MINNEAPOLIS – People with chronic insomnia don’t have to take the sedative-hypnotic agent zolpidem every night for it to remain efficacious, a randomized trial found.
Investigators enrolled in the trial 56 patients who had had a response to a priming phase of 4 weeks of nightly zolpidem (Ambien) 10 mg and assigned them to three maintenance strategies: nightly dosing, intermittent dosing (whereby the drug was taken 3-5 nights per week of the patient’s choice), and partial reinforcement dosing (whereby a capsule was taken every night, but half were placebos).
Dr. Michael L. Perlis
Use of partial reinforcement after a priming phase, during which the drug is repeatedly paired with sleep, taps into the phenomenon of conditioning, explained lead author Michael Perlis, Ph.D., director of the behavioral sleep medicine program, University of Pennsylvania, Philadelphia. "In this kind of paradigm, on the nights when there is no medication, they are getting a conditioned response; on the nights when there is medication, you are reinforcing the capsule as the conditioned stimulus for that physiologic response."
Analyses based on the 41 compliant patients showed that after 1 month, the three maintenance regimens were statistically indistinguishable in terms of measures such as time to relapse, sleep latency, and waking after sleep onset.
Total sleep time was longer with nightly dosing (463 minutes) and partial reinforcement dosing (459 minutes) than with intermittent dosing (429 minutes) (P = .002 across groups). Also, sleep efficiency was better with nightly dosing (90%) and partial reinforcement (91%) than with intermittent dosing (88%) (P = .002 across groups).
The frequency of medical symptoms, possibly adverse effects, was statistically indistinguishable across groups, although they tended to be least frequent with the partial reinforcement strategy and most with the intermittent dosing strategy.
"The present findings suggest that in compliant subjects, any of the three 10-mg strategies evaluated may be used to maintain treatment response over time. If a trend is evident, it’s that subjects in the intermittent dosing group condition do not do as well as nightly dosing and as in partial reinforcement, and that’s especially and significantly true for total sleep time and sleep efficiency," Dr. Perlis commented. "The take-home message is interspersing placebos between active doses appears to be a reasonable approach for maintaining clinical gains following priming, in other words, obtention of treatment response with a full-dose strategy."
In upcoming research, the investigators plan to see how low they can go with the partial reinforcement strategy as far as nights of zolpidem – even down to zero capsules of active drug – and still maintain the benefit of nightly dosing. If this proves successful, "then it may be possible to one, maintain treatment response for long periods of time with fractional amounts of medication. Second, we have a potential to reduce tolerance and side effect risks. Third, we would massively be able to reduce the cost of maintenance therapy considering placebos are basically free," he said.
"Finally and most important..., if this approach works as applied to insomnia, it may be a powerful tool for the management of medications with narrow therapeutic indices. Put differently, the partial reinforcement approach may be a strategy for managing medications that have nearly as much risk as they do benefit. That’s where the money is," said Dr. Perlis, who disclosed no relevant conflicts of interest.
In an interview, Brandy Roane, Ph.D., one of the session cochairs and a psychologist at the University of North Texas Health Science Center in Fort Worth, noted that the study is interesting in that it sheds light on why patients on intermittent dosing might become increasingly dependent on the medication.
"You have the patient who becomes more likely to increase their use even if it’s not effective, because they end up taking that dose on the night when they do sleep better because it would be a typical what we call crash night, where their body is already so physically fatigued and their homeostatic sleep pressure is so increased that they take it and it pairs it with that [sleep], and it’s a learned response: ‘I took medication and I slept so much better.’ Whereas if you hadn’t paired it with that, they would have slept better anyway," she explained.
"So I think it does look more at that real world type of setting and starts to speak to some of that possible use actually increasing the likelihood that they are going to take the medication, whether it’s effective or not, and then not use behavioral interventions that might be more effective."