Mr. R also was referred to the sleep laboratory for a polysomnogram (PSG) because of reported loud snoring and witnessed apneas, especially because sleep apnea can cause nightmares and dream enactment behaviors. The PSG was negative for sleep apnea or excessive periodic limb movements of sleep, but showed increased electromyographic (EMG) activity during REM sleep, which was consistent with his report of dream enactment behaviors. Two months later, he reported improvement in nightmares and depression, but not in dream enactment behaviors. Because of prominent anxiety and irritability, he was started on gabapentin, 300 mg, 3 times a day.
What factor increases the risk of NREM parasomnias with zolpidem compared with benzodiazepines?
a) greater preservation of Stage N3 sleep
b) lesser degree of muscle relaxation
c) both a and b
d) none of the above
The authors’ observations
Factors that increase the likelihood of parasomnias include:
- zolpidem >10 mg at bedtime
- concomitant use of other CNS depressants, including sedative hypnotic agents and alcohol
- female sex
- not falling asleep immediately after taking zolpidem
- personal or family history of parasomnias
- living alone
- poor pill management
- presence of sleep disruptors such as sleep apnea and periodic limb movements of sleep.1,4,5,10
Higher dosages of zolpidem (>10 mg/d) have been identified as the predictive risk factor.5 In the Chopra et al4 case report on sleep-related suicidal behavior related to zolpidem, 10 mg at bedtime, concomitant dehydration and alcohol use were implicated as facilitating factors. Dehydration could increase serum levels of zolpidem resulting in greater CNS effects. Alcohol use was implicated in the Gibson et al8 case report as well, and the patient had multiple episodes of sleepwalking and sleep-related eating.However, Mr. R was not dehydrated or using alcohol.
An interesting feature of Mr. R’s case is that he was taking fluoxetine. Cytochrome P450 (CYP) 3A4 is involved in metabolizing zolpidem, and norfluoxetine, a metabolite of fluoxetine, inhibits CYP3A4. Although studies have not found pharmacokinetic interactions between fluoxetine and zolpidem, these studies did not investigate fluoxetine dosages >20 mg/d.11 The inhibition of CYP enzymes by fluoxetine likely is dose-dependent,12 and therefore concomitant administration of high-dosage fluoxetine (>20 mg/d) with zolpidem might result in higher serum levels of zolpidem.
Mr. R also was taking several sedating agents (gabapentin, hydroxyzine, melatonin, and tramadol). The concomitant use of these sedative-hypnotic agents could have increased his risk of parasomnia. A review of the literature did not reveal any reports of gabapentin, hydroxyzine, melatonin, or tramadol causing parasomnias. This observation, as well as the well-known role of zolpidem5 in etiopathogenesis of parasomnias, indicates that the pseudo-suicidal behavior Mr. R displayed while asleep likely was a direct result of zolpidem use in presence of other facilitating factors. Gabapentin, which is known to increase the depth of sleep, was added to his regimen 1 month before his parasomnia episode. Therefore, gabapentin could have triggered parasomnia with zolpidem therapy.1,13
Conditions that provoke repeated cortical arousals (eg, periodic limb movement disorder [PLMD] and sleep apnea) or increase depth or pressure of sleep (intense exercise in the evening, fever, sleep deprivation) are thought to be associated with NREM parasomnias.1-4 However, Mr. R underwent in-laboratory PSG and tested negative for major cortical arousal-inducing conditions, such as PLMD and sleep apnea.