To our knowledge this is the first NPSG study to have assessed rebound insomnia repeatedly in the same participants and over 12 months of nightly use of a BzRA hypnotic. No rebound insomnia was observed on either of the discontinuation nights and the likelihood of rebound insomnia did not increase relative to placebo over the 12 months of nightly zolpidem use. Some individual insomniacs did show rebound insomnia on the discontinuation nights, approximately 30–40% of participants. But the percentage of ‘rebounders’ did not differ between the placebo and zolpidem groups and did not increase systematically across the 12 months. The results of this study also showed that no clinically significant withdrawal symptoms were observed on the discontinuation nights over the 12 months of nightly use.
The results of this study confirm the short-term studies that have failed to find rebound insomnia with a 10 mg dose of zolpidem (Ware et al., 1997
; Voderholzer et al., 2002
). The one study that reported rebound insomnia with zolpidem utilized an extended release preparation which is a total 12.5 mg dose (Roth et al., 2006
). This again supports the finding that dose is critical to the risk of rebound insomnia. Our earlier studies with triazolam found rebound at a 0.50 mg dose, but not the 0.25 mg dose (Roehrs et al., 1992
). It may be that a 10 mg dose of zolpidem is the threshold dose beyond which rebound insomnia is more likely to occur.
These rebound insomnia results extend those of a previous short-term study regarding the impact of duration of use (Merlotti et al., 1991
). Rebound insomnia severity as function of duration of administration was assessed by administering the 0.50 mg dose of triazolam for 1, 6, or 12 consecutive nights. Sleep efficiency was reduced on the first discontinuation night after triazolam compared with placebo, but the severity of the rebound did not differ after 1, 6 or 12 consecutive nights of administration. Here we report that the likelihood of rebound with a clinical dose of zolpidem (10 mg) does not increase relative to placebo across 1, 4, and 12 months of nightly hypnotic use.
Some participants did show poorer sleep than baseline during the two discontinuation nights of months 1, 4, and 12. This suggests that there may be some individual differences in the expression of rebound insomnia. The present study with its three separate discontinuations for each participant (i.e. month 1, 4, and 12) will allow us to assess the repeatability of rebound within an individual and to look for possible predictors of the likelihood of experiencing rebound insomnia. Such analyses are being conducted currently for a future report.
One limitation of the present study is that it did not include a positive control which many of the short-term studies included, typically triazolam 0.50 mg. Given the chronic nature of this study we considered it unethical to administer, for 12 months, a treatment known in short-term studies to produce adverse effects. The sensitivity of this experiment to detect changes in NPSG sleep, and potentially worsened sleep, can be evaluated through the efficacy assessments done in this study during month 1 and month 8. We reported that zolpidem relative to placebo significantly increased total sleep time by 48 min in month 1 and 42 min in month 8 (Randall et al., 2010
). Moreover, this study showed significantly improved sleep on discontinuation night 7 in month 12 in the zolpidem group relative to the placebo group.
The Tyrer Withdrawal Symptom ratings clearly indicate that a clinically significant withdrawal is not associated with 12 months of nightly use of zolpidem. The mean total Tyrer scores never exceeded a mean of 3 on any of the 6 discontinuation nights (i.e. 2 each in month 1, 4, and 12) and scores of greater than 20 are considered to be clinically significant. Importantly, there was no zolpidem group specific systematic increase in scores across the 12 months. Interestingly, there was a main effect of months indicating that there was an overall increase in Tyrer ratings over the 12 months. The scores averaged across groups were: month 1: 1.4, month 4: 1.7, and month 12: 2.1, increases of 0.3 and 0.4 from months 1 to 4 and 4 to 12. The reason(s) for this non-specific increase across months is not clear. This is especially perplexing as the placebo subjects simply kept taking placebo during the ‘discontinuation’ week.
While overall there were no drug group differences in the expression of withdrawal symptoms, a drug group difference was seen on the two discontinuation nights of month 4. The higher Tyrer scores of the zolpidem group in month 4 can be attributed to higher ratings of symptoms reflecting increased light sensitivity. Spontaneous written participant comments suggest this may have been an artifact of laboratory awakening procedures with the abrupt illumination of bright overhead room lights at the time of arising. Month 4 nights 1 and 2 were the first return to the laboratory for participants after 3 months of sleeping at home and for the zolpidem group, as opposed to the placebo group, continuous sleep throughout their 8-hour bedtimes at home. This may have made them more sensitive to an abrupt bright light awakening on the first nights back in the laboratory. Clearly, this finding needs replication and further clarification.
These findings of an absence of clinically significant withdrawal suggest that 12 months of BzRA hypnotic use by primary insomniacs at a clinical dose is not sufficient for development of dependence and withdrawal. In an analysis of patients from general practice and outpatient psychiatric clinics the duration of BzRA use in patients showing dependence ranged from 18 to 90 months with the mean duration 30 months (Kan et al., 2004
). Thus, the 12 months of this study may not have approached the threshold for dependence development. Another important variable for dependence liability, dose, was carefully monitored in this study with weekly telephone reporting of nightly use and also monthly dispensing of medication. In an analysis of case reports of zolpidem dependence, dose was an important factor with the daily dose range being 40 mg to 1120 mg (i.e. four times and greater than the clinical dose) (Victorri-Vigneau et al., 2007
Another important factor in evaluating physical dependence liability of BzRAs is likely to be duration of receptor occupancy. The reports of withdrawal associated with BzRA use typically are for anxiolytics, which are long-acting and thereby BzRA receptors are occupied for the full 24 hours. Most hypnotics, and specifically zolpidem, are short-acting and thus receptors are occupied for approximately a third of the 24 hour day. Thus, longer durations of nightly hypnotic use may be required to produce physical dependence on a hypnotic as compared with an anxiolytic.
It also has been suggested that the repeated daily receptor occupation followed by non-occupation (i.e. 8 hours on, 16 hours off) may operate as a kindling process to sensitize receptors and thus induce a withdrawal (Allison and Pratt, 2004
). However, if kindling is the critical process, the present data would suggest one year of nightly kindling is not sufficient to induce rebound insomnia and withdrawal symptoms. This explanation seems less feasible, given the short kindling exposure typically used in animal studies.
It must be recognized that the participants of this study were carefully screened.
Any history of drug or alcohol abuse was an exclusion criterion in this study. Other medical, psychiatric, and primary sleep disorders were ruled out as well. The probable difference between the results of this study and reports of BzRA dependence in the general population is the patient population being treated and not the medication. The clinician may consider the patients of this study to be highly non-representative of their insomnia patients. However, these data do set the best case limits and inform the clinician of the conditions under which chronic hypnotic use is relatively safe.