Efficacy, acceptability, and safety of antidepressants for low back pain: a systematic review and meta-analysis

Background Antidepressant medicines are used to manage symptoms of low back pain. The efficacy, acceptability, and safety of antidepressant medicines for low back pain (LBP) are not clear. We aimed to evaluate the efficacy, acceptability, and safety of antidepressant medicines for LBP. Methods We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, the EU Clinical Trials Register, and the WHO International Clinical Trial Registry Platform from inception to May 2020. We included published and trial registry reports of RCTs that allocated adult participants with LBP to receive an antidepressant medicine or a placebo medicine. Pairs of authors independently extracted data in duplicate. We extracted participant characteristics, study sample size, outcome values, and measures of variance for each outcome. We data using random-effects meta-analysis models and calculated estimates of effects and heterogeneity for each outcome. We formed judgments of confidence in the evidence in accordance with GRADE. We report our findings in accordance with the PRISMA statement. We prespecified all outcomes in a prospectively registered protocol. The primary outcomes were pain intensity and acceptability. We measured pain intensity at end-of-treatment on a 0–100 point scale and considered 10 points the minimal clinically important difference. We defined acceptability as the odds of stopping treatment for any reason. Results We included 23 RCTs in this review. Data were available for pain in 17 trials and acceptability in 14 trials. Treatment with antidepressants decreased pain intensity by 4.33 points (95% CI − 6.15 to − 2.50) on a 0–100 scale, compared to placebo. Treatment with antidepressants increased the odds of stopping treatment for any reason (OR 1.27 [95% CI 1.03 to 1.56]), compared to placebo. Conclusions Treatment of LBP with antidepressants is associated with small reductions in pain intensity and increased odds of stopping treatment for any reason, compared to placebo. The effect on pain is not clinically important. The effect on acceptability warrants consideration. These findings provide Level I evidence to guide clinicians in their use of antidepressants to treat LBP. Trial registration We prospectively registered the protocol for this systematic review on PROSPERO (CRD42020149275). Supplementary Information The online version contains supplementary material available at 10.1186/s13643-021-01599-4.


Methods
We prospectively registered the protocol [24] for this systematic review on PROSPERO (CRD42020149275) and report our findings according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [25] (Checklist S1 in Additional file 1).

Primary outcomes
The primary outcomes were pain intensity and acceptability. Pain intensity was measured at the follow-up assessment closest to the end of treatment. Acceptability, defined as overall acceptability of the medicine, was measured using all-cause discontinuation during treatment [15,26].

Secondary outcomes
The secondary outcomes included low back-specific function, symptoms of depression, safety, harm, and tolerability. Low back-specific function and symptoms of depression were measured at the follow-up assessment closest to the end of treatment. Safety and harm, defined as the incidence of adverse effects and serious adverse effects [27], were measured by reports of adverse effects and serious adverse effects during treatment. Tolerability was defined as the tolerability of adverse effects sustained during treatment, measured by reports of discontinued treatment due to adverse effects.

Data sources
We used comprehensive search strategies to search electronic databases and clinical trial registries for records of randomized clinical trials of antidepressant medicines in LBP (Appendix S1 in Additional file 2) [28,29]. We piloted the strategies using records of trials included in a previous systematic review [23]. We searched the Cochrane Back and Neck Group's Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library), MEDLINE, Embase (Ovid), and CINAHL (EBSCO) databases from inception to May 15, 2020. We searched ClinicalTrials.gov (ClinicalTrials.gov), the EU Clinical Trials Register (www.clinicaltrialsregister.eu), and the WHO International Clinical Trial Registry Platform (apps.who.int/ trialsearch/Default.aspx) from inception to May 15, 2020. We included records written in English, Italian, Spanish, Portuguese, German, and French.
We included published and trial registry reports of randomized controlled trials (RCTs) that allocated adult participants with LBP to receive (i) a systemically administered dose of an antidepressant medicine or (ii) a sham (placebo) medicine, (iii) continuation of usual care, (iv) a waiting list, or (v) no-treatment. LBP was defined as pain of any duration between the 12th rib and buttock crease, with or without associated leg pain [30]. Trials that only included participants with symptoms of nerve root compromise (sciatica) [31] or LBP due to specific medical conditions (e.g., spinal fracture, inflammatory disease, aortic dissection, malignancy, or infection) were excluded. We included trials of mixed samples (e.g., nonspecific LBP and LBP with sciatica, or non-specific LBP and large joint osteoarthritis) if separate data for the non-specific LBP sample were available. We included trials that tested the efficacy of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCA), heterocyclic antidepressants (HCAs), monoamine oxidase inhibitors (MAOIs), or atypical antidepressants, provided they were listed on the WHO ATC [32] and licensed in at least one of the following jurisdictions: USA (FDA) [33], Australia (TGA) [34], UK (MHRA) [35], or Europe (EMA) [36].
We screened records for inclusion in two stages. Pairs of authors from a team of six (MCF, MAW, AGC, MDJ, HBL, RRNR) independently screened record titles and abstracts in duplicate. The full texts of potentially eligible records were retrieved and independently screened again (MCF, MAW) to confirm inclusion. Disagreements were resolved through discussion or recourse to a third author (MKB or JHM).
We linked records to identify unique studies using a hierarchy. Records that were published and reported the results of a trial were classified as primary records, followed by other published records of a trial (e.g., secondary analyses), conference abstracts, and lastly, trial registry records. We classified the trial registry record as the primary record if there was no evidence of publication.

Data extraction and risk of bias assessment
Pairs of authors (MCF, MAW, AGC, HBL, RRNR, and MDJ) independently extracted data using standardized, piloted, data extraction forms and assessed study-level risk of bias using the Cochrane "Risk of bias" tool (version 5.1.0) [37] and published recommendations [38,39]. Outcomes were rated as low overall risk when three or fewer domains are rated "unclear" risk, and no domains were rated "high"; moderate risk if a single domain was rated as "high" risk, but four or more were rated as "unclear" and high overall risk in all other instances. We resolved conflicts by consensus or, where necessary, through arbitration with a third author (MKB, JHM). We extracted, for each trial, the following: participant age, sex, duration of symptoms, and sample size; outcome value and measure of variance for pain intensity, function, and symptoms of depression; number of adverse and serious adverse effects; and the number of participants that discontinued treatment for any reason or due to adverse effects. We used an established hierarchy to preference data from continuous measures of pain, function, and symptoms of depression and converted all outcome data to a 0-100-point scale [24]. We used recommended methods [40,41] to calculate standard deviations when these were not available.

Effect measures and interpretation
We used the difference in means and accompanying 95% confidence intervals for analyses of effects of antidepressant medicines on continuous outcomes (pain, function, symptoms of depression). We followed recommended guidance for trials with multiple arms by dividing the control group sample size by the number of arms in the study (Cochrane Handbook, Version 6) [42]. For cross-over trials where we were unable to obtain the first phase outcome data from the study authors, we included the overall effect (reflecting both phases) adjusted to correct for the correlation between the two phases [41]. The minimal clinically important difference in means is established as 10 points on a common 0-100point scale for both pain and function [42]. We used the odds ratio and accompanying 95% confidence intervals for analyses of effects of antidepressant medicines on binary outcomes (acceptability, safety, harm, tolerability).

Data synthesis Main analysis
We synthesized the data for each outcome using frequentist random-effectsmeta-analysis models. We fit the models using Restricted Maximum Likelihood (REML) in the R (version 3.6.2) package metafor (version 2.4-0) [43,44]. We calculated the Q statistic to estimate heterogeneity, the estimate of between-study variance (τ 2 ), and the proportion of this variance not due to sampling error (I 2 ). We calculated the 95% prediction interval for the pooled effect and displayed this on the forest plot alongside the pooled effect estimate and 95% confidence interval.

Investigation of heterogeneity
We specified symptom duration, medicine type, and dose as covariates for investigation of important heterogeneity in the main analyses. Symptom duration had three levels: 0-6 weeks, 6-12 weeks, and > 12 weeks. Medicine type had seven levels: atypical, HCA, MAOI, SSRI, SNRI, TCA, TeCA. We included an additional level of medicine dose, compared to the protocol: standard dose range (SDR), less than SDR, and above SDR according to the Prescriber's Digital Reference [45]. We conducted subgroup analyses, using the covariate levels as strata.

Sensitivity analyses
We tested the effect of the definition of non-specific LBP and of imputing missing measures of variance by repeating the main analyses with and without the relevant studies.

Influence of a hypothetical RCT
We constructed extended funnel plots using Stata (version 14.2) [46] to simulate the influence of hypothetical parameters of a future RCT on the pooled effect estimate for pain intensity [47,48]. The extended funnel plot augments a funnel plot with overlays to provide an illustration of the impact of a new trial on a given metaanalysis [48]. We used 10 points on a 0-100 pain intensity scale as the threshold for the smallest worthwhile effect. We did not perform this analysis for acceptability as there is no known smallest worthwhile effect for this outcome.

Confidence in cumulative evidence
Two authors (MCF, MAW) used the Grading of Recommendations Assessment Development and Evaluation (GRADE) [49] framework to develop judgements of high, moderate, low, or very low confidence in the evidence for each outcome. We assessed the domains of study limitations, inconsistency, imprecision, and publication bias, using planned criteria [24]. Publication bias was evaluated using visual assessment of funnel plot symmetry, and Egger's tests where 10 or more studies were available for an outcome [50].

Search results
The search identified 2598 records. We removed 371 duplicates and screened the titles and abstracts of 2227 records for inclusion. We excluded 2104 records and retrieved the full-texts of 123 potentially eligible records     1). We excluded 63 records and included 60 records that comprised 23 unique trials [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] (Table 1). Eighteen trials used a parallel design, and five trials used crossover designs. Four trials were reported in trial registries. We identified a single ongoing trial, a single withdrawn trial, and a single terminated trial. Seventeen trials provided data for inclusion in the meta-analysis. These 17 trials randomized a total 2517 participants to one or more of 11 different antidepressant medicines or placebo. We did not identify any trials of antidepressant medicines compared to waiting list, usual care or notreatment. The analyses presented below are for the effect of antidepressant medicines compared to placebo.

Risk of bias
We assessed completed trials (n = 20) for overall risk of bias (Table S1 in Additional file 2); 15 were assessed as high risk, four at moderate risk, and a single trial at low risk of bias. All twenty trials reported an appropriate method of blinding. Fourteen trials reported either high dropout rates or differences in dropouts between arms.
Seven trials reported that they maintained complete control over the publication of results or had no fundingrelated conflicts of interests.

Assessment of publication bias
Visual inspection of funnel plots for each outcome suggested that the effects were evenly distributed around the mean (Figures S1-14 in Additional file 2). For all outcomes, visual inspection of contour-enhanced funnel plots provided no evidence of effects clustered around the threshold for statistical significance. Egger's tests were conducted for outcomes with 10 studies; only a single study indicated statistically significant asymmetry. A single completed trial report from a trial registry (NCT01225068) was included in our analyses.

Confidence in evidence
The GRADE assessment of confidence in the evidence for each main analysis is presented in Appendix S2 in Additional file 2 and referred to below.    Fig. 3 All-cause discontinuation (acceptability) of antidepressants compared to placebo for patients with LBP. Odds ratio greater than 1 indicates greater odds of discontinuation in antidepressant group (i.e., effect favors placebo)

Primary outcome: pain
Sixteen of the 23 included trials reported data for pain. We downgraded confidence in the evidence by two levels due to trial limitations. There is low confidence that the pooled effect of antidepressant medicines compared to placebo is − 4.33 [95% CI − 6.15 to − 2.50; Tau 2 = 2.20] on a 0-100 point scale (Fig. 2).

Primary outcome: acceptability
Fourteen of the 23 included trials reported data for acceptability (all-cause discontinuation). We downgraded confidence in the evidence by two levels due to trial limitations. There is low confidence that the odds of allcause discontinuation are higher for antidepressants than for placebo: odds ratio 1.27 [95% CI 1.03 to 1.56; Tau 2 = 0] (Fig. 3).

Secondary outcome: function
Six of the 23 included trials reported data for function. We downgraded confidence in the evidence by two levels due to trial limitations. There is low confidence that the pooled effect of antidepressants compared to placebo is − 3.22 [95% CI − 4.96 to − 1.48, Tau 2 = 0] on a 0-100 point scale ( Figure S15 in Additional file 2).

Secondary outcome: symptoms of depression
Four of the 23 included trials reported data for symptoms of depression. We downgraded confidence in the evidence by two levels for trial limitations and an additional level for imprecision. There is very low confidence that the pooled effect of antidepressants compared to placebo is − 1.72 [95% CI − 3.88 to 0.44; Tau 2 = 0] ( Figure S16 in Additional file 2) on a 0-100 point scale.

Secondary outcome: safety
Nine of the 23 included trials reported data for safety (adverse effects). We downgraded confidence in the evidence by two levels for trial limitations. There is low confidence that the odds of experiencing an adverse effect are higher for antidepressants than for placebo: odds ratio 1.58 [95% CI 1.28 to 1.93; Tau 2 = 0] ( Figure S17 in Additional file 2).

Secondary outcome: harm
Six of the 23 included trials reported data for harm (serious adverse effects). We downgraded confidence in the evidence by two levels for trial limitations and an additional level for imprecision. There is very low confidence that the odds of experiencing a serious adverse effect are higher for antidepressants than for placebo: odds ratio 1.29 [95% CI 0.56 to 2.94; Tau 2 = 0] ( Figure  S18 in Additional file 2).

Secondary outcome: tolerability
Ten of the 23 included trials reported data for tolerability (discontinuation due to adverse effects). We downgraded confidence in the evidence by two levels for trial limitations. There is low confidence that the −

Subgroup analyses
We conducted subgroup analyses for pain by antidepressant type and dose to provide additional clinical information (Fig. 4). There were no trials that evaluated the efficacy of HCA or MAOI antidepressants on LBP symptoms. The results for additional subgroup and sensitivity analyses are presented in Supplementary results with corresponding forest plots in Figures S20-23 in Additional file 2.

Influence of further research on results
The extended funnel plots ( Figures S24, S25 in Additional file 2) suggest the upper bound of the confidence interval for the pooled effect would cross the threshold for clinical meaningfulness if the meta-analysis included an additional hypothetical trial with approximately 400 participants per arm and an effect for pain of approximately − 30 on a 0-100 scale (antidepressants more favorable than placebo).

Post hoc effects of duloxetine
Duloxetine is noted in the 2017 American College of Physicians guideline to have small effects on pain and function compared to placebo, for chronic LBP [11]. We repeated the main analyses on five trials that evaluated duloxetine compared to placebo. The effect of duloxetine on pain intensity post-treatment was − 5.87 [95% CI

Post hoc sensitivity analyses
The REML estimator may underestimate between-study variance for binary outcomes when events are rare [70]. We repeated the analyses for acceptability, safety, harm, and tolerability using DerSimonian-Laird, Paule and Mandel and Mantel-Haenszel methods of estimation (Table S2 in Additional file 2). A single additional post hoc sensitivity analysis is reported in Supplementary Results and Figure S31 in Additional file 2.

Discussion
We conducted a systematic review to evaluate the effect of antidepressant medicines for patients with LBP. We included 23 trials in the systematic review and up to 17 in the meta-analyses. There is low confidence in evidence that, on average, patients with LBP treated with antidepressant medicines will experience a small improvement in pain and function and no improvement in symptoms of depression, compared to placebo. These effects are not clinically important [42,71]. There is low confidence in evidence that patients are at increased odds of experiencing an adverse or serious adverse effect and at increased odds of stopping treatment due to an adverse effect or another reason, compared to placebo. Taken together, these data indicate treatment of LBP symptoms with antidepressants has no important benefit; is less acceptable, less safe and less tolerable; and may be harmful, compared to treatment with a placebo medicine.
A recent overview of clinical guidelines reported that 6 of 8 international guidelines recommend the use of antidepressants for chronic LBP where necessary [72]. The current American College of Physicians clinical guideline for the management of LBP [11] recommends the use of duloxetine for chronic LBP as second-line therapy where non-pharmacological therapy has been unsuccessful. This might be reconsidered in view of our findings. The analyses of duloxetine specifically showed a small effect on pain that is unlikely clinically important [73] and higher odds of adverse effects and dropout due to adverse effects compared to placebo.
Our work has a number of strengths. We adhered to a prospectively registered protocol and reported findings in line with recommendations [74]. Our searches are extensive and up to date and we included data from trial registry reports [29,75,76]. We also evaluated the acceptability, safety, harm, and tolerability of antidepressant medicines, in addition to effects on symptoms. This addresses limitations of the most recent review, which included 11 fewer trials and did not evaluate adverse effects [23]. The observed low heterogeneity across all outcomes, together with the improved precision of the estimates, substantiates our findings and interpretation. We determined that different methods of estimation did not influence these observations and note that similar homogeneity for binary outcomes has been reported in other large meta-analyses for antidepressant medicines [15]. We estimated parameters for a hypothetical future trial that would meaningfully impact the effect estimate for pain, to assist readers' interpretation of the need for further trials.
We were unable to estimate effects for the long-term efficacy and acceptability of antidepressants because such data were reported in a single trial [61]. We were also unable to evaluate the effects of antidepressants in patients with acute LBP because we identified no usable data. The hypothetical future trial parameters estimated with the extended funnel plot do not consider risk of bias and are not estimable for binary outcomes.

Conclusion
This review demonstrates that treatment of LBP symptoms with antidepressants has no important benefit; is less acceptable, less safe, and less tolerable; and may be harmful, compared to treatment with a placebo medicine. This evidence is supported by homogenous, precise effect sizes across outcomes. These findings provide Level I evidence to guide clinicians in their use of antidepressants to treat LBP. Authors' contributions MCF had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. JHM and MKB conceived the study idea and designed the study; MCF, MKB, and MAW created the search terms and conducted the database searches; MCF, MAW, AGC, HBL, RRNR, and MDJ extracted the data; MCF and MAW analyzed the data; MCF drafted and revised the manuscript; MKB, JHM, CKL, RD, and SMG made substantial contributions to the interpretation of results and critical revision of the manuscript. All authors approved the final version of the manuscript.

Availability of data and materials
The dataset used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.