1. Treatment of Chronic Insomnia: A Literature Search of Practice Guidelines, Meta-Analyses, and Review Articles Praveen Kambam, PGY-2 EBM Seminar 10/27/2005

2. What would you recommend for treatment? 45 year-old man with primary insomnia and difficulty initiating sleep 83 year-old woman with depression treated with fluoxetine and complaints of repeated awakenings throughout the night 25 year-old man with anxiety and difficulty initiating sleep 12 year-old girl with early morning awakening

3. Searching the Literature Online resources able to be accessed from UM Clinical Home Page or internet only Searches on PubMed, Medline, Up To Date, MD Consult Keywords:  “Insomnia” and “treatment”  “Soporific”  “Trazodone” and “quetiapine”

4. Pharmacological Treatments Trials for continuous use do not exceed 6 months for eszopiclone, 12 weeks for temazepam, 6 weeks for trazodone, 5 weeks for zolpidem (12 weeks for intermittent use 2 ), and 4 weeks for zapelon 1,6

5. Diphenhydramine RCT’s suggest improved sleep subjectively but limited by small numbers, short duration, lack of objective measurements 2 No recent data of efficacy over 3 weeks; tolerance within a few days 1 Considerations: next day neurocognitive effects, anticholinergic effect, orthostasis, increased liver enzymes

6. Melatonin Conflicting results Studies limited by small numbers, short periods, various dosages and formulations 2 Considerations: not regulated by FDA so unknown formulation and dosage

7. Trazodone Limited data, and especially limited on primary insomnia (only 2 studies) Lack of objective efficacy measures Short duration of trials (longest is 6 weeks) Consideration for side effects (sedation, dizziness, orthostasis, psychomotor impairment, priapism, etc.) Some evidence of tolerance (after 1-2 weeks) especially for primary insomnia _________________________________________________________________________________________________________ 6. Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005 Apr;66(4):469-76.

8. Trazodone vs. zolpidem 14 day, placebo controlled, primary insomnia Subjective sleep latency and duration showed significant improvement with both trazodone and zolpidem vs. placebo Effect was greater with zolpidem __________________________________________________________________________________________________________ 2. Silber MH. Clinical practice. Chronic insomnia. N Engl J Med. 2005 Aug 25;353(8):803-10.

9. Benzodiazepines Subjective and objective improvements in sleep maintenance measures (WTSO, number of awakenings) greater for longer- acting agents (flurazepam, quazepam, estazolam) vs. triazolam However next-day sedation as well as cognitive and psychomotor function impairment worse. Objective sleep lab data on temazepam to improve number of awakenings is equivocal _________________________________________________________________________________________________________ 1. Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv. 2005 Mar;56(3):332-43.

10. Benzodiazepines and non- benzodiazepine agonists Reduction in sleep onset latency greater than that for antidepressants and melatonin by indirect comparisons Risk for harm greater for benzodiazepines vs. non- benzodiazepines based on indirect comparisons Strong evidence of publication bias __________________________________________________________________________________________________________ 3.Buscemi N et al. Manifestations and Management of Chronic Insomnia in Adults. Evidence Report/Technology Assessment. Agency for Healthcare Research and Quality. 2005 Jun;125:1-11.

11. Benzodiazepines and non- benzodiazepine agonists Less evidence of subjective and objective next-day residual effects associated with zolpidem vs. benzos Less evidence of subjective next-day impairment with zaleplon, even if given in the middle of the night Efficacy for sleep-onset, not for maintenance Less drug-drug interactions _________________________________________________________________________________________________________ 1. Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv. 2005 Mar;56(3):332-43.

12. Non-benzodiazepine agonists Next day benefits of zolpidem not clearly defined (only improvement in somatic complaints over placebo) _________________________________________________________________________________________________________ 1. Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv. 2005 Mar;56(3):332-43.

13. Quetiapine ??? Emerging case reports for PTSD and anxiety Consideration of cost, metabolic side effects, tardive dyskinesia

14. Behavioral Treatments Well-established treatments:  Stimulus Control  Paradoxical Intention  Progressive Muscle Relaxation Probably efficacious treatments:  Sleep Restriction  Sleep Hygiene education  Cognitive Therapy  Biofeedback _________________________________________________________________________________________________________ 4. Chesson AL et al. Practice Parameters for the Nonpharmacologic Treatment of Chronic Insomnia. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22(8):1128-1133.

15. Considerations - Behavioral Cost Lack of availability Potential problems with patient motivation and adherence Training Limited if any side effects Differences in insomnia and outcome measures make comparison of study results difficult 3

16. Pharmacologic vs. Behavioral Treatments Evidence favoring pharmacologic therapy over behavioral therapy or vice versa was inconclusive 1 Hypnotic drugs may result in more rapid improvements in the first 1-4 weeks Clinical benefit not as well maintained over time (6-24 months) after discontinuation of treatment Combined treatments did worse than behavioral therapy alone

17. Pharmacological Treatment vs. CBT vs. Combo CBT>combo after treatment termination (10-24 month follow-up) 1,2 Pharmacological therapy tended to be superior in the first 2 weeks

18. Conclusions No prospective studies demonstrating treatment of insomnia improves outcomes of its associated comorbid conditions 1 Limited duration of studies No conclusive evidence to favor pharmacological vs. behavioral therapy but limited evidence to guide specific treatment goals and settings In the absence of evidence, need to match nature of sleep problem with treatment, availability, cost tolerance, side effect tolerance, and co-morbid conditions

19. Selected Articles 1. Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv. 2005 Mar;56(3):332-43. 2. Silber MH. Clinical practice. Chronic insomnia. N Engl J Med. 2005 Aug 25;353(8):803-10. 3. Buscemi N et al. Manifestations and Management of Chronic Insomnia in Adults. Evidence Report/Technology Assessment. Agency for Healthcare Research and Quality. 2005 Jun;125:1-11. 4. Chesson AL et al. Practice Parameters for the Nonpharmacologic Treatment of Chronic Insomnia. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22(8):1128- 1133. 5. Nowell PD et al. Benzodiazepines and Zolpidem for Chronic Insomnia: A Meta-analysis of Treatment Efficacy. JAMA. 1997 Dec;278(24):2170-2177. 6. Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005 Apr;66(4):469-76.