This study appears to have been the first to assess the long-term effects of hypnosedative use among Vietnam War veterans with PTSD. Although it is clear that there is a high prevalence of comorbid psychiatric illnesses, including substance use disorders, among Vietnam War veterans, research into the characteristics of hypnosedative usage in this patient population has been modest and limited to the acute setting and has not focused specifically on zopiclone. This research was undertaken in an attempt to gain more detailed insight into the effects of zopiclone when used for extended periods by veterans with PTSD.
PTSD associated with combat exposure in Vietnam War veterans has previously been demonstrated to be associated with poor overall sleep, frequent waking, and difficulty staying asleep. Lavie discussed sleep disturbances in patients with war-related PTSD, noting that some have severely disordered sleep, while others have sleep patterns indistinguishable from healthy controls. Although the subjects in our study frequently reported poor sleep and were observed in many cases to have relatively poor sleep efficiency on sleep actigraphy, there was considerable interindividual variability of results between patients. It is of interest that in 8 of 13 cases, after remeasurement of sleep efficiency at 6-month follow-up, the overall mean sleep efficiency values had not changed relative to baseline. In a number of cases of subjects with severe PTSD, sleep efficiency was observed to be normal despite poor self-reported sleep quality. Some evidence suggests that self-reported sleep characteristics of Vietnam War veterans with PTSD may not correlate well with more objective measures such as polysomnography. The same authors also point out that, because of high rates of disturbed sleep among those with PTSD, the inclusion of well-framed questions regarding sleep behavior in surveys may provide higher quality information that is more likely to correlate with objective sleep measures.
There have been conflicting findings from previous research addressing sleep patterns among subjects with combat-related PTSD. Over 25 years ago, Lavie et al. found that soldiers who had returned from the 1973 Yom Kippur War showed significantly longer sleep latencies, lower sleep efficiency indices, a lower percentage of rapid eye movement (REM) sleep, and longer REM latencies. Mellman et al. found that recurrent awakenings, threatening dreams, thrashing movements during sleep, and awakenings with startle or panic features represented the most prevalently reported sleep-related symptoms for those with combat-related PTSD, accompanied by laboratory findings of longer time awake, micro-awakenings, and a trend for patients to exhibit body and limb movements during sleep. Mellman et al. subsequently undertook further research, comparing 25 patients with combat-related PTSD, 16 men with a principal diagnosis of major depression, and 10 male controls using polysomnography under medication- and substance-free conditions. Sleep efficiency was decreased in the PTSD group compared with those with depression and the control group, but REM density was increased in both PTSD and depressed patients. Brown and Boudewyns found that the incidence of periodic limb movements of sleep was 76% among a cohort of combat veterans with sleep complaints and suggested that this finding warrants further investigation as a means to elucidate the possible causes for PTSD-related sleep disorders. Using polysomnographic techniques, 2 separate studies found no differences between subjects with PTSD and control subjects on standard measures of sleep disturbance, regardless of history of trauma or major depression in the controls.[24,25]
Actigraphy techniques have also been used to assess sleep parameters for patients with PTSD. One study conducted using a cohort with PTSD not related to combat found that, although the survivors of motor vehicle accidents reported markedly poor sleep, these subjects had largely normal actigraphy values, suggesting that PTSD may actually be associated with altered sleep perception rather than sleep disturbance itself. Another study addressed actigraphy characteristics among a cohort with combat-related PTSD, again finding that although the subjects reported poor sleep, actigraphy data did not correlate with self-assessment of sleep. In that study the cohort comprised 16 randomly selected men with diagnostically confirmed PTSD from the Lebanon war. Individuals with major sleep disorders and other medical disorders that might affect sleep were excluded and patients were free of sleep-affecting drugs for at least 10 days prior to the study. Self-evaluation of sleep was poorly correlated with actigraphy, which essentially revealed normal sleep efficiency for more than 85% of both subjects with PTSD and controls. This study was different from our research, as our study is the first research to use home-based actigraphy to assess sleep parameters for veterans with PTSD currently using a hypnosedative (in this case, zopiclone).
Vietnam War veterans at Repatriation General Hospital have previously reported anecdotally that zopiclone provides better relief from insomnia and some symptoms of PTSD (mainly nightmares) than do benzodiazepines, and many express a strong preference for this agent. However, previous case reports document the development of physical dependence and abuse of zopiclone, particularly in polydrug abusers.[28,29] Hajak et al. have specifically examined the issue of the potential for dependence on the most popular nonbenzodiazepine hypnosedatives, zolpidem and zopiclone. In a pharmacoepidemiologic study, these authors were able to locate 22 reported cases of zopiclone dependence and commented that, in view of the widespread usage of the drug (including nonprescription status in countries such as Greece and Romania), the risk for dependence and abuse was not only extremely low, but also very much lower than for the benzodiazepines. The authors also discussed German data suggesting that the approximate rate for reporting of zopiclone abuse is in the order of 4.5 cases/10,000 defined daily doses (DDDs), comparing very favorably with the rate reported for benzodiazepines (106.7 cases/10,000 DDDs). An earlier review also found that tolerance, rebound, and withdrawal phenomena were marginal and mild with zopiclone.
In our study of men with PTSD who had used zopiclone for 6 months or longer, the score on the tranquilizer dependence rating scale exceeded the diagnostic cutoff point in 30% of the original cohort and in 38% of the follow-up cohort (corresponding to likely dependence in 6/13 subjects, compared with an incidence of 4/13 in the same cohort of men 6 months previously). Moreover, the subjects in the cohort did not report the use of zopiclone at a dose or frequency greater than that prescribed. An important consideration in relation to this study cohort is the extreme chronicity of the PTSD symptoms—in many cases the men involved had symptoms spanning a period of decades and, arguably, it could be expected that significant changes in sleep patterns would not be expected over a 6-month period.
Previous research has documented a tendency of patients treated with benzodiazepines to oppose discontinuation of treatment even before the appearance of withdrawal signs considered to be characteristic of dependence. It is of interest that our study demonstrates that the perceived need subscale of the rating scale made the largest contribution to the overall tranquilizer dependence score among these long-term users of zopiclone, despite the objective finding that sleep efficiency data were often normal even when participants subjectively reported poor sleep quality.
Hajak et al. provided a warning that patients with significant psychiatric illnesses and those with substance use disorders (including alcoholism) are at increased risk for zopiclone dependence. This accords with current treatment recommendations for the management of PTSD, in which authorities suggest that hypnosedatives should not be used routinely, because of the risk of dependence.[33,34] In that it is known that alcoholism and other substance use disorders are common among those with PTSD, it has been hypothesized that PTSD and substance use disorders are functionally related, with research suggesting that substances may be used by patients to modify PTSD symptoms. Physiological arousal that may arise as a result of substance withdrawal syndromes may exacerbate PTSD symptoms, thereby contributing to a relapse of substance use.
Our study has a range of limitations. Because of the small number of patients, the power of the study is not adequate to allow for statistical analysis; thus, these findings must be interpreted with caution. Moreover, although actigraphy was used to assess sleep efficiency, it could be argued that polysomnography might have provided a more accurate method for sleep assessment. The disadvantage of polysomnography is that it is applied in the context of a sleep laboratory and does not allow replication of the subjects' normal home sleeping arrangements. This study is the only work to date specifically examining the incidence of zopiclone dependence among Vietnam War veterans who are long-term users of the drug. The cohort was drawn from a population with intimate and/or regular contact with the only veterans' psychiatric treatment facility in South Australia, and it may not be possible to generalize the results to veterans not in close contact with the hospital system. The benzodiazepine dependence questionnaire developed and validated by Baillie and Mattick was extrapolated to cover zopiclone in this study, although the validity of this extrapolation has not been formally validated.
Overall, the results of this study suggest that, although the subjects in the follow-up phase of the research continued to use zopiclone on a regular basis for an extended period, the efficacy of this intervention for addressing PTSD - related sleep disturbance was low. It is clear that pharmacotherapy should be only one part of the overall management strategy used for patients with severe combat-related PTSD and that the understanding of the relative role of various drugs (including nonbenzodiazepine hypnosedatives such as zopiclone) continues to evolve. With continued international deployments of military personnel to armed conflicts in Iraq, Afghanistan, and elsewhere, it is clear that further research will be needed to elucidate the optimal pharmacologic treatment and overall management strategies for combat-related PTSD.
Dr. Alderman, Pharmacy Department, Repatriation General Hospital, Daw Park SA 5041, Australia, fax 618 83740225, firstname.lastname@example.org
The Annals of Pharmacotherapy. 2009;43(10):1576-1582. © 2009 Harvey Whitney Books Company
Cite this: A Qualitative Investigation of Long-term Zopiclone Use and Sleep Quality among Vietnam War Veterans with PTSD - Medscape - Oct 01, 2009.