Benzodiazepines: Comparative Effectiveness and Strategies for Discontinuation. Ann M. Hamer, PharmD, BCPP Rural Oregon Academic Detailing Project

Transcription

1 Benzodiazepines: Comparative Effectiveness and Strategies for Discontinuation Ann M. Hamer, PharmD, BCPP Rural Oregon Academic Detailing Project

2 This project is funded through a grant from the Pew Charitable Trusts and support from the Oregon Department of Human Services

3 Topics Comparisons Comparative Effectiveness vs. Nonbenzodiazepines for Insomnia Agent comparison Data on withdrawal

4 Comparative Effectiveness Insomnia Comparison Outcome Hypnotic Finding Benzodiazepine Zaleplon compared with triazolam Effectiveness outcomes Zolpidem compared with flurazepam Zaleplon 5, 10mg = Triazolam 0.25mg Zaleplon 20mg Triazolam 0.25mg Zaleplon 40-60mg Mixed Triazolam 0.25mg Safety Zaleplon 5, 10mg = Triazolam 0.25mg Nausea Zaleplon 5mg > Triazolam 0.25mg Effectiveness Zolpidem 10, 20mg > Flurazepam 30mg outcomes Safety Zolpidem 10mg = Flurazepam 30mg Zolpidem 20mg < Flurazepam 30mg

5 Comparative Effectiveness Insomnia Comparison Outcome Hypnotic Finding Benzodiazepine Zolpidem compared with temazepam Effectiveness outcomes Zolpidem 5mg = Temazepam 15mg Zolpidem 10mg = Temazepam 20mg Less rebound Zolpidem 10mg = Temazepam 20mg

6 Comparative Effectiveness Insomnia Comparison Outcome Hypnotic Finding Benzodiazepine Zolpidem compared with triazolam Effectiveness outcomes Zolpidem 5mg > Triazolam 0.125mg Zolpidem 10mg = Triazolam 0.25mg Zolpidem 10mg > Triazolam 0.5mg Less rebound Zolpidem 5mg > Triazolam 0.25mg Zolpidem 10mg, > Triazolam 0.25mg Zolpidem 10mg > Triazolam 0.5mg

7 Agent Comparison Drug Long-Acting Chlordiazepoxide (Librium) Onset of Action Peak Onset (hrs) Int (parent) (metab) Diazepam (Valium) Rapid (parent) (metab) Half-life (hrs) Elimination Dose Equivalent Oxidation Oxidation 10mg Flurazepam (Dalmane) Rapid (metab) Oxidation 30mg Intermediate Acting Alprazolam (Xanax) Int (parent) Oxidation 0.5mg Clonazepam (Klonopin) Int (parent) Oxidation 0.25mg Lorazepam (Ativan) Int (parent) Conjugation 1mg Oxazepam (Serax) Slow (parent) Conjugation 15mg Temazepam (Restoril) Slow (parent) Conjugation 30mg Short Acting Triazolam (Halcion) Int (parent) Oxidation 0.5mg Onset of Action: Rapid=within 15 min; Intermediate=15-30min; Slow=30-60min 5mg

8 Benzodiazepines: Adverse Effects Sedation Delirium Psychomotor impairment Memory impairment Respiratory depression Dependence Falls Hip fracture Traffic accidents

9 Benzodiazepine Withdrawal Is long-term use synonymous with dependence? One study demonstrated the prevalence rate for dependence 40% general practice pts; 63% psychiatric pts Factors associated with long-term use over short-term use: DSM-IV disorder and psychiatric comorbidity, older age, less educated, living alone and using more avoidance coping behavior. Kan CC, et al. Acta Psychiatr Scan 1997;96:85-93 Zandstra SM, et al. Fam Pract 2004;21:266-9

10 Benzodiazepine Withdrawal Advantage of withdrawal Study by Curran, et al. Reviewed changes in elderly pts cognitive function, quality of life, mood and sleep Findings: 60% of pts had been taking the bz for >10yrs 27% of pts had been taking the bz for >20yrs Those that tapered off of the bz showed improvement on several cognitive and psychomotor tasks Withdrawers vs. control did not differ in sleep or benzodiazepine withdrawal symptoms Curran HV, et al. Psychol Med 2003;33:

11 Benzodiazepine Withdrawal Signs and Symptoms Tremors Anxiety Perceptual disturbances Dysphoria Psychosis Seizures Abrupt withdrawal can be dangerous

12 Withdrawal Strategies Taper schedules Early stages of withdrawal are easier to tolerate than the later and last stages. Consider switching to a longer-acting benzodiazepine (e.g. diazepam) for a smoother withdrawal. Taper success for long vs. short-acting = 68% vs 58% Optimal duration is not clear and may vary from patient to patient. In most patients, an 8-12 week taper is possible 25% reduction per week for first 2 weeks Then by 12.5% for the next 4 6 weeks

13 Benzodiazepine Conversions Benzodiazepine Equivalent Diazepam mg Alprazolam 10 Chlordiazepoxide 0.4 Clonazepam 2.5 Flurazepam 0.6 Lorazepam 5 Oxazepam 1 Temazepam 1 For example, the equivalent diazepam dose for 12 mg daily of lorazepam would be 12*5 = 60 mg daily (typical administered in 3-4 divided doses) Miller NS, Gold MS, Management of withdrawal syndromes and relapse prevention in drug and alcohol dependence. Am Fam Physician Jul;58(1):139-46

14 Example Benzodiazepine taper Baseline dose diazepam 60 mg daily Week 1: 15 mg tid (daily dose 45 mg) Week 2: 10 mg tid (daily dose 30 mg) Week 3: 7.5 mg tid (daily dose 22.5 mg) Week 4: 5 mg tid (daily dose 15 mg) Week 5: 2.5 mg tid (daily dose 7.5 mg) Week 6: 2 mg tid (daily dose 6 mg) Week 7: 1 mg tid (daily dose 3 mg) Week 8: 1 mg qd-bid (daily dose 1-2 mg) Week 9: D/C

15 Withdrawal Strategies Taper schedules In patients who have tried and failed to withdraw previously, a 6-month schedule may be necessary. Week % of baseline dose Dosage (diazepam equivalents) % % % % % % % % % % % % % % 0 (STOP) % of original dose 100.0% 100.0% 75.0% 50.0% 73.3% 56.7% 40.0% 23.3% 25.0% 31.7% 13.3% 6.7% 16.7% 3.3% 10.0% 0.0% 5.0% 1.7% 0.0% Week Number

16 Withdrawal Strategies Other considerations: Patients with underlying depressive illness should be treated with an antidepressant before withdrawal is started (consider an antidepressant with low withdrawal potential) Augmentation during taper has been minimally studied (weak evidence) Carbamazepine mg/d Imipramine 150mg/d

17 Summary Long-term benzodiazepine use is rarely warranted Withdrawal has led to improvements in cognitive function, balance and memory without worsening of insomnia (particularly in frail elderly) Discontinuation should always include tapering Rate of taper remains controversial Remain flexible, but try to avoid prolonging the process >6 months Use of adjunctive medication is not firmly established Depressed patients should be treated appropriately