What are the risks associated with long-term use of Trazodone (triazolopyridine antidepressant)?

Long-Term Trazodone Use: Significant Risks Outweigh Benefits

The 2019 VA/DoD guidelines explicitly advise against using trazodone for chronic insomnia due to low-quality efficacy evidence that is outweighed by its adverse effect profile, and there is insufficient data on long-term safety for any indication. 1

Primary Concerns with Long-Term Use

Limited Efficacy Evidence

• Systematic reviews show trazodone improved only subjective sleep quality compared to placebo, with no differences in sleep efficiency, sleep onset latency, total sleep time, or wake after sleep onset 1
• Studies evaluating trazodone had very short durations (mean 1.7 weeks) with follow-up of only 1-4 weeks, providing no data on long-term effectiveness 1
• The efficacy for insomnia is not well established, especially for long-term use 1

Cardiovascular Risks

• Trazodone may be arrhythmogenic in patients with preexisting cardiac disease, including isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes 2
• Post-marketing reports document torsade de pointes at doses as low as 100 mg or less 2
• The drug should be avoided in patients with cardiac arrhythmia history, symptomatic bradycardia, hypokalemia, hypomagnesemia, or congenital QT prolongation 2
• Not recommended during initial recovery phase of myocardial infarction 2
• Post-marketing surveillance has identified cardiac arrest, myocardial infarction, atrial fibrillation, ventricular tachycardia, and QT prolongation 2

Orthostatic Hypotension and Falls

• Orthostatic hypotension is a notable concern, particularly in elderly patients or those with heart disease 3
• This risk increases the potential for falls and related injuries in vulnerable populations 3

Priapism

• Priapism is a rare but serious adverse effect requiring close monitoring 2, 4
• This can occur unpredictably and requires immediate medical intervention 2

Central Nervous System Effects

• Drowsiness/somnolence/sedation is the most commonly reported adverse effect 1, 3, 5
• Trazodone causes higher incidence of somnolence compared to bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine 1
• Other CNS effects include dizziness, headache, and potential for cognitive and motor impairment 2

Suicidality Risk

• While low-dose doxepin (another sedating antidepressant) has no black box warning for suicide risk, the risk for suicidal ideation with low-dose trazodone as a hypnotic agent is unknown and cannot be excluded 1
• The FDA requires monitoring for suicidal thoughts and behaviors, especially during initial treatment and dosage changes 2

Other Significant Adverse Effects

• Serotonin syndrome risk, particularly when combined with other serotonergic drugs (SSRIs, SNRIs, triptans, tramadol, fentanyl, lithium, MAOIs) 2
• Increased bleeding risk when combined with antiplatelet drugs, NSAIDs, or anticoagulants 2
• Hepatotoxicity with liver enzyme alterations, jaundice, cholestasis, and hyperbilirubinemia reported post-marketing 2
• Hyponatremia 2
• Angle-closure glaucoma 2
• Discontinuation syndrome upon abrupt cessation 2

Clinical Context and Alternatives

Guideline Recommendations

• The American Academy of Sleep Medicine (2008) noted that antidepressants including trazodone are not FDA-approved for insomnia and their efficacy for this indication is not well established 1
• These medications are employed at lower than antidepressant therapeutic dosages for insomnia, but evidence supporting this practice is limited 1

Safer Alternatives

• For chronic insomnia, cognitive behavioral therapy for insomnia (CBT-I) should be first-line treatment 1
• If pharmacotherapy is needed, low-dose doxepin (3-6 mg) has better evidence for sleep efficiency improvement with similar tolerability to placebo in short-term studies 1
• Nonbenzodiazepine BZRAs (zolpidem, zaleplon, eszopiclone) show superior efficacy data, though they should be used at lowest effective doses for shortest duration 1

Critical Monitoring Requirements If Used Long-Term

Despite recommendations against long-term use, if trazodone is continued:

• Cardiac monitoring is essential, especially in patients with any cardiovascular risk factors or preexisting disease 2
• Monitor for orthostatic hypotension, particularly in elderly patients 2, 3
• Assess for emergence of suicidal thoughts, especially during initial months and dosage changes 2
• Screen for serotonin syndrome symptoms if combined with other serotonergic agents 2
• Evaluate for priapism risk and educate patients to seek immediate care if it occurs 2
• Monitor liver function given post-marketing hepatotoxicity reports 2
• Assess for hyponatremia, particularly in elderly patients 2
• Counsel patients about increased bleeding risk if taking anticoagulants or antiplatelet drugs 2

Key Pitfall to Avoid

The most common clinical error is prescribing trazodone long-term for insomnia based on anecdotal experience rather than evidence. The widespread off-label use of trazodone as a hypnotic is not supported by high-quality long-term data, and the known cardiovascular and other serious risks make this practice particularly problematic in elderly patients and those with cardiac disease 1, 2.