Original ArticleDurability of treatment response to zolpidem with three different maintenance regimens: a preliminary study
Introduction
While it has long been the case that insomnia has been classified as both an acute and a chronic disorder [1], [2], the medical treatment of the chronic disorder has always been fraught with difficulties [1], [3], [4], [5]. This is true for both general and specific reasons. The general reasons include: (1) the characterization of insomnia as a symptom versus a disorder [1], [6], and (2) the implicit analogy that chronic insomnia is “like chronic pain” and that sleep medications are “like analgesics.” [4] The former suggests that insomnia should not be the focus of treatment (rather, the focus should be on the primary disorder). The latter suggests that medical option is, at best, palliative and that hypnotics should be used sparingly. The specific reasons include the concern that hypnotics cannot be used for maintenance therapy as their clinical effects cannot be maintained ad infinitum (for years and decades) and that with long-term use there is an increased risk of psychological dependence and/or adverse events.
With the advent of the International Classification of Sleep Disorders, Third Edition (ICSD-3) [7] and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [8] and the elimination of the distinction between primary and secondary insomnia, it is now clear (at least from a nosologic point of view) that insomnia should be the focus of targeted treatment. The question moving forward is “What constitutes the best practice for maintenance therapy for insomnia?” In the absence of a specified regimen, it would be whatever approach yields the best initial treatment response, the most durable efficacy, and lowest levels of dose escalation and side effects. At present, the approach that appears to best fit this profile is that of intermittent dosing (prn use of medication on 3–5 nights per week). When evaluated week to week, the sleep continuity effects with intermittent dosing appear to be comparable to, and at least as durable as, those obtained with nightly dosing [9], [10]. This said, there are no data to suggest that such a strategy results in similar time to treatment response, extends the “efficacy half-life” of hypnotics, or results in less dose escalation and/or side effects. What is clear from the given data is that there are no treatment effects on non-medication nights [11]. The recurrence of insomnia on non-medication nights is problematic, and for at least two reasons. First, the insomnia is not treated on 2–4 nights a week. Second, the recurrence of insomnia on 2–4 nights per week may lead to a form of chronic insomnia that is especially persistent and may enhance the likelihood that patients become psychologically dependent on the medication.
One yet untested alternative to intermittent dosing is to provide placebos on non-medication nights. This approach, by virtue of expectancy alone, would be expected to provide for better outcomes on non-medication nights. This approach may also serve to extend the therapeutic response to non-medication nights based on the principles of conditioning and reinforcement. That is, it is possible that placebos (the medication vehicle) may become a conditioned stimulus for the pharmacotherapeutic effects of hypnotics on non-medication nights [12], [13], [14], and that periodic reexposure to active medication via intermittent dosing may serve as partial reinforcement. In order to evaluate whether a partial reinforcement strategy (nightly pill use with 50% active medication and 50% placebos) may be used for maintenance therapy, this approach was compared to two nightly dosing strategies (5 mg and 10 mg zolpidem) and an intermittent dosing approach (3–5 nights per week with 10 mg zolpidem). The outcome measures included relapse, latency to relapse, rate of relapse per unit time, and average sleep continuity prior to relapse. It was hypothesized that the partial reinforcement strategy would not significantly differ from nightly dosing with 10 mg but would be superior to nightly dosing with 5 mg and intermittent dosing with 10 mg.
Section snippets
Study overview (Fig. 1)
The data presented here are from a larger study on the role of partial reinforcement in the long-term management of insomnia. The parent study (which was funded as an R01 by the National Center for Complementary and Alternative Medicine [NCCAM]) had a mixed model design with four phases and four groups. The study design (as can be seen in Fig. 1) and the conduct of the investigation were overseen by the Internal Review Board of the University of Pennsylvania and by a Data Safety and Monitoring
Subject attrition
As can been seen in Fig. 2, 318 interested individuals completed a screening survey. Of these, 129 individuals were eligible for, and were enrolled into, Phase 1 (2-week assessment period) of the study, and 82 individuals exhibited a treatment response and were advanced to Phase 3 (randomization to one of the four treatment maintenance groups). Seventy-four subjects completed Phase 3. Of these subjects, 55 were identified as compliant with the medication regimens (PRS-10 = 65% [n = 13/20]),
Discussion
The present study evaluated whether nightly dosing (10 or 5 mg), intermittent dosing (10 mg, 3–5 nights per week), and partial reinforcement (50% 10 mg, 50% 0 mg) differed regarding their utility as maintenance dosing strategies for chronic insomnia. It was found, in compliant subjects, that any of the four strategies evaluated may be used to maintain treatment response over time (i.e., prevent or delay relapse). For the subjects that remained in remission, the subjects in the IDS-10 group
Funding source
This project was supported by a grant from NCCAM, R01AT003332.
Conflict of interest
The authors declare no financial conflicts of interests.
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.06.015.
References (33)
- et al.
Acute insomnia: current conceptualizations and future directions [Review]
Sleep Med Rev
(2012) - et al.
The challenge of chronic insomnia: is non-nightly hypnotic treatment a feasible alternative? [Review]
Eur Psychiatry
(2003) - et al.
Validation of the Insomnia Severity Index as an outcome measure for insomnia research
Sleep Med
(2001) - et al.
The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C),and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression
Biol Psychiatry
(2003) - et al.
Self-reported sleep across the menstrual cycle in young, healthy women
J Psychosom Res
(2004) NIH State-of-the-Science Conference on manifestations and management of chronic insomnia in adults
(2005)Consensus conference. Drugs and insomnia. The use of medications to promote sleep
JAMA
(1984)- et al.
Intermittent and long-term use of sedative hypnotics [Review]
Curr Pharm Des
(2008) - et al.
Clinical guideline for the evaluation and management of chronic insomnia in adults
J Clin Sleep Med
(2008)
International classification of sleep disorders: diagnostic and coding manual
Diagnostic and statistical manual of mental disorders
The state of insomnia and emerging trends [Review]
Am J Manag Care
Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia
J Clin Psychiatry
Conditioned immunopharmacological effects in animals: implications for a conditioning model of pharmacotherapy
The role of conditioning in pharmacotherapy
Cited by (34)
Blinded Pain Cocktails: A Reliable and Safe Opioid Weaning Method
2023, Anesthesiology ClinicsInsomnia
2022, The LancetCitation Excerpt :Head-to-head trials are needed to evaluate the relative efficacy of nightly dosing, intermittent dosing, and as-needed dosing both overall and for specific medications. An alternative to these three dosing options is the behavioural-pharmacotherapeutic approach,141 where treatment responses can be maintained with a form of intermittent dosing in which the patient takes a placebo on nights when they do not take the medication. Prescriptive strategies have historically focused on the type of medication, the dose, the route of administration, the time medication is administered, and the number of times per day medication is administered.
Durability of treatment response to zolpidem using a partial reinforcement regimen: does this strategy require priming?
2021, Sleep MedicineCitation Excerpt :Second, the recurrence of insomnia on 2–4 nights per week may lead to a form of the disorder that is especially persistent and/or may enhance the likelihood that patients become psychologically dependent on medication. In 2015, our group evaluated a modified intermittent dosing regimen which included the provision of placebos on non-medication nights [6]. This approach, by virtue of expectancy alone, was expected to provide for better overall outcomes.
Role of placebo effects in pain and neuropsychiatric disorders
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Similarly, Perlis and colleagues applied a reinforced therapeutic schedule to medically manage chronic insomnia using 10 mg zolpidem pill with 50% active medication and 50% placebos for 12 weeks. The partial reinforcement group showed the same clinical benefit as the groups randomized to 10 mg or 5 mg or intermittent 10 mg nightly dosing (Perlis et al., 2015). Children with ADHD showed a therapeutic benefit when placebo pills were paired with a 50%-reduced dose of amphetamine (Sandler and Bodfish, 2008; Section 3.2).
How representative are insomnia clinical trials?
2018, Sleep MedicineCitation Excerpt :Thus, a trial excluding comorbid insomnia will be studying only a sub-sample of the insomnia population. To provide an example of the participant and investigator level selection rates in previous studies, we did a search (not intended to be exhaustive) for papers reporting clinical trials of the FDA-approved hypnotics zolpidem [7], zolpidem XR [8,9], zolpidem sublingual [10], zaleplon [11] eszopiclone [12,13], doxepin [14,15], ramelteon [16,17], and suvorexant [18,19] and several agents investigated as potential hypnotics: gabapentin [20] and esmirtazepine [21,22]. None of these trials described the number of potential participants lost from the initial contact to the clinic screen.
Placebos Without Deception: Outcomes, Mechanisms, and Ethics
2018, International Review of NeurobiologyCitation Excerpt :Pairing a conditioned stimulus (CS) with amphetamines produced placebo-conditioned responses that allowed children with ADHD to be treated effectively with a lower dose of stimulant medication. Moreover, Perlis and colleagues randomized patients with chronic insomnia to distinct regimes of 10 mg zolpidem including nightly treatment with 10 or 5 mg, intermittent treatment with 10 mg, or partial reinforcement treatment with placebos and 10 mg for 12 weeks (Perlis et al., 2015). The partial reinforcement group maintained treatment response that were similar to the full treatment groups and better than the outcomes observed in those patients assigned to the intermittent treatment who exhibited poorer sleep quality.
Performance Site: University of Pennsylvania, Philadelphia, PA, USA.
- †
In memoriam.