Trazodone

What trazodone is

Trazodone is an antidepressant from the triazolopyridine group. It has been approved in the US since 1981; in Germany it is on the market as a prescription-only drug for depressive disorders. It has no approval for sleep disorders, either here or in the US; its use as a sleeping pill is off-label use under medical responsibility.

What is rated is the state of knowledge for sleep. As an antidepressant, trazodone has been described for decades. For insomnia, by contrast, there are only a few, mostly small and short studies. If you want to compare alternatives: the approved sleeping pills zopiclone and orexin receptor antagonists have their own pages, as do melatonin and Sleep & sleep hygiene.

How it works

According to the German summary of product characteristics, trazodone is a non-tricyclic antidepressant with a sedating component. It only weakly inhibits the reuptake of serotonin and noradrenaline, but has a pronounced affinity for alpha-1 adrenoceptors. The US prescribing information additionally describes a blockade of 5-HT2 receptors.

A pharmacokinetic simulation of receptor occupancy in the brain concluded in 2018 that low doses, typically 50 mg, are sufficient to block the receptors responsible for the sleep-promoting effect, whereas the antidepressant effect requires higher doses. The same receptor occupancy explains typical side effects such as dry mouth, a drop in blood pressure and priapism. This has not been measured directly in humans.

What the studies show

Yi 2018: meta-analysis of seven studies

The analysis included only randomized, placebo-controlled studies, 429 patients in total. Sleep efficiency did not differ (SMD 0.09), perceived sleep quality was better under trazodone (SMD minus 0.41, p = 0.05), and the number of nighttime awakenings was lower (SMD minus 0.51). Time to fall asleep, total sleep time and wake time after sleep onset did not differ from placebo. The authors therefore see trazodone at an advantage mainly for staying asleep and for perceived quality.

Everitt 2018: Cochrane review

The review found 23 studies on antidepressants for insomnia, seven of them on trazodone versus placebo. Three could be pooled and showed a moderate improvement in subjective sleep quality. Two studies with polysomnography and 169 participants found little or no difference in sleep efficiency (1.38 percentage points). Two studies reported more morning grogginess, dry mouth and thirst than under placebo. The authors’ conclusion: few, mostly small and short studies; there are no data on long-term use.

Camargos 2014: Alzheimer’s dementia

In this double-blind study, 30 patients with Alzheimer’s dementia and sleep disorders received 50 mg of trazodone at 10 p.m. or placebo for two weeks. According to actigraphy, they slept 42.5 minutes longer per night under trazodone, and the proportion of the night spent asleep rose by 8.5 percentage points. Daytime sleepiness, cognition and everyday functioning did not change, and side effects were no more frequent than under placebo. The study is small and short.

De Crescenzo 2022: in the large comparison

The network meta-analysis in the Lancet of 154 double-blind studies counts trazodone among the drugs that may be effective in the acute treatment of insomnia, but that come with limited tolerability or for which long-term data are lacking.

Where the data stop

• Objectively measured sleep. In the sleep lab, sleep efficiency, time to fall asleep and total sleep time did not differ from placebo. The benefit shows mainly in people’s own perception and in the number of awakenings.
• Long-term use. Many people take trazodone for months or years to sleep. According to Cochrane, there are no studies on the efficacy and safety of such long-term use.
• The recommendation of professional societies. The American Academy of Sleep Medicine advises, with a weak recommendation, against using trazodone for difficulty falling or staying asleep. The European guideline permits it only short term.
• Older people. In a Canadian observational study of 3,002 nursing home residents, a new trazodone prescription was associated with a similar number of injurious falls, fractures and deaths as zopiclone. The authors conclude that neither drug should be regarded as a safer alternative to the other.

Status, approval and legal

In Germany, trazodone is approved for depressive disorders and is prescription-only; it is not listed in the Narcotics Act. According to the summary of product characteristics, the approved dosage in outpatient treatment of depression is 100 mg in the first week, then 200 to 400 mg daily, and up to 600 mg in inpatient settings. There is no approval for sleep disorders and therefore no approved dose; its use as a sleeping pill is under medical responsibility.

In the US, trazodone has been approved since December 24, 1981 (Desyrel), likewise only for depression. Like all antidepressants, the US prescribing information carries a boxed warning on suicidal thoughts in children, adolescents and young adults.

Safety

The US prescribing information lists as important risks orthostatic hypotension up to fainting, prolongation of the QT interval on the ECG, serotonin syndrome in combination with other serotonergic drugs, and an increased bleeding tendency in combination with anticoagulants or pain relievers such as aspirin. The German summary of product characteristics also warns of QT prolongation and of rare priapism, a painful persistent erection that must be treated by a doctor immediately.

In the insomnia studies, morning grogginess, dry mouth and thirst occurred more often. According to the summary of product characteristics, trazodone has a minor to moderate influence on the ability to drive; anyone taking it should only drive once it is clear that drowsiness or dizziness do not occur. Alcohol and other psychotropic drugs increase the effect.

The observational data from nursing homes show that falls and fractures are about as frequent under trazodone as under zopiclone. Dedicated safety studies are lacking for low-dose long-term use for sleep disorders.

Sources

• Yi XY et al., Sleep Med 2018 – trazodone for insomnia, meta-analysis of 7 placebo-controlled studies
• Everitt H et al., Cochrane Database Syst Rev 2018 – antidepressants for insomnia in adults
• Camargos EF et al., Am J Geriatr Psychiatry 2014 – trazodone for sleep disorders in Alzheimer’s dementia, RCT with 30 patients
• Sateia MJ et al., J Clin Sleep Med 2017 – American Academy of Sleep Medicine guideline on pharmacological treatment of insomnia
• De Crescenzo F et al., Lancet 2022 – network meta-analysis of sleeping pills for insomnia, 154 studies
• Riemann D et al., J Sleep Res 2023 – European insomnia guideline 2023
• Settimo L, Taylor D, J Psychopharmacol 2018 – dose-dependent receptor occupancy of trazodone
• Watt JA et al., Can Geriatr J 2023 – falls and fractures under zopiclone or trazodone in nursing homes, cohort study
• Summary of product characteristics Trazodon-neuraxpharm 100 mg (as of April 2023)
• FDA, Drugs@FDA – Desyrel (trazodone, NDA 018207), approval 1981-12-24