1、,BENZODIAZEPINESMEL POHL, MDLAS 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 criti
2、cally 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 (Libri
3、um) 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 Tri
4、azolam (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,Short- acting,Imidazo- pyridine,Triazolo ring,Antagonist,Beta- carboline,tetrac
5、yclic,Cyclo- pyrrolone,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
6、-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 sp
7、ecifically 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 Gamm
8、a 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 ET
9、OH 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-limi
10、ted Insignificant decrease in sleep latency-1 hour increase in sleep duration -? effect on sleeparchitecture ( 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
11、-fasterthan SSRIs for panic. long-acting, low potency preferred (clonazepam or chlordiazepoxide) best used for exacerbations of anxiety-short term vscontinuous use,Adverse Effects,Diminished psychomotor performance Impaired reaction time Loss of coordination, decreased attention Ataxia Falls Excessi
12、ve 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
13、 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 ofd
14、rug 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 histo
15、ry of addiction, rarely see doseescalation 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 & reboundanxiety upon discontinuing drug. Withdrawal-time-limited (not part of
16、 original anxiety state) Relapse-reemergence of original anxiety Rebound - increased anxiety baseline Also see insomnia, fatigue, headache, muscletwitching, tremor, sweating, dizziness, tinnitusdifficulty concentrating, nausea, depression, abnormal perception of movement, irritability,Dependence/Wit
17、hdrawal, cont.,rarely -seizures, delirium, confusion, psychosis. triggering of depression, mania, OCD. 90% of long-term users (8mo-1yr) experiencesignificant withdrawal insignificant wd if used less than 2 weeks mild-moderate if used 8 weeks Slow taper (30days) with +/- carbamazepine, valproic acid,
18、 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 l
19、evels 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) -morereinforcing than oxazepam or temazepam lorazepam best for IM
20、 (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 cytochrom
21、e P450-levels increased by-SSRIs - (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 bin
22、d 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 abus
23、e - recreational abuse (nonmedical use to get high quasi-therapeutic use - long-term drug-taking inconsistent with accepted medicalPractice - multiple MDs 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 wa
24、y 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, severeanxiety, sleeplessness, backaches, anorexia
25、, 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 5mgper day because of co
26、nfrontation 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, bu
27、t 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),Subs
28、titution 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 Freque
29、nt visits - withdrawal agreement,Tolerance Testing,High or erratic dose, illicit source, polysubstanceor 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 stabilizi
30、ng 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. Va
31、lproic acid - attenuates withdrawal - GABA-ergic 250 mg TID In conjunction with phenobarbital or cdp taper Continue for 2-3 wks or more after taper Need to check LFTs prior to starting GI upset, bone marrow supression pancreatitis,Additional Measures, cont,Gabapentin - 200-300 mg TID - edema, fatigu
32、e 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,
33、gradual decrease in dosage (e.g. .5 mgAlprazolam every 3-5 days or as slow as .25mgEvery 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 Onl
34、y benzo dependence (no other drugs/ETOH) Supportive therapy Limited Rx - withdrawal agreement,Mels 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 - SSRIs, buspirone, quetiapine,
