BACKGROUND: Antidepressants are commonly used to treat low back pain and spine-related leg pain. However, their benefits and harms are uncertain. This is an update of a 2008 Cochrane review of antidepressants for non-specific low back pain.
OBJECTIVES: To assess the benefits and harms of antidepressants for non-specific low back pain and spine-related leg pain.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and EU Clinical Trials Register from inception to 14 November 2024.
SELECTION CRITERIA: We included randomised controlled trials that compared antidepressants with placebo, usual care, or no treatment/waiting list. Participants were 18 years of age or older with non-specific low back pain or spine-related leg pain of any duration. We excluded participants with low back pain due to spinal fracture, inflammatory disease, aortic dissection, malignancy, or infection. Primary outcomes were pain intensity and disability, measured at short-term follow-up (> 4 to 14 weeks post-randomisation), and total adverse events. Secondary outcomes were serious adverse events, withdrawals due to adverse events, depressive symptoms, and health-related quality of life.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened records to determine study inclusion, extracted data, and evaluated risk of bias using RoB 1 tool. Where possible, we conducted meta-analyses. We used GRADE to assess the certainty of evidence.
MAIN RESULTS: We included 26 randomised controlled trials. Eighteen studies included 2535 participants with non-specific low back pain, seven studies included 329 participants with spine-related leg pain, and one study included 68 participants with either condition. Most participants had pain lasting more than three months, with a mean duration between 18 months and 20 years. Mean ages ranged from 27 to 59 years. Studies evaluated serotonin and norepinephrine reuptake inhibitors (SNRIs; eight studies), selective serotonin reuptake inhibitors (SSRIs; two studies), tricyclic antidepressants (TCAs; 14 studies), tetracyclic antidepressants (TeCAs; two studies), or 'other antidepressants' (two studies). All studies were placebo-controlled. Outcomes were measured at short-term follow-up in 73% of studies. All included studies had at least one domain judged at high risk of bias, with 69% at high risk of attrition bias. Non-specific low back pain (benefits) Moderate-certainty evidence demonstrated that SNRIs probably have a small effect on pain intensity (mean difference (MD) (0 to 100 scale) -5.25, 95% confidence interval (CI) -7.17 to -3.34; I= 0; 4 studies, 1415 participants) and a trivial effect on disability (MD (0 to 24 scale) -0.91, 95% CI -1.30 to -0.51; I= 0; 4 studies, 1348 participants) at short-term follow-up. Low-certainty evidence showed that SSRIs may have little to no effect on pain intensity (MD 1.20, 95% CI -4.90 to 7.30; I= 0; 3 studies, 199 participants) and disability (MD -2.20 (0 to 100 scale), 95% CI -8.11 to 3.71; 1 study, 92 participants) at short-term follow-up. Moderate-certainty evidence demonstrated that TCAs probably have little to no effect on pain intensity (MD -2.00, 95% CI -7.25 to 3.24; I² = 31%; 4 studies, 417 participants), but probably have a small effect on disability (MD (0 to 24 scale) -1.76, 95% CI -2.70 to -0.82; I= 0; 3 studies, 330 participants) at short-term follow-up. The effects of TeCAs (MD -4.50, 95% CI -17.59 to 8.59; 1 study, 52 participants) and other antidepressants (MD -5.40, 95% CI -23.08 to 12.28; 1 study, 39 participants) on pain intensity at short-term follow-up are unclear (very low-certainty evidence). No studies assessed the effects of TeCAs or other antidepressants on disability. Spine-related leg pain (benefits) The effects of SNRIs on pain intensity (MD -46.10, 95% CI -89.29 to -2.91; 1 study, 11 participants) and disability (MD (0 to 100 scale) -4.40, 95% CI -20.25 to 11.45; 1 study, 11 participants) at short-term follow-up are very uncertain (very low-certainty evidence). Low-certainty evidence showed TCAs may have a large effect on pain intensity at short-term follow-up (MD -23.00, 95% CI -32.12 to -13.88; 1 study, 60 participants), and a moderate effect on disability (MD (0 to 100 scale) -13.00, 95% CI -19.42 to -6.58; 1 study, 60 participants). There were no studies that assessed the effects of SSRIs, TeCAs, or other antidepressants in people with spine-related leg pain. Non-specific low back pain and spine-related leg pain (harms) Moderate-certainty evidence demonstrated that SNRIs probably increase the risk of adverse events (risk ratio (RR) 1.17, 95% CI 1.07 to 1.27; I= 0%; 5 studies, 1510 participants), but it is unclear whether they increase the risk of serious adverse events (Peto odds ratio (OR) 1.75, 95% CI 0.79 to 3.89; 5 studies, 1510 participants; very low-certainty evidence). It is unclear whether TCAs increase the risk of adverse events (RR 1.76, 95% CI 0.79 to 3.90; 7 studies, 474 participants; low-certainty evidence) or serious adverse events (Peto OR 6.64, 95% CI 0.41 to 106.72; I² = 0%; 1 study, 142 participants; very low-certainty evidence). It is unclear whether SSRIs (RR 1.83, 95% CI 0.14 to 24.19; I² = 95%; 2 studies, 107 participants; very low-certainty evidence) or TeCAs increase the risk of adverse events (RR 0.93, 95% CI 0.79 to 1.09; 1 study, 52 participants; very low-certainty evidence). No studies assessed the risk of serious adverse events for these classes. No studies measured total adverse events for other antidepressants. It is unclear whether other antidepressants increase the risk of serious adverse events (Peto OR 0.90, 95% CI 0.16 to 4.96; 1 study, 42 participants; very low-certainty evidence). 2 2 2 2 2
AUTHORS' CONCLUSIONS: We found that in people with non-specific low back pain, SNRIs probably have small effects on pain intensity, trivial effects on disability, and are probably associated with adverse effects. TCAs probably do not reduce low back pain intensity, but may have a small effect on disability. The effects of antidepressants on spine-related leg pain are uncertain, though SNRIs and TCAs might be prioritised over other classes for future investigations. Evidence for the safety of SSRIs, TCAs, TeCAs, and other antidepressants in non-specific low back pain and spine-related leg pain remains unclear.
