LAS VEGAS RECOVERY CENTER BENZODIAZEPINES MEL POHL, MD LAS VEGAS RECOVERY CENTER

Doctors who treat the symptom tend to give a prescription; Doctors who treat the patient are more likely to offer guidance. J. Apley 1978

“Emerging research suggests that optimum benzodiazepine therapy consists of judicious, circumspect, and critically monitored use of benzodiazepines in terms of target symptoms and diagnoses” Rickels et al

Secondary Substances for Primary Benzo Admissions Dasis report 11/21/03

Dosage Conversion Table for Benzodiazepines Benzodiadepines Dosages (mg) Half-life* Alprazolam (Xanax) 1 6-10 Chlordiazepoxide (Librium) 25 5-100+ Clonazepam (Klonopin) .5 18-50 Clorazepate (Tranxene) 15 30-200 Diazepam (Valium) 10 30-100+ Estazolam (Prosom) 4 20-120 Flurazepam (Dalmane) 30 1-120 Midazolam (Versed) n/a Lorazepam (Ativan) 2 10-20 Oxazepam (Serax) 30 3-21 Quazepam (Doral) 30 20-120 Temazepam (Restoril) 30 10-12 Triazolam (Halcion) 1 2-3 Zolpidem (Ambien) 20 2.5 Zaleplon (Sonata) 20 1 Adapted from Giannini AJ. Drugs of abuse. 2d ed. Los Angeles: Practice Management Information Corp., 1997:121-5. *Includes metabolites - in hours

new Beta- carboline tetracyclic Antagonist Triazolo ring Short- acting Cyclo- pyrrolone Imidazo- pyridine

Other sedative-hypnotics Barbiturates - pentobarbital,phenobarbital, secobarbital, butalbital (Fiorinal) Barb-like: glutethimide, chloral hydrate, ethhchlorvynol (Placidyl), meprobamate (carisoprodol/Soma) Azapirone: buspirone (2-10 mg TID - max 60 mg/d) -slow onset of action (1-3 wks) -not abused, no withdrawal -effective for anxiety disorders-not for acute -does not block benzo withdrawal -not sedating, anticonvulsant or mm relaxing -no resp dep/ cognitive/psychomotor impair

Non-Benzo Hypnotics Zolpidem (Ambien) imadozopyridine Zaleplon (Sonata) pyrazolopyrimidine Bind to specifically to BZ-1 sites Both rapid onset (1h-2.5 h) - short action/1/2 life Decrease sleep latency, increase REM sleep 5-20 mg dose range Safe in older adults, metab in liver, no active metabolites Potentiate ETOH impairment Both reinforcing, potentially abusable, and performance-impairing

GHB Gamma Hydroxybutyrate Club drug - “G” “liquid ecstasy Aqueous solution - variable concentration Relaxation, disinhibition, euphoria Rapid onset, short half-life (20 minutes) Dependence and withdrawal occur Narrow therapeutic window-side effects: Dizziness, nausea, emesis, dec resp, coma Additive with ETOH and other sed-hypnotics

Therapeutic Uses Sedative-hypnotic Anxiolytic Panic disorder Generalized anxiety disorder Muscle relaxants Anticonvulsants Alcohol withdrawal Premenstrual syndrome Psychoses Adjunct in mania of bipolar disorder

Sedative/Hypnotic Transient - lowest effective dose- time-limited Insignificant decrease in sleep latency-1 hour increase in sleep duration -? effect on sleep architecture ( REM, stages 3 and 4) Rebound insomnia - worsening of sleep - worse than before trying benzos. Daytime drowsiness, dizziness, lightheadedness

Anxiety benzos good for immediate symptom relief-faster than SSRI’s for panic. long-acting, low potency preferred (clonazepam or chlordiazepoxide) best used for exacerbations of anxiety-short term vs continuous use

Adverse Effects Diminished psychomotor performance Impaired reaction time Loss of coordination, decreased attention Ataxia Falls Excessive daytime drowsiness Confusion Amnesia Increase of existing depressed mood Overdose rarely lethal

Treatment of Overdose Airway assessment and maintenance Ventilatory support if necessary NG suction - activated charcoal Flumazenil - competitive antagonist May need to repeat Q30-60 minutes Can induce withdrawal seizures in dependent pts.

REINFORCING EFFECTS Increased with rapid drug effect - eg alprazolam Subjective effects - high - e.g. diazepam, lorazepam, triazolam, flunitrazepam, and alprazolam. Speed of onset of pleasurable effects - eg GHB Increased reinforcement in those with history of drug abuse

Tolerance Time-dependent decrease in effect. Neurochemical basis unclear Varying rates for different behavioral effects: sedative and psychomotor effects diminish first (e.g. few weeks) memory and anxiety effects persist despite chronic use. Varying rates with different benzos. If no history of addiction, rarely see dose escalation or overuse Cross-tolerance with ETOH and other sed-hyp

Dependence Negative reinforcement of withdrawal - major deterrent to discontinuing use. Difficult to distinguish between wd & rebound anxiety upon discontinuing drug. Withdrawal-time-limited (not part of original anxiety state) Relapse-reemergence of original anxiety Rebound - increased anxiety > baseline Also see insomnia, fatigue, headache, muscle twitching, tremor, sweating, dizziness, tinnitus difficulty concentrating, nausea, depression, abnormal perception of movement, irritability

Dependence/Withdrawal, cont. rarely -seizures, delirium, confusion, psychosis. triggering of depression, mania, OCD. 90% of long-term users (>8mo-1yr) experience significant withdrawal insignificant wd if used less than 2 weeks mild-moderate if used >8 weeks Slow taper (>30days) with +/- carbamazepine, valproic acid, trazodone, imipramine. CBT effective in dc-ing benzos and controlling panic/anxiety.

Predictors of severe withdrawal High-potency-quickly eliminated (e.g. alprazolam, lorazepam, triazolam) higher daily dose more rapid rate of taper (esp last 50%) diagnosis of panic disorder (not GAD) high pretaper levels of anxiety and depression ETOH or other substance dependence/abuse personality pathology -e.g. neurotic or dependent Not motivated to discontinue use

Pharmacology ABSORPTION tablets > capsules some rapidly absorbed (e.g. diazepam) -more reinforcing than oxazepam or temazepam lorazepam best for IM (cdp precipitates, poorly absorbed, diazepam absorption unpredictable. lipophilic - cross blood brain barrier easily conjugated in liver- form water soluble metabolites (different metabolism for different benzos)

Pharmacology Drug Interactions: additive with other CNS depressants utilizes cytochrome P450-levels increased by -SSRI’s - (less with paroxetine/Paxil, citalopram/Celexa, and sertraline/Zoloft) -ketoconazole, intraconazole -antibiotics - erythromycin -cimetidine, omeprazole -ritonavir -grapefruit juice C-P450 impaired in elderly or liver failure- inc effects

Mechanisms of Action Benzos bind to sites on GABA-A receptors (primary inhibitory neurotransmitter in CNS) Opens chloride ion channel 20-30% of all synapses in mammalian brain endogenous benzos exist in human brain/blood chronic use - changes in gene expression on GABA-A receptor function

Benzodiazepine Abuse Two patterns of abuse - recreational abuse (nonmedical use to get high quasi-therapeutic use - long-term drug- taking inconsistent with accepted medical Practice - multiple MD’s 467 internet sites to access scheduled Rx- websites are short-lived -

CASE 1 ERIC C. Recreational Use 34 yo caucasian male, single-lives in 1/2 way house Alprazolam 2mg - chews up to 5-10 tabs per day- Tolerance developed 4 months ago Oxycodone 10 mg - up to 20 per day Clonazepam 1mg - 6-8 per day for 2 weeks History of ETOH - 1pint/day - DC 3 months ago Withdrawal - tremors, nausea, vomiting, severe anxiety, sleeplessness, backaches, anorexia, sweats Supervised release from prison in ‘02-on probation. Minimal depression, no SI, no psych Rx.

CASE 2 - Sharon Z. Quasi-therapeutic Use 68 yo caucasian female, married, working as a home health aide, husband is verbally abusive Lorazepam 2mg - 9-10 per day - cut back to 5mg per day because of confrontation with daughter Ran out 2 days prior to admit - tried to get from another MD who encouraged admission WD - sever anxiety, tremor, diarrhea, neck pain, sleep disturbance, decreased energy, depression. No other substances - gambles $100/day if using pills Attempted inpatient Rx 2 yrs ago, but left AMA SI but no plan - tried venlafaxine, caused GI distress.

Detoxification Traditional Taper Method - using benzo Substitution and taper Anticonvulsants (possibly decrease electrical excitation in the limbic system) Carbamazepine (Tegretol) Gabapentin (Neurontin) Valproic acid (Depakote)

Substitution and Taper- simple and uncomplicated Phenobarbital, chlordiazepoxide or clonazepam Calculate equivalent dose - provide in divided dose Add prn doses of benzos during 1st week After dose stabilized, gradually reduce dose - 10% of starting dose. Slow last 25% of dose - hold to stabilize Frequent visits - withdrawal agreement

Tolerance Testing High or erratic dose, illicit source, polysubstance or alcohol plus benzo use. In 24-hour medically monitored setting 200 mg pentobarbital PO Q 2h - hold for intoxication, slurred speech, ataxia, somnolence. After 24-48 hrs, calculate 24 hr stabilizing dose Give stabilizing dose for 24 hrs divided Switch to phenobarbital (30mg = 100mg pentobarbital) Initiate gradual taper

Additional Measures Carbamazepine - decreased subjective symptoms 200 mg TID In conjunction with phenobarbital or cdp taper GI upset, neutropenia, thrombocytopenia, low Na. Valproic acid - attenuates withdrawal - GABA-ergic 250 mg TID Continue for 2-3 wks or more after taper Need to check LFT’s prior to starting GI upset, bone marrow supression pancreatitis

Additional Measures, cont Gabapentin - 200-300 mg TID - edema, fatigue Tiagapine (Gabitril) - gaba-ergic - Propranolol - diminish adrenergic s/s (60-120 mg/d) Clonidine - not effective Buspirone - not effective Trazadone - decreases anxiety-improve sleep - helpful CBT - improves rate of successful discontinuation and rate of abstinence from benzos

Taper Method Slow, gradual decrease in dosage (e.g. .5 mg Alprazolam every 3-5 days or as slow as .25mg Every 7-14 days (or 10% of starting dose per wk) Last doses are hardest to eliminate - (?5% per wk) Varies from patient to patient Ambulatory setting - reliable followup Best with therapeutic-dose benzo dependence Only benzo dependence (no other drugs/ETOH) Supportive therapy Limited Rx - withdrawal agreement

Mel’s Method Phenobarbital protocol - uses modified CIWA VS and score Q 2 hrs for first 24-48 hrs. -Score 4-7 - 15 mg -Score 8-15 - 30 mg -Score 16-24 - 45 mg -Score 25-30 - 60 mg -Adjust dose upward based on symptom relief -Anticonvulsant - gabapentin, valproic acid,tiagabine -Psych eval - SSRI’s, buspirone, quetiapine