The acknowledged drugs of choice for the pharmacological treatment of insomnia are the benzodiazepine receptor ligand hypnotics (BzRL). Our nighttime studies show that with therapeutic doses used either short-term or chronically, the abuse liability of BzRLs in insomnia is not seen universally and is relatively low The data from our last grant, a first-ever study, showed the abuse liability of chronic zolpidem use in insomniacs was low. Yet case reports and retrospective studies continue to report BzRL dependence and for the majority of these cases the abuse developed through initial therapeutic use. In our study some subjects showed an increase in dose across time. Understanding the transition from therapeutic use to abuse and identifying risk factors, such as specific patient and drug characteristics, is both mechanistically and clinically important. Our preliminary data have shown that a subset of insomniacs, those insomniacs that have signs of hyperarousal as reflected by elevated Multiple Sleep Latency Test (MSLT) scores, increased their nightly zolpidem dose across time. BzRLs have differential receptor binding affinities and associated anxiolytic or antidepressant properties. Zolpidem has selective alpha 1 BzRL affinity and little mood activity and thus may show less risk for transition from therapeutic use to abuse than another currently frequently prescribed BzRL with less alpha subtype selectivity such as eszopiclone. We propose to study the abuse liability of a selective (zolpidem) vs nonselective (eszopiclone) hypnotic during chronic use (six months) in an at-risk sub-population (insomniacs with hyperarousal shown by elevated MSLTs). The proposal is highly innovative as it reflects a paradigm shift in understanding the abuse liability of hypnotics. In the end, this proposal will generate a unique set of data addressing a number of previously clinically important unanswered questions regarding hypnotic abuse by insomniacs (i.e., its likelihood as a function of arousal state and specific hypnotic pharmacology, of dose escalation over time and change in mood/drug effect ratings over time). It will provide clinicians with behavioral indicators of abuse risk.

Public Health Relevance

This proposal will assess risks for transition from therapeutic hypnotic use to abuse in people with insomnia. We will study a hypothesized at-risk sub-population, insomniacs with hyperarousal, and compare two hypnotics, a drug with mood effects, eszopiclone, versus one without mood effects, zolpidem.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Aklin, Will
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Henry Ford Health System
Independent Hospitals
United States
Zip Code
Roehrs, Timothy; Roth, Thomas (2018) Insomnia as a path to alcoholism: tolerance development and dose escalation. Sleep 41:
Huls, Hendrikje; Abdulahad, Smedra; Mackus, Marlou et al. (2018) Inclusion and Exclusion Criteria of Clinical Trials for Insomnia. J Clin Med 7:
Roehrs, T; Verster, J C; Koshorek, G et al. (2018) How representative are insomnia clinical trials? Sleep Med 51:118-123
Pillai, Vivek; Roth, Thomas; Roehrs, Timothy et al. (2017) Effectiveness of Benzodiazepine Receptor Agonists in the Treatment of Insomnia: An Examination of Response and Remission Rates. Sleep 40:
Roehrs, Timothy A; Roth, Thomas (2016) Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem. J Clin Sleep Med 12:319-25
Roehrs, T A; Roth, T (2016) Hyperarousal in insomnia and hypnotic dose escalation. Sleep Med 23:16-20
Roehrs, Timothy A; Roth, Thomas (2015) Sleep Disturbance in Substance Use Disorders. Psychiatr Clin North Am 38:793-803