdrawal.N Engl J Med 2003;348:1786-95.
•
Webster,J, et al. Aspects of tolerability of centrally acting antihypertensive drugs.J Cardiovasc Pharm 1996;27(suppl.3):49-54.
•
Black, K, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria.J Psychiatry Neurosci 2000;25(3):255-61.
Acknowledgements
•
•
S.R. Rose, PharmD, DABAT
•
Stacy A. Voils, Pharm.D.
•
Brent Morgan, MD
