Trazodone For Sleep Disturbance During Methadone Maintenance

More than three quarters of individuals enrolled in methadone maintenance treatment report sleep complaints according to multiple research articles (e.g., Oyefeso et al in Drug Alc Dependence (1997)). It appears that the dose and duration of treatment with methadone is not causative of significant sleep disturbances, but the presence of co-morbid psychiatric disorders, chronic pain or other drug use is associated with severity of sleep symptoms.

The possible mechanisms causing sleep disturbance in the methadone maintained patient include:

• Opioids decrease acetylcholine in some brain regions that cause a decrease in REM sleep
• Opioid administration suppresses GABA transmission in the dorsal raphe nucleus which promotes wakefulness
• Opioids cause a reduction in the nucleoside adenosine in the basal forebrain, which is a neurochemical modulator of the sleep drive

Whatever the cause, it appears that methadone patients who have sleep disturbances average less than six hours of sleep per day and that this sleep restriction could lead to daytime impairment manifested by lower treatment adherence, cognitive difficulties, risk of injury and motor vehicle accidents. It has been found that over half of the OTP patients report use of approved medications or illicit drugs to help with sleep, though the use of illicit drugs is in itself causative of more sleep problems and functional impairment.

Trazodone is a triazolopyridine derivative, distinct from other antidepressants and has been prescribed in an off-label manner for insomnia (using sub-therapeutic antidepressant doses of 100mg or less) because of its sedating qualities. Trazodone is a popular medication in the substance using patient because it is non-addictive, available as a generic, is not scheduled as a controlled substance, has little risk for overdose and has low risk for life-threatening withdrawal syndromes.

Trazodone has been tried in alcohol dependent patients and shown improved subjective sleep quality but produced an increase in the number of drinks per drinking days and a lowering of abstinence after cessation. Trazodone had not been studied in the opiate dependent patient until the work of Stein et al in Drug and Alc Dependence (2012).

Stein et al recruited 137 persons from eight methadone maintenance programs in the northeastern United States, who were receiving methadone for at least one month with an average dose of 100mg. The patients underwent a Pittsburgh Sleep Quality Index and two polysomnography (sleep) studies; one at baseline and one a month later. Urine drug toxicologies were also performed. Interviews assessed sleep over the past 30 days at baseline and at one, three and six month follow-ups. Participants were randomized to Trazodone 50 mg or placebo. Research staff instructed participants to take one to three capsules as needed at bedtime, so that participants could self-titrate to an effective dose ranging from 50 to 150 mg. After the one month follow-up assessment, participants were given an additional 180 pills with the same instructions. Adherence to the medication protocol was monitored through pill counts at follow-up visits, self report in participant sleep diaries, and on the questionnaire following sleep studies.

The effect of Trazodone on mean sleep scores during the six month follow-up was not statistically significant (p = .10). Trazodone neither significantly increased nor decreased illicit drug use relative to placebo. Trazodone did not improve subjective or objective sleep in methadone-maintained persons with sleep disturbance.

There are several possible explanations for this negative finding:

• There is little empirical support for Trazodone’s clinical efficacy.
• It is possible that Trazodone had no significant effect on past month subjective sleep scores because overall medication adherence was low. There was no biological confirmation of medication adherence.
• Outcomes might have been more robust if a higher dose of Trazodone was used and/or if the sample size was larger. However, higher doses are associated with more frequent side effects, including drowsiness and impaired next-day function.
• Trazodone does not specifically target any of the postulated mechanisms of sleep disturbance in opioid dependent persons. The mechanism of action of Trazodone’s sedating effects is not known.
• Methadone-maintained persons have many ongoing risks for chronic insomnia such as: high rates of depressive symptoms and chronic pain; 90% smoked cigarettes, most used caffeine, and a minority used other illicit drugs (e.g., cocaine) that interfere with sleep.

The researchers concluded that “Trazodone remains popular and is well-tolerated in this population and appears safe in combination with methadone. Besides dry mouth, other side effects were not reported more often in the Trazodone group than in the placebo group”. They did not perform electrocardiograms, but torsades de pointes, a rare variety of ventricular tachycardia characterized by prolongation of the QTc (heart rate interval)) has been observed in patients receiving Trazodone (Mazur et al., 1995).? The majority of studies have found that Trazodone did not have a significant or lasting effect on QT interval (Mendelson, 2005). Torsades has also been reported in persons receiving methadone (Demarie et al., 2011; George et al., 2008), suggesting future studies that include high doses of Trazodone should perform electrocardiograms.

Conclusions: Trazodone did not improve subjective or objective sleep in methadone-maintained persons with sleep disturbance. Other pharmacologic and non-pharmacologic treatments should be investigated for this population with high rates of insomnia.