Study Examines Adverse Effects of Low Dose Antidepressants for Chronic Pain

Interview with Michael Clark, MD

Antidepressants are commonly prescribed to manage chronic pain so a meta-analysis was conducted to determine how well this class of medications was tolerated, and the extent of adverse effects occurring in patients with chronic pain.

Chronic pain affects 36% of the US population and accounts for 12% of all medication prescriptions written.¹ With the pressure to avoid prescribing opioids continuing to intensify, alternatives to traditional opioid pain medications are actively being sought. One possible option for certain patients may be antidepressants, which have been shown as efficacious in the treatment of some chronic pain conditions in randomized controlled trials.²

To provide clinicians with some assurance about the efficacy of low dose antidepressant therapy for treatment of pain, a team of researchers from Canada and Germany conducted a meta-analysis of the side effects of low dose antidepressants;³ the findings were published in Frontiers in Neurology.

Analysis of Antidepressant Use in Pain Management

Timo Siepmann, MD, and colleagues noted that while the efficacy of using antidepressants to treat chronic pain conditions has been well documented, the study of the various side effects of these drugs was inconsistent.^2,3

The researchers examined the literature for the adverse effect profiles and tolerability of antidepressants when used to provide relief for patients with chronic pain.³ They believe that their findings may be useful in identifying multimodal treatment regimens for patients with chronic pain conditions by allowing consideration of patients’ comorbidities and co-medications.³  (The authors did not respond to multiple requests for comment.)

Some 1,975 articles were collected but the researchers only used 33 papers for their review, 23 of which were used in the final meta-analysis.³

The study selection criteria were established based on the following criteria:³

• Population of interest —The population of interest had to include patients with neuropathic, inflammatory/joint-related, or non-inflammatory/non-neuropathic chronic pain.
• Intervention used — The intervention had to be an antidepressant used to treat chronic pain in at least 2 randomized controlled trials that reported adverse effects.
• Inclusion of control group — All studies had to include a placebo group as a control.
• Notation of outcome — The outcome of any side effects had to be reported, and tolerability was defined as discontinuation due to antidepressant therapy. The adverse effects had to be reported as quantitative data.

Insights into Tolerability and Side Effects

The medications included in the meta-analysis were amitriptyline, nortriptyline, desipramine, milnacipran, venlafaxine, duloxetine, mirtazapine, and fluoxetine.³

The authors found over 60 different adverse events reported in the included studies.³ The risk ratio (RR) for overall adverse side effects were highest for fluoxetine (3.78, with a 95% confidence interval (CI) of 1.25; 11.43), and lowest for duloxetine (1.17, with 95% CI 1.06; 1.30).³ The highest RR for withdrawal due to adverse effects was 6.31 for desipramine (95% CI 1.20; 33.14) and lowest for nortriptyline at 0.81 (with intermediate evidence, 95% CI 0.12; 5.44).³

The most commonly reported adverse events were dry mouth, dizziness, nausea, headache, and constipation.³ The risk differences of each adverse effect were also reported for each antidepressant. The highest risk of dry mouth occurred in desipramine, amitriptyline, nortriptyline, and mirtazapine.

The highest risk for dizziness was seen with the use of mirtazapine, and the highest rate of nausea was seen with venlafaxine, duloxetine, and milnacipran. The authors noted that this type of detailed analysis may be useful to inform physicians’ decisions when weighing the risks and benefits of the different antidepressant medications.

The authors concluded that there is good tolerability for low dose antidepressants in treating chronic pain.³ They report there is a different profile of adverse effects in a low dose vs. a high dose of these medications. The results of the meta-analysis may be useful in determining multimodal treatment options, which takes comorbidities and co-medications into account.

Caution With Use Advised by Leading Pain Psychiatrist

“If you’re reluctant to prescribe these medicines because of concerns about side effects, then take heart because they are generally well-tolerated. But understand that the major limitation of the study is that they are not reviewing the efficacy, so you shouldn’t be led to believe that low dose is the preferred treatment for every patient with chronic pain,” Michael Clark, MD, an associate professor at Johns Hopkins University School of Medicine and Director of the Chronic Pain Treatment Program, who was not affiliated with the study.

“These findings are addressing tolerability of low dose treatment, which is what we typically start patients on. However, the efficacy goes beyond low dose as titration may still be necessary in order to give the patient the full benefit desired,” Dr. Clark told Practical Pain Management.

More importantly, “there is a danger in the premise of this study in that the concept of low dose antidepressants for pain versus depression is a myth. One of the biggest problems with pain practitioners using [antidepressant] medicines is that they under prescribe and under dose,” he said.

“So while the findings from this meta-analysis may be reassuring for a primary care doctor who views these medicines as more tolerable than they thought and less problematic, yet the results may also reinforce that low dose antidepressants are the way to go, but that simply isn’t the case”, said Dr. Clark.

View Sources

1. Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain. 2002;18(6):355-65.
2. Jackson KC 2nd, St Onge EL. Antidepressant pharmacotherapy: considerations for the pain clinician. Pain Pract. 2003;3(2):135-43.
3. Riediger C, Schuster T, Barlinn K, Maier S, Weitz J, Siepmann T. Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis. Front Neurol. 2017;8:307.