Management of withdrawalProf.Dr.Aznan Lelo,PhD,SpFK

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi & TerapeutikFak.KedokteranU S U

Withdrawal SyndromeThe characteristic group of signs and symptoms that typically develop after : = a rapid or = marked decrease or = discontinuation of a substance of dependence, which may or may not be clinically significantly of life threatening.

The characteristic group of signs and symptoms that typically develop after : = a rapid or = marked decrease or = discontinuation of a substance of dependence, which may or may not be clinically significantly of life threatening.

Withdrawal SyndromeWithdrawal severity and duration depend on several factors:

Nature of substanceHalf-life and duration of actionLength of time substance usedAmount usedUse of other substances Presence of other medical and psychiatric conditions Individual biopsychosocial variables

Alcohol Withdrawal

Delirium Tremens

Approximately 5% of patients withdrawing from alcohol will experience delirium tremens characterized by:HallucinationsDisorientationTachycardiaHypertensionLow grade feverAgitationDiaphoresisTime scaleMinor withdrawal symptoms = 6-12 hoursAlcoholic hallucinations = 12-24 hoursWithdrawal seizures = 24-48 hoursDelirium Tremens = 48-72 hoursRisk factors for DTs includeHistory of sustained drinkingHistory of previous DTsAge>30>2 days since the last drink

*Our patient= 17 HIGH!3400050050Minimal to mild= 15

Withdrawal Assessment Clinical Institute Withdrawal Assessment-Alcohol, revised (CIWA-Ar)

NauseaTremorDiaphoresisAnxietyAuditory disturbancesOrientationAgitationTactile disturbancesVisual disturbancesHeadaches

Withdrawal Severity: 0 (not present) to 67 (extreme); Higher = >risk8-10 Mild Supportive, no Meds (i.e. Social Detox)10-15 Moderate - Some meds (BZP) (i.e. Medically Supported Detox)15/> Severe - DT Risk (i.e.. Hospitalization)N.B. May also be used to monitor recovery and medication management

Treatment**Benzodiazepines-

The preferred agents for treating the symptoms of alcohol withdrawal syndrome.

Diazepam and Chlordiazepoxide are long acting agents. The long half life makes withdrawal symptoms and rebound from the Benzos less likely to occur.Ex: Diazepam 5mg IV (2.5mg/min). If initial dose is not effective, repeat in 5-10minutes. If the second dose is not effective, use 10mg for 3rd and 4th doses every 5-10 minutes. If not effective, use 20mg for the 5th and subsequent doses until sedation is achieved,. Use 5-20mg/hour as needed to maintain light somnolence (5)

With appropriate treatment, mortality rate from DTs is

Alcohol withdrawal treatmentShort acting benzos like lorazepam may be better for pts who are elderly or have substantial liver disease and prolonged sedation is a risk.

Diazepam, Lorazepam may be administered parenterally when oral dosing is impossible.

Fixed Dose or Loading dose vs. symptomatic therapyFixed dose allows stable control of symptoms followed by a 4-7 day taperSymptomatic- Pts use less benzodiazepines but must have trained/available nurses to administer

Choice of a BZD Long half-life (chlordiazepoxide, diazepam): Seizures: ~ 58% Distress (smoother detox)

Shorter half-life (lorazepam, oxazepam) Oversedation Safer in elderly / liver impairment

Alcohol withdrawal treatmentB-Blockers in conjunction with benzos to control persistent HTN and tachycardia. There is no evidence these improve outcome.

Carbamazepine can be used to treat the seizures, this is done more in Europe than in the US.

Haldol can be used to treat agitation and hallucinationsNutrition support: Thiamine to avoid Wernicke-Korskoff, Mg supplementation, folate if needed.

Acamprosate, disulfiram appropriate for abstinence therapy NOT withdrawal

DetoxificationAlcohol WithdrawalAutonomic dysfunction-Insomnia-AnxietyOnset 8+ hrs, Peak 48hrs, Diminished 5dys, Duration 3-6 months Withdrawal Syndromes:Mild, moderate or life-threatening severity (increased severity with BAL>100mg/dl)3% Withdrawal Seizures (w/in 48hrs of abstinence)Delirium Tremens (DTs) Medical Emergency! (w/in 48-72hrs of abstinence)(4-5% Prev., M&M

Sample Medication ProtocolDays 1-2 : Lorezepan 1-2 mg three times a dayDays 3-4: Lorezepam 1-2 mg twice dailyDay 5: Lorezepam 1-2mg, daily *Adjust dosage and duration for intoxication or prolonged withdrawal

Adjunctive treatments:Seizure history: Tegretol 200mg/Neurontin 400mg (5dy taper)Sympathetic activity: Clonidine 0.1-0.2q8hrs (3-5dys)Fluids, MVI, ThiamineManage co-morbid conditions

Carbamazepine and Valproate Effective in: Mild to moderate AW / protracted AW distress and faster return to work No abuse potential / alcohol interactions No toxicity in 7-day trials

Limitations: Not better than BZDs Side effects Cost Limited data in AW seizures/delirium

Other Agents Antipsychotics: seizures, agitation -Adrenergic antagonists and clonidine: Autonomic activity, may hide impending seizures Magnesium: levels in AW, supplement does not severity Ethyl Alcohol: No evidence of efficacy, toxic + expensive

Nonpharmacological Treatment Quiet environmentNutrition and hydration:Oral thiamine (prevents Wernicke-Korsakoff) / folic acidOral fluids / electrolytesOrientation to realityBrief interventions / motivate to changeReferral to AA / relapse prevention tx.

ConclusionsAW common complication in AD patientsClinicians must screen for AD / AW During AW, excitatory neurotramsmissionIf untreated AW can be deadly or lead to morbidityBZD most effective, safest and cheapest treatment

BENZODIAZEPINES

General ConsiderationSedative-hypnotic (Benzodiazepine) DetoxificationSymptoms similar to alcohol but no objective measure/scoring systemHigh risk of delirium, seizures and death requires treatmentSub-clinical symptoms may persist for monthsTolerance develops within 3-4 weeks of regular use Onset of withdrawal symptoms determined by half-life of compound

BenzodiazepineDetoxification guidelines:Slow-tapering of the compound or use of a longer acting benzodiazepine recommended(i.e., Clonazepam TID with 10% tapering daily)Sedatives for insomnia (i.e. antidepressants)Avoid beta blockers (mask symptoms) Anti-seizure medications adjusted and monitored

General ConsiderationDetoxificationSymptoms similar to alcohol but no objective measure/scoring systemHigh risk of delirium, seizures and death --- requires treatmentSub-clinical symptoms may persist for monthsTolerance develops within 3-4 weeks of regular use Onset of withdrawal symptoms determined by half-life of compoundSedative-hypnotic (Benzodiazepine)

Barbiturate withdrawal Symptoms may range from rebound insomnia (from hypnotic doses) to delirium and seizures (from higher doses) similar to those of alcohol withdrawal Management involves substitution of a long-acting benzodiazepine (diazepam) to reduce severity of symptoms and aid in slow and careful tapering off of offending barbiturate

POPPY PLANTSOPIATE/OPIOID

Opiate Indications for Use

1.Addiction Maintenance TherapyMethadone (Pure Mu Opioid Agonist) Naltrexone (Opioid Antagonist)Buprenorphine (Opioid Agonist- Antagonist)(N.B. LAMM now Minimally Available)2. Pain Management

Opiate Withdrawal Syndrome1. Not life threatening, Extremely uncomfortable

2. Symptom onset and duration, half-life dependent

3. Common Sns & Sxs:YawningSweatingTearingAbdominal CrampsNausea and/vomitingDiarrheaWeaknessDilated PupilsGoose bumpsMuscle twitching aches and painAnxietyInsomniaIncreased pulseIncreased Resp rateElevated Blood pressure

Opiate Detoxification

Key Considerations:Medical Detoxification = Standard of Care Methadone short-term substitution therapy = the preferred method of detoxification, butGoal of treatment = reducing withdrawal discomforts, with or without Methadone or Narcotic Substitution

Opiate DetoxificationLevels of CareInpatient SettingDuration: 4-7 daysUsual dose to suppress symptoms: 30-40mg/day MethadoneImmediate Referral to drug-free treatment settingClonidine (Catapres) can be considered an effective alternative treatment for inpatient opioid detoxification but not outpatientOutpatient Setting21 day protocol sufficient for most stable, motivated patients180 day protocol, done within an opioid agonist therapy program, should be considered to work on patients early recovery problems, while stabilized on relatively low dose (50-60mg) Methadone

Opiate DetoxificationAdvantages of MethadoneDaily dosing due to 24 hour half-life, requiring slower tapering schedule Long half-life safe for all opiatesSafe in pregnancyMay be used in combination with other medications for co-occurring disorders or mild withdrawal symptomsDecreases morbidity and mortality, hepatic damage, and HIVException: licensing requirements, very addictive

Opiate Detoxification

Methadone Guidelines:Stabilize Withdrawal: 5-10 mg prn every 4-6 hours to control objective signs of withdrawalMonitor respiratory depression and excessive sedation until stabilizedDetoxification: Reduce by 10%/day after stabilized for 2-3 daysClonidine 0.1-0.2mg/day for duration

Opiate DetoxificationPharmacological Guidelines (cont.)Adjunctive TreatmentsNonsteroidal Anti-inflammatory Agents for pain and fever (i.e. Tylenol, Aleve)Alpha-adrenergic blocker for sympathetic hyperactivity such blood pressure, nausea, vomiting, diarrhea, cramps and sweating (i.e. Clonidine/Catapres)Antidiarreals and anti-emetics to control gastrointestinal symptoms (i.e. Bentyl, Phenergan)Antidepressants/Antipsychotic for dysphoria, anxiety and insomnia (i.e. Trazedone/Elavil/Seroquel with/without Lexapro) Psychotropics for co-morbid psychiatric conditions along with medications for medical conditions

Used to block autonomic signs and symptoms of withdrawal:crampsnauseavomitingtachycardiasweatinghypertension

ANS EFFECTSClonidineMotivational:PleasureRewardEuphoriaNEDA2-ARClonidine, an agonist at a2-AR.TreaTreatment of opiate withdrawal

VTAVTA

SN

LC

NA

Opiate Detoxification

Buprenorphine

History: October 2000amended Control Substance Act: 30 patient/MD max for opioid dependence treatment, with DEA waiver; Goal: accessibility, expanded treatment capacityPartial mu agonist antagonist: ceiling effect (safer), sublingual absorption, Suboxone preferredDosing instructions dependent on half-life of substituted opiateAverage tolerable maintenance dose is 4-32 mg SL/day to every 3rd dayDetox at 10%/day as tolerated

Medically-Assisted Withdrawal (Detoxification)Outpatient and inpatient withdrawal are both possibleHow is it done?Switch to longer-acting opioid (e.g., buprenorphine) Taper off over a period of time (a few days to weeks depending upon the program)Use other medications to treat withdrawal symptomsUse clonidine and other non-narcotic medications to manage symptoms during withdrawal

naloxone (Narcan)Competes for opiate receptor sitesHas a shorter duration of action than narcotics, so it must be given repeatedly

The Clinical AssessmentThe diagnosis of dependence is made through a careful patient history and physical examination, focusing on the following information:Drug type, route and duration of use, symptoms with cessation and last useRisk factors, symptoms and previous testing for blood-bourn pathogensPast Medical History and review of symptoms of chronic use such as malnutrition, tuberculosis infection, trauma, endocarditis, and sexually transmitted diseasesPhysical Examination to include vital signs, and cardiac status for evidence of fever, heart murmur, or hemodynamic instability; exam should focus on skin areas for scarring, atrophy, infectionLaboratory Evaluation should include a complete blood count, comprehensive chemistry panel, HIV testing, EKG, Chest x-ray, screening for STDsUrine Drug Screens and Breath Analysis (Alcohol)

DetoxificationThe physiological process of withdrawal from a substance of dependence which requires medication management, careful monitoring, and the availability of lifesaving emergency interventions.

b-Adrenoceptor and Dopamine Receptor Agonists Dobutamine Dopamine

Mechanism of Action: Dobutamine Stimulation of cardiac b1-adrenoceptors: inotropy > chronotropy

peripheral vasodilatation

myocardial oxygen demand

Mechanism of Action: Dopamine Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors

Splanchnic and renal vasodilatation

Therapeutic Use Dobutamine: management of acute failure only

Dopamine: restore renal blood in acute failure

Adverse Effects Dobutamine Tolerance TachycardiaDopamine tachycardia arrhythmias peripheral vasoconstriction