by Karim Yahia Jaffer; Tiffany Chang; Brigitte Vanle, PhD; Jonathan Dang, MD; Alexander J. Steiner, PsyD; Natalie Loera, BA; Marina Abdelmesseh, MD; Itai Danovitch, MD; and Waguih William IsHak, MD, FAPA

Mr. Jaffer is with the Faculty of Medicine, Cairo University, Egypt. Ms. Chang is with the University of California Los Angeles, Los Angeles, California. Dr. Vanle, Dr. Dang, Ms. Loera, Dr. Abdelmesseh, and Dr. Danovitch are with the Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California. Dr. Steiner is with the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Dr. IsHak is with the Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, and the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Funding: This manuscript encompasses the analyses of the authors associated with the Department of Psychiatry and Behavioral Neurosciences at Cedars-Sinai Medical Center.

Financial Disclosures: All authors report no conflicts of interest or relevant financial disclosures.

Abstract: Objective.?While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant. In this systematic review, we examined the evidence for the efficacy and safety of trazodone for insomnia.

Methods.?A literature search was conducted using MEDLINE/PubMed databases from the past 33 years (1983–2016) and the keywords insomnia, trazodone, sedative, treatment, and hypnotics. The results were restricted to English language and human subjects. All randomized clinical trials, meta-analyses, observational studies, and placebo-controlled trials regarding trazodone for the treatment of primary or secondary insomnia were reported, per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study selection process yielded a total of 45 studies.

Results. Evidence for the efficacy of trazodone has been repeatedly demonstrated for primary insomnia, as well as secondary insomnia, including for symptoms that are a result of depression, dementia, and being a healthy man. Earlier studies (1980–2000) focused on utilizing trazodone at high doses (?100mg/d) for the treatment of insomnia among the depressed population; however, since the 2000s, the utility of trazodone has been expanded to treat secondary insomnia among the non-depressed population as well. The side effects are dose-dependent, and the most common is drowsiness.

Conclusion. A review of the literature suggests that there are adequate data supporting the efficacy and general safety of the low-dose use of trazodone for the treatment of insomnia. keywords: insomnia, hypnotics, treatment, trazodone, sedative

Keywords: insomnia, hypnotics, treatment, trazodone, sedative

Innov Clin Neurosci. 2017;14(7–8):24–34

Introduction

Insomnia is characterized by difficulty falling asleep, difficulty staying asleep, or waking too early1 and is associated with significant impairments in daytime activities, which might occur despite adequate opportunities for sleep.2–6 Primary insomnia is an organic illness in which sleep disturbances last longer than one month and have no identifiable etiology.7 Secondary insomnia might be caused by psychiatric or medical disorders, environmental factors, changes in circadian rhythm, or medication use. Effective treatment requires appropriate diagnosis, as well as behavioral and pharmacological therapy. Currently, benzodiazepine receptor agonists (BzRAs), such as zolpidem (Ambien) have been the preferred treatment of insomnia. However, trazodone was recently among the most widely prescribed sleep aids in the United States, despite being approved for depression by the Food and Drug Administration (FDA).8–10 Given this widespread use, it seems beneficial to evaluate the literature on the efficacy and safety of trazodone when administered for the treatment of insomnia. A MEDLINE search of the literature from 1983 through 2016 was conducted using the keywords insomnia, trazodone, sedative, and hypnotics and restricted to English language and human subjects. This strategy identified 173 articles that were screened; 55 were related to the topic. Two reviewers conducted a focused analysis using the full-text articles independently and reached a consensus on the studies to include in this review. The study selection process yielded 45 studies (Figure 1).

Pharmacology of Trazodone

Trazodone is a triazolopyridine derivative that was approved in 1982 for the treatment of depression. It belongs to the class of serotonin antagonist and reuptake inhibitors (SARI). Trazodone behaves as an antagonist at the serotonin type 2 (5-HT2) receptors, an antagonist at the alpha1 adrenergic receptors, and as an inhibitor of serotonin reuptake transporter (SERT). Of note, another consistent finding in the literature is that trazodone moderates cortisol suppression of the hypothalamic-pituitary-adrenal axis, which likely contributes to the efficacy of trazodone for insomnia. In addition, trazodone has moderate antihistamine and low anticholinergic activity.11 Although its mechanism of action is not fully understood, the main pharmacological action of trazodone is blockade of the serotonin 5-HT2A receptor (1mg of trazodone roughly blocked half of brain 5-HT2A receptors). Increasing trazodone dose (50mg) causes antagonism on histamine H1 and alpha1-adrenergic receptors. The blocking of the 5-HT2A, histamine H1, and alpha receptors is thought to produce the hypnotic effect reported for low doses of trazodone (25–100mg).11 At these low doses, trazodone induces and maintains sleep without causing daytime drowsiness or tolerance, mainly because of its short half-life (3–6 hours).11–13 For the medication’s antidepressant effects to reach efficacy, simultaneous blocking of 5-HT2A and SERT is required, which occurs at higher doses (150–600mg).11 Tolerance can occur during the combined antagonism actions of 5-HT2A and SERT.11

Overview of Included Studies

A significant number of clinical trials have evaluated the hypnotic effectiveness of trazodone in the treatment of insomnia. We identified 45 previous studies that evaluated trazodone’s effect on sleep outcomes (Table 1).14–58 Studies are grouped in the table from the most recent to the least recent and are also divided based on the type of insomnia studied (i.e., primary or secondary insomnia). The majority of these studies (95.5%, 43/45 studies) concluded that trazodone was effective in the treatment of insomnia. Only two studies did not support the use of trazodone for sleep.26,47 Twenty-one of the studies were performed with depressed patient populations where insomnia was either secondary to depression or induced by antidepressants.20,29,33,35,38,39,41,42,44,48,50–57 Of all studies included in the current review, 23 evaluated trazodone’s effects in non-depressed patients with sleep disorders: five were performed in primary insomnia,14–18 one for patients during pregnancy,19 one for women post-menopause,21 one with Alzheimer’s disease patients,22 one with cancer patients,23 one with dementia patients,25 one with methadone-maintenance patients,26 four with healthy men,28,31,43,49 three with alcohol-related participants,30,36,37 one with somatoform pain disorder patients,32 three with psychiatric patients,24,34,40 and one with self-reported “poor sleepers.”57

Efficacy in Primary Insomnia

Five controlled clinical trials evaluated trazodone for the treatment of primary insomnia.14–18 The original placebo-controlled, randomized clinicaltrial (RCT) was conducted by Walsh and colleagues and placed 306 subjects (21–65 years) to receive trazodone 50mg (n=100), zolpidem 10mg (n=102), or placebo (n=104) nightly for 14 days.18 Sleep measures were assessed using subjective sleep questionnaires. During the first week, trazodone decreased the time to fall asleep (sleep latency) significantly more than placebo, and zolpidem decreased sleep latency more than either trazodone or placebo.18 During the second week, sleep latency was still shorter in patients receiving zolpidem; however, the effects of trazodone on sleep latency were comparable with placebo.18

Approximately a decade later, three additional studies examined trazodone’s effects in the treatment of insomnia.15–17 Roth and colleagues examined the hypnotic efficacy and daytime effects of trazodone in a randomized, double-blind, placebo-controlled crossover study that enrolled 16 adults.15 They found that 50mg of trazodone administered 30 minutes before bedtime was effective for sleep maintenance but that it was possibly associated with motor and cognitive impairments.15 Zavesicka et al evaluated the clinical efficacy of cognitive behavioral therapy (CBT) alone and in combination with trazodone in a randomized comparative trial of 20 subjects, and they reported that CBT+trazodone was the most effective for management of primary insomnia.16 Wichniak et al studied long-term insomnia treatment by treating 28 subjects with trazodone (dosed ranges 25–150mg/d) for three months and concluded that trazodone improved sleep quality and daytime functioning.17 In a recent randomized controlled trial conducted across two phases, 224 adults were randomized to receive either behavioral therapy or zolpidem in phase 1, while those who were unable to achieve remission were randomized to a second six-week treatment involving trazodone (50–150mg/d), zolpidem, or behavioral therapy; this clinical trial is currently ongoing and expected to provide new information about the optimal treatment for managing insomnia.14

Efficacy in Secondary Insomnia

Evidence of trazodone’s effect in depressed subjects with insomnia. The first RCTs that evaluated the efficacy of trazodone for the treatment of insomnia among depressed populations originated from two studies in the 1980s.56,57 Since that time, the interest in the hypnotic effects of trazodone has significantly increased. Likewise, the clinical efficacy of trazodone for treating patients suffering from insomnia associated with depression has been discussed in more depth recently.51–55 Of the 21 studies in the current review that examined depressed patient populations,20,29,33,35,38,39,41,44,46–48,51–57 seven were conducted in the 1980s51–57; these studies primarily focused on the antidepressant activity of trazodone (high dose ?100mg) and included subjective measures of sleep endpoints as a secondary analysis (Table 1). Wheatley et al and Ather et al used a visual analogue scale (VAS) to subjectively assess patients’ quality of sleep, and both of these studies reported improved sleep quality for participants, with drowsiness being the most commonly reported side effect.56,57 Three clinical trials employed the Leeds Sleep Evaluation Questionnaire and reported “ease of getting to sleep” and “quality of sleep” following six weeks of treatment with trazodone (150mg/d).51,52,54

More recently, eight studies were performed with depressed or dysthymic patients, and these studies focused on the effects of trazodone in treating medication-induced or depression-associated insomnia.41,42,44–48,50 In an open-label, six-week RCT, the effective dose of trazodone was evaluated in 75 subjects, with a 50mg/d trazodone dose for two weeks, and then participants were randomized to receive 50, 75, or 100mg/d for the remaining four weeks. All doses improved sleep symptoms, as rated by sleep items on the Hamilton Depression Rating Scale (HAM-D), while the optimal result was achieved at 100mg/d of trazodone.41 Three trials evaluated trazodone’s effects with medication-induced insomnia, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors; it was reported that trazodone was effective and safe for treating antidepressant-induced insomnia.42,45,50 The remaining four studies had small sample sizes (6–9 subjects) with unconventional methodology, making it difficult to analyze the results.44,46–48

Finally, the sedative effects of trazodone were evaluated in four studies conducted in dysthymic and depressed patients during the 2000s.29,35,38,39 In a placebo-controlled, crossover study, one night of treatment with trazodone (100mg) was reported to increase slow-wave sleep but not sleep latency or total sleep time.39 A subsequent study from the same authors reported that 100mg of trazodone increased the total sleep time but did not shorten sleep latency.38 In a multicenter open-label study, Saletu-Zyhlarz and colleagues treated 549 patients with 50 to 300mg of controlled-release trazodone, and patients reported significant improvement on the HAM-D across the six-week study.35 In a randomized placebo-controlled study, 206 subjects were randomized to receive 150 to 375mg of trazodone and reported improvements in middle and late insomnia.29 In a pilot study conducted in 2016, Giannaccini et al investigated the relationship between melatonin and trazodone in a group of 17 patients suffering from insomnia associated with mood disorders and reported that trazodone normalized sleep and mood by interacting with melatonin.20

Evidence of trazodone’s effect in non-depressed subjects with insomnia. As indicated in Table 1, 19 studies enrolled non-depressed subjects with secondary insomnia.19,21–28,30–32,34,36,37,40,43,49,58 Three of these studies were conducted with healthy men and employed objective polysomnographic (PSG) measures, which revealed improved time spent in deep sleep (increased slow wave) without affecting normal sleep architecture.31,43,49 Three additional studies were conducted with alcohol-dependent subjects.30,36,37 In a small, placebo-controlled trial, Le Bon et al treated 16 patients with 50mg of trazodone initially and gradually increased the dosage to 200mg; the PSG measures demonstrated improved sleep efficiency for patients on Day 3 but not on Day 28.37 In a larger, placebo-controlled trial conducted over 12 weeks, 88 patients with alcohol dependence were prescribed 50 to 150mg of trazodone, and study findings revealed that trazodone significantly improved sleep, as measured by the Pittsburgh Sleep Quality Index (PSQI).30 Interestingly, discontinuation of trazodone was associated with increased drinking.30

In the past 10 years, the treatment efficacy of trazodone for primary insomnia has been well documented.14–16 In addition, the efficacy of trazodone for treating secondary insomnia related to depression, post-menopause, advanced cancer, dementia, methadone maintenance, post-traumatic stress disorders (PTSD), and somatoform pain disorders also has been demonstrated.21,23,25,26,32,40

More recently, the effectiveness of trazodone was compared to quetiapine among psychiatric inpatients, and trazodone was reported to be more effective than quetiapine for improvement of total sleep.24 A recent double-blind, controlled trial randomized 36 patients to receive either trazodone or matching placebo for two weeks and showed that 50mg/d was safe and effective in the treatment of insomnia for patients with Alzheimer’s disease.22

Finally, the sedative effects of trazodone for the treatment of insomnia were evaluated in 67 pregnant patients who were randomized to receive one of the following: trazodone (50mg/d), diphenhydramine, or placebo. The researchers used a wrist actigraphy to record total sleep time and assess sleep efficiency, and the team concluded that the use of trazodone or diphenhydramine to treat insomnia during the third trimester of pregnancy could help prevent postpartum depression.19

Safety

The most common adverse side effects of trazodone are relatively mild and include daytime sleepiness, headache, and orthostatic hypotension.59 As trazodone is an ?1-adrenergic antagonist, trazodone might carry the risk of causing hypotension, namely postural hypotension. Therefore, in clinical practice, clinicians are encouraged to consider the risk of hypotension when patients take trazodone. Postural hypotension can be a potentially serious condition, particularly in the elderly, who might fall and injure themselves when they get up, especially at night. In a double-blind, two-week, placebo-controlled study, the effective dose of 50mg/d was evaluated in 15 Alzheimer’s patients; trazodone was well tolerated, and adverse effects were transient, mild, and safe.22 Although impaired next-day memory performance, equilibrium, and muscle endurance have not been mentioned in the literature,22 findings from this study were consistent with other previous studies.18,19,33,38 Nonetheless, the literature has reported some adverse problems, both clinically and in prior clinical trials, although it is not common or problematic for the majority of older adult patients. Roth and colleagues reported cognitive and motor impairments after three weeks of 50mg/d trazodone use.15 In a recent double-blind, placebo-controlled study conducted over six months, 69 subjects were prescribed trazodone (50–150mg/d), and findings revealed that trazodone was safe and well tolerated in combination with methadone.26 Similar results (little to no adverse effects) have been observed in studies with low doses (25–100mg/d) of trazodone for the treatment of insomnia in non-depressed populations.16,17,20,22,23,25 At higher doses of trazodone (>100mg/d), drowsiness has been reported.52,54,56 As drowsiness has been a reported side effect of trazodone, there is the concern that patients might “nod off” while driving. Given the sedative nature of trazodone, patients should be encouraged to refrain from driving while taking the medication. Rarely, trazodone can cause priapism (between 1 in 1,000 and 1 in 10,000), and increased libido has been reported in clinical practice, which is one of the primary reasons it has been considered effective in the treatment of sexual dysfunction.60,61 Gastric distress, nausea, vomiting, and decreased appetite are rarely reported as side effects for trazodone.62 Trazodone presents with minimal anticholinergic features, and it is known to have fewer cardiovascular side effects than tricyclic antidepressants (TCAs).63 Nevertheless, Rausch and colleagues reported that one young woman developed significant QT prolongation after acute trazodone overdose.64 In sum, trazodone is generally safe and well tolerated, but it carries some risk and has a side-effect profile that differs from other widely used hypnotics, including but not limited to QT prolongation, abnormal bleeding, hyponatremia, priapism, acute angle glaucoma, neuroleptic malignant syndrome (particularly in older women), problems in select cardiac patients, drug-drug interactions (especially via 3A4), and switches into mania/hypomania. Furthermore, upswitching into impulsive suicidality can occur. For more information pertaining to the safety of trazodone, readers are encouraged to examine additional review studies that were not included in the current manuscript.65,66

Discussion

The relevant studies demonstrate that trazodone is effective in decreasing sleep latency and increasing sleep duration. Furthermore, trials with active treatment periods from 6 to 12 weeks reported significant improvement in quality of sleep.16,17,19,29,30,35,41,52,54 The majority of earlier studies have focused on utilizing high doses of trazodone (e.g., >100mg/d) for insomnia among depressed patient populations.47,48,52–54,56 However, since the 2000s, the utility of low doses of trazodone (25­–100mg) has been expanded to treat secondary insomnia among the non-depressed population as well. For example, trazodone has been shown to improve sleep in healthy adults who initially developed insomnia as a result of chronic caffeine intake.28 Trazodone can improve sleep in patients who experience insomnia comorbid with other general conditions as well (e.g., somatoform pain disorder) and has been shown to be highly effective in the treatment of insomnia among patients with Alzheimer’s disease, pregnant women with insomnia, and patients with other comorbid psychiatric conditions. It also has been particularly effective for patients who have insomnia comorbid with PTSD. In cases where insomnia is a feature and result of a depressive episode, trazodone is the preferred recommended therapeutic, especially among patients with cardiac disorders.67

Limitations

One limitation of the current review was the lack of systematic analysis of measuring insomnia. Depending on the location of the study, some measurement questionnaires have been adapted by previous investigators so that foreign subjects could better comprehend items on the questionnaires or measures used in each study. Another limitation stems from myriad subjective and objective measurement tools that are available and used in research studies, which complicates the literature and makes it difficult to examine treatment efficacy across studies. As the types of scales and assessments used were not uniform, there is an inherent challenge that arises when trying to systematically compare results of multiple studies. Last, there was no evidence from equipment-based measurements in confirming the effect of trazodone on insomnia and patient-reported outcomes among different psychiatric disorders.

Conclusion

The findings in this review show that trazodone is a generally safe therapeutic that has been repeatedly validated as an efficacious treatment for insomnia, particularly for patients with comorbid depression. Trazodone has been effective for insomnia across many different populations. While it is not currently a drug indicated for insomnia, it is among the most common off-label choices for treating insomnia. This review article has found that trazodone can be an effective option when treating insomnia with little to no risk in most cases. Of note, trazodone produces a low risk for habit-formation and addiction. In addition, trazodone also produces few adverse reactions, with select exceptions (e.g., drug interactions). Most of the studies included in this review reported minimal to no side effects with trazodone. While the initial onset of insomnia is typically habituated by patients’ responses, as earlier stated, trazodone might be able to negate those responses while patients go through recommended courses of cognitive behavioral therapy. Findings from the current study are especially promising for the treatment of comorbid conditions. While the current findings are encouraging, larger randomized clinical trials using objective measures are still needed in order to better understand the effectiveness of trazodone in treating insomnia. Future researchers should focus on the long-term benefits of insomnia treatment with trazodone, investigate its safety and efficacy in pediatric populations or other patient populations with secondary insomnia (e.g., sleep apnea, chronic pain, fibromyalgia, psychotic disorders), and explore and investigate the role that remission from insomnia might possibly play in contributing to the prognosis of other psychiatric conditions.

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