Evidence-Based Reviews

Insomnia in patients with addictions: A safer way to break the cycle

Current Psychiatry. 2008 May;7(5):97-109

References

1. Friedmann PD, Herman DS, Freedman S, et al. Treatment of sleep disturbance in alcohol recovery: a national survey of addiction medicine physicians. J Addict Dis 2003;22:91-103.

2. Brower KJ. Alcohol’s effects on sleep in alcoholics. Alcohol Res Health 2001;25:110-25.

3. Cohn TJ, Foster JH, Peters TJ. Sequential studies of sleep disturbance and quality of life in abstaining alcoholics. Addict Biol 2003;8(4):455-62.

4. Wong MM, Brower KJ, Fitzgerald HE, Zucker RA. Sleep problems in early childhood and early onset of alcohol and other drug use in adolescence. Alcohol Clin Exp Res 2004;28(4):578-87.

5. Weissman MM, Greenwald S, Nino-Murcia G, Dement WC. The morbidity of insomnia uncomplicated by psychiatric disorders. Gen Hosp Psychiatry 1997;19:245-50.

6. Brower KJ, Aldrich MS, Robinson EAR, et al. Insomnia, self-medication, and relapse to alcoholism. Am J Psychiatry 2001;158:399-404.

7. Kuhlwein E, Hauger RL, Irwin MR. Abnormal nocturnal melatonin secretion and disordered sleep in abstinent alcoholics. Biol Psychiatry 2003;54(12):1437-43.

8. Irwin M, Gillin JC, Dang J, et al. Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics. Biol Psychiatry 2002;51(8):632-41.

9. Peppard PE, Austin D, Brown RL. Association of alcohol consumption and sleep disordered breathing in men and women. J Clin Sleep Med 2007;3(3):265-70.

10. Aldrich MS, Shipley JE, Tandon R, et al. Sleep-disordered breathing in alcoholics: association with age. Alcohol Clin Exp Res 1993;17:1179-83.

11. Aldrich MS, Shipley JE. Alcohol use and periodic limb movements of sleep. Alcohol Clin Exp Res 1993;17:192-6.

12. Gann H, Feige B, Fasihi S, et al. Periodic limb movements during sleep in alcohol dependent patients. Eur Arch Psychiatry Clin Neurosci 2002;252(3):124-9.

13. Bootzin R, Nicassio P. Behavioral treatments for insomnia. In: Hersen M, Eissler R, Miller P, eds. Progress in behavior modification. Vol. 6. New York, NY: Academic Press; 1978:1-45.

14. Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in bed. Sleep 1987;10:45-55.

15. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999;281(11):991-9.

16. Arnedt JT, Conroy D, Rutt J, et al. An open trial of cognitivebehavioral treatment for insomnia comorbid with alcohol dependence. Sleep Med 2007;8:176-80.

17. Currie SR, Clark S, Hodgins DC, el-Guebaly N. Randomized controlled trial of brief cognitive-behavioural interventions for insomnia in recovering alcoholics. Addiction 2004;99:1121-32.

18. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 2005;66(suppl 9):31-41.

19. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse side effects. Arch Gen Psychiatry 2006;63:1149-57.

20. Karam-Hage M, Brower KJ. Gabapentin treatment for insomnia associated with alcohol dependence [letter]. Am J Psychiatry 2000;157:151.-

21. Karam-Hage M, Brower KJ. Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiatry Clini Neurosci 2003;57:542-4.

22. Brower KJ, Kim HM, Karam-Hage M, et al. A double-blind randomized clinical trial of gabapentin vs. placebo for treating alcohol dependence. Biol Psychiatry 2003;53(8S):84S-85S.

23. Le Bon O, Murphy JR, Staner L, et al. Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol 2003;23(4):377-83.

24. Friedmann PD, Rose JS, Swift RM, et al. Trazodone for sleep disturbance after detoxification from alcohol dependence: a double-blind, placebo-controlled trial. Paper presented at: Annual Meeting of the American Academy of Addiction Psychiatry, December 1-2, 2007; Coronado, CA.

25. Monnelly EP, Ciraulo DA, Knapp C, et al. Quetiapine for treatment of alcohol dependence. J Clin Psychopharmacol 2004;24(5):532-5.

26. Kampman KM, Pettinati HM, Lynch KG, et al. A double-blind, placebo-controlled pilot trial of quetiapine for the treatment of Type A and Type B alcoholism. J Clin Psychopharmacol 2007;27:344-51.

Precautions about hypnotics. The newer alpha-1-selective benzodiazepine receptor agonists (zolpidem, zaleplon, and eszopiclone) and the older nonselective benzodiazepines (such as flurazepam, temazepam, and triazolam) share an equivalent range of abuse liability.¹⁸ Consequently, all benzodiazepine receptor agonists are classified as Schedule IV controlled substances and should be used with caution, if at all, in substance-abusing or substance-dependent patients (Table 2).

In general, most physicians who specialize in treating addictions would not recommend these drug classes as first choice in postwithdrawal, substance-dependent patients complaining of chronic insomnia. Nevertheless, you are likely to encounter patients with a history of substance abuse/dependence who are taking legally prescribed benzodiazepine receptor agonists for insomnia, and they may be very reluctant to discontinue these medications.

Weigh and discuss with the patient the risks and benefits of taking vs discontinuing the hypnotic, as well as alternatives. Because chronic hypnotic use may interfere with addiction recovery, it is important to discuss the patient’s recovery plan.

If you decide to prescribe a hypnotic with abuse liability, the newer alpha-1-selective benzodiazepine receptor agonists are preferable—as they would be for non-addicted patients—because they are less likely to disrupt sleep architecture. They are also less likely than the long-acting benzodiazepines (such as flurazepam) to accumulate over time and result in daytime impairment.

Patient contracts. A written agreement can be useful whenever you prescribe a controlled substance for a patient with an addiction history. Include these issues:

frequency of clinic visits for monitoring response and refills, requests for early refills, and telephone refills
obtaining prescriptions from only one prescriber and one pharmacy
abstinence from other abused substances
urine drug screens and pill counts
authorization for you to share information with other care providers or significant others
an addiction recovery plan for other abused substances
consequences of nonadherence.

Ramelteon, a melatonin receptor agonist, is the only noncontrolled substance FDA-approved for treating insomnia. It may be preferred in alcohol-dependent patients, given its lack of abuse liability¹⁹ and preliminary evidence of decreased melatonin levels in alcoholic patients.⁷ Nevertheless, no studies have examined ramelteon in patients with substance use disorders.

Table 2

FDA-approved benzodiazepine receptor agonists for insomnia*

Agent	Dose range (mg)	T_MAX (hr)	T_½ (hr)
Benzodiazepine receptor agonists (benzodiazepine structures)
Estazolam	1 to 2	0.5 to 1.6	10 to 24
Flurazepam	15 to 30	3 to 6	50 to 100^†
Quazepam	7.5 to 15	2	25 to 100^†
Temazepam	15 to 30	2 to 3	10 to 17
Triazolam	0.125 to 0.5	1 to 2	1.5 to 5.5
Selective benzodiazepine receptor agonists (nonbenzodiazepine structures)^‡
Eszopiclone	1 to 3	1	~6
Zaleplon	5 to 20	1	~1
Zolpidem	5 to 10	1.6	2.5 (1.5 to 3.8)
Zolpidem CR	6.25 to 12.5	1.5	2.8 (1.6 to 4)
T_MAX: time to reach maximal plasma concentrations; T_½: elimination half-life (all values are approximate for any given individual)
* All benzodiazepine receptor agonists are Schedule IV controlled substances. Use with caution, if at all, in alcohol-dependent patients
† Including active metabolites
‡ Selective GABA_A receptor agonists bind the alpha-1 protein subunit of GABA_A receptors. Alpha-1 containing GABA_A receptors are thought to mediate sedative and amnesic effects but not antianxiety or muscle relaxant effects of the GABA system

Off-label sedatives for insomnia

Like ramelteon, sedating agents that do not have abuse liability are first-choice medications for patients with addiction and co-occurring insomnia (Table 3):

The most studied are gabapentin and trazodone.
Quetiapine and mirtazapine may be considered as second-choice options.

Gabapentin. The sedative properties of selected anticonvulsants can be useful in alcohol-dependent patients, in part because these agents do not lower the seizure threshold—an important issue given the risk of seizures in this population. Gabapentin can help to improve sleep in some alcohol-dependent patients. It has little known abuse potential (although it may have some), is not metabolized by the liver, does not interfere with metabolism of other medications, and does not require blood monitoring for toxicity.

In 2 open-label pilot studies of alcohol-dependent patients with insomnia:

gabapentin (mean dose 953 mg) significantly improved sleep quality over 4 to 6 weeks²⁰
both gabapentin (mean 888 mg qhs) and trazodone (mean 105 mg qhs) significantly improved Sleep Problems Questionnaire scores, but patients receiving gabapentin were less likely than those taking trazodone to feel tired upon awakening.²¹

In a controlled study, however, 6 weeks of gabapentin treatment did not improve insomnia more than placebo in recovering alcohol-dependent patients.²²

Although gabapentin and the anticonvulsant pregabalin increase slow-wave sleep in healthy control subjects, evidence of a similar effect is lacking in alcohol-dependent patients.

Trazodone is the most commonly prescribed antidepressant for insomnia because of its sedating effect and low abuse potential. Trazodone was associated with greater sleep improvements vs placebo as measured via PSG in a randomized, double-blind trial of alcohol-dependent patients with insomnia.²³ In a second study, sleep outcomes were better with trazodone vs placebo over 12 weeks in alcohol-dependent patients, although patients in the trazodone group drank more heavily.²⁴