key: cord-0031008-phkpj1dm authors: Cheng, Darren K; Lai, Ka Sing Paris; Pico-Espinosa, Oscar Javier; Rice, Danielle B; Chung, Chadwick; Modarresi, Golale; Sud, Abhimanyu title: Interventions for Depressive Symptoms in People Living with Chronic Pain: A Systematic Review of Meta-Analyses date: 2021-08-09 journal: Pain Med DOI: 10.1093/pm/pnab248 sha: e27c90dcf21413365ac680dea0a4613c8be7b19c doc_id: 31008 cord_uid: phkpj1dm OBJECTIVE: This review investigated the effectiveness of clinical interventions on depressive symptoms in people with all types of chronic pain. METHODS: We searched seven electronic databases and reference lists on September 15, 2020, and included English-language, systematic reviews and meta-analyses of trials that examined the effects of clinical interventions on depressive outcomes in chronic pain. Two independent reviewers screened, extracted, and assessed the risk of bias. PROSPERO registration: CRD42019131871. RESULTS: Eighty-three reviews were selected and included 182 meta-analyses. Data were summarized visually and narratively using standardized mean differences with 95% confidence intervals as the primary outcome of interest. A large proportion of meta-analyses investigated fibromyalgia or mixed chronic pain, and psychological interventions were most commonly evaluated. Acceptance and commitment therapy for general chronic pain, and fluoxetine and web-based psychotherapy for fibromyalgia showed the most robust effects and can be prioritized for implementation in clinical practice. Exercise for arthritis, pharmacotherapy for neuropathic pain, self-regulatory psychotherapy for axial pain, and music therapy for general chronic pain showed large, significant effects, but estimates were derived from low- or critically low-quality reviews. CONCLUSIONS: No single intervention type demonstrated substantial superiority across multiple pain populations. Other dimensions beyond efficacy, such as accessibility, safety, cost, patient preference, and efficacy for non-depressive outcomes should also be weighed when considering treatment options. Further effectiveness research is required for common pain types such as arthritis and axial pain, and common interventions such as opioids, anti-inflammatories and acupuncture. Chronic pain (CP) is a common and disabling group of health conditions defined as pain that persists or recurs for longer than 3 months [1] . CP affects approximately 20% of North American adults [2, 3] . Mental illness comorbidities like major depressive disorder (MDD) are disproportionately prevalent in people with CP, with rates ranging from 18% to 85% in various care settings [128] . This stands in stark contrast to the much lower 12-month prevalence for MDD in the general US population of 8-10% [5, 6] . In many cases, the comorbid prevalence of CP and MDD may also be underestimated and complicated by the common and overlapping symptomatology between these two conditions [7] as well as from effects of treatments such as medications. CP and MDD are known to exacerbate one another. CP increases the frequency and duration of depressive episodes [8] . Likewise, MDD contributes to significantly lower mental and physical quality of life in people with CP [9, 10] and may also intensify and reduce capacity to tolerate pain in pain populations [11, 12] . Overall, people living with the comorbidity report poorer well-being and functionality compared to those living with CP alone [9, 13] . Recent studies have also found that the development of chronic pain and depression are associated with changes in neuroplasticity in overlapping regions of the brain [14] . The cyclical and interactive nature of this comorbidity presents unique challenges that may not be sufficiently accounted for in clinical guidance for treatment of MDD alone. Meta-analyses for MDD treatments outside of the CP population may over-or underestimate treatment effects within the CP population. For example, psychotherapies and antidepressant medications could have synergistic effects on both MDD and CP, and thus greater overall effectiveness for people living with this comorbidity compared to those living with MDD alone. However, we also know that the effects of medications on mood can be hampered by severe and prolonged pain [4] . Furthermore, treating chronic pain is already complicated by analgesic polypharmacy [15] [16] [17] , but the addition of antidepressants and anxiolytics can further complicate treatment by reducing the analgesic efficacy of opioids [18] and increasing the overall burden of adverse effects [19, 20] . Given the high coprevalence, significant effects on overall quality of life, and challenges extrapolating evidence for MDD treatment in the general population to people living with pain, there is an evident need to synthesize the effects of commonly used CP interventions on depressive symptoms. This need for synthesis is further highlighted by the scant available guidance in clinical practice guidelines-one national guideline cited only a single randomized controlled trial for its single recommendation for MDD management in CP [21] . In the last decade, there have been more primary studies of interventions for improving depression in CP (e.g., [22] ), and there has been a corresponding proliferation of systematic reviews examining psychological, physical and pharmacological interventions for CP [23] [24] [25] , many of which report depressive symptom outcomes. However, there have been no reviews focused on capturing the effects of all clinical interventions on depressive symptoms among patients with all types of CP. The majority of existing reviews have focused on specific interventions (e.g., psychological therapies) [26, 27] or specific types of CP (e.g., low-back pain) [28, 29] . Investigating the effects across all interventions and CP types will allow for comparisons across groups and allow for the identification of areas of under-and overinvestigation. To better understand how existing interventions commonly used for people with CP may beneficially or negatively affect depressive symptoms, we conducted a systematic review of systematic reviews synthesizing any intervention in any type of CP that included a metaanalysis of depressive symptom outcomes. We developed a protocol guided by the Joanna Briggs Institute (JBI) recommendations [30] (PROSPERO registration: CRD42019131871). Our primary research questions were: 1) What clinical interventions demonstrate an effect on depressive symptoms in CP? 2) What are the effects of clinical interventions for depressive symptoms in CP and how do effects vary across interventions and pain types ? We searched MEDLINE, EMBASE, PsycINFO, CINAHL, AMED, the Cochrane Database of Systematic Reviews and the JBI Database of Systematic Reviews and Implementation Reports from inception to March 14, 2019 , with an update September 15, 2020. Findings from a small subset of reviews focused specifically on mindbody interventions and based only on the initial search from March 2019 have been reported elsewhere [31] . We initially developed the search strategy for MEDLINE and included a combination of controlled vocabulary and keywords for the concepts of "chronic pain" and "depression," then limited to a validated "systematic review" filter [32] . The search was validated against relevant studies previously identified for inclusion, peer-reviewed as per PRESS guidelines [33] , and adapted for the remaining databases (See Supplemental File 1 for MEDLINE Search Strategy). We identified additional records through hand-searching references of ten overviews of systematic reviews [26] [27] [28] [29] [34] [35] [36] [37] [38] [39] and included reviews. We included systematic reviews that examined adults with CP, defined as pain of any etiology, involving any body part lasting !3 months [41] (and present !15 days per month for chronic persistent headache [40] . We only included diseases with pain as a primary and necessary symptom (e.g., arthritis, but not chronic fatigue). We excluded pediatric populations (!50% of sample size <18 years of age) and cancer or end-of-life pain [42] . Formal MDD diagnosis was not an inclusion criterion. We included reviews of any kind of clinical intervention intended to address CP or a related aspect of CP. Interventions did not need to be explicitly developed for improving pain or depression in CP populations. No limitations were used for comparator type (e.g., placebo, usual care, active). We excluded reviews of nonclinical interventions such as public health interventions. We only included studies that reported quantitative syntheses of depressive symptoms using validated scales. Although there is no accepted list of validated scales for depressive symptoms in CP, expected scales included, but were not limited to, the Beck Depression Inventory, and the Hamilton Depression Rating, Montgomery-Asberg Depression Rating, and Centre for Epidemiological Studies Depression scales. Reviews lacking depressionspecific outcomes (e.g., mental health, "mood") were excluded, as were reviews that only reported surrogate (e.g., physiological) outcomes. Other outcomes such as pain or function were not evaluated in this systematic review. We included completed, published reviews that synthesized efficacy or effectiveness studies using experimental designs and included a meta-analysis of depression outcomes across multiple studies. We excluded nonintervention reviews or reviews that only included a narrative synthesis. Only the most up-to-date reviews of duplicate publications were included. We did not set limits in terms of outcome timeframe, context, or setting of reviews or their synthesized primary studies. We only included records published in English. After removing duplicates, we calibrated screening using a random set of 50 records, which were screened independently by all the screeners (A.S., K.L., D.C., C.C., O.P., and D.R.). All calibration screening discrepancies were discussed until consensus on screening decisions were reached. We then conducted title and abstract screening and full-text review independently and in duplicate (A.S., K.L., D.C., C.C., O.P., and D.R.) and conflicts were resolved by consensus or by a third author. We contacted systematic review authors to clarify record details as needed. We collected the following data: review details (citation, objectives, type of review, funding source, lead author country), target population (CP type, age, gender), number of included participants (total, intervention and control), intervention and comparator, primary study types, settings and contexts, search dates, nondepression outcomes reported, instrument for primary study quality, details of primary studies in depression syntheses (number, study type, depression symptom outcome scale, outcome timeframe, full study citation), depression synthesis outcome (effect size, confidence interval, measure of heterogeneity, P values of overall effect), methods of synthesis, and any additional comments. Outcome timeframe was categorized as short (immediately post-treatment), medium (<1 year post-treatment), or long (!1 year posttreatment). Prior to data extraction, two authors (D.C., A.S.) independently piloted a data extraction form on two reviews. We extracted data using the finalized form independently and in duplicate (A.S., K.L., D.C., C.C., O.P., G.M., D.R.). Inconsistencies and conflicts were resolved through consensus or by a third reviewer. We contacted authors for important missing information. We used the AMSTAR 2 quality appraisal tool to assess the risk of bias of included reviews. This 16-item checklist is widely used, comprehensive, has clear guidance on appropriate use, and is designed specifically for systematic reviews of healthcare interventions [43] . We completed the checklist [44] independently and in duplicate (A.S., K.L., D.C., C.C., O.P., and D.R.). Conflicts in scoring were resolved by consensus between raters or by a third rater. As recommended by developers, we reported an overall confidence in the review results as high, moderate, low, or critically low, determined by the matrix of responses. Ratings were not used as an inclusion criterion. Our principal summary measure was the synthesized effect size and 95% confidence interval (CI) for the depression outcome, which we described using Cohen's Effect Size (<0.2 ¼ trivial, 0.2 to 0.49 ¼ small, 0.5 to 0.79 ¼ medium, !0.8 ¼ large) [45] . Negative effect sizes indicated a reduction in depressive symptoms in response to the intervention evaluated, whereas positive effect sizes indicated either a worsening of depressive symptoms or that the comparator was more effective in reducing depressive symptoms. Some reviews reported positive effect size as improvement in depressive symptoms, and so such effects were converted to negative effects to align with the majority of reviews. We described, compared and contrasted results using visual and narrative approaches [30] . Data across studies were compared in terms of review quality, CP types, interventions, comparators, outcome timeframes, and the included underlying primary studies. Narrative results focused on moderateand high-quality reviews (see Supplementary Data for study-by-study findings). In order to visualize the breadth of the included literature and relationships between the included reviews and the primary studies they synthesized for depression outcomes, we created a network visualization using Gephi (software version 0.9.2) and Adobe Illustrator. We displayed each included systematic review and the primary trials they synthesized. Nodes (circles) represented reviews in grey and primary trials in blue and green, and the inclusion of trials in syntheses was represented by edges (connecting lines). Trial node size and color reflect the number of times it was synthesized in reviews (blue ¼ synthesized in one review; green ¼ synthesized in two or more reviews; size ¼ number of times synthesized). The size of review nodes reflected the number of trials that it synthesized. Reviews are considered as "overlapping" when they synthesize the same trial(s), which is visualized by edges connecting to the same trial node(s). We established pain type groups based on included populations reported in the reviews. Intervention types were also grouped based on descriptions reported in the reviews. In cases where reviews did not clearly define the intervention, we considered the described intervention components as well as the review's network connection with other reviews that more clearly defined interventions. Our search yielded 8,435 unique records, which were screened by title and abstract, leaving 496 for full-text review. Initially, 106 records were included. During data extraction, two updated reviews were identified: one replaced a review that was initially included; the other was added in addition to the original review, as different syntheses were conducted. In total, we excluded 25 studies during data extraction, leaving 83 included reviews ( Figure 1 ). Full-text-and data extraction-level exclusion reasons are included in Supplementary Data. Included reviews were published from August 1987 to December 2020 and synthesized depression outcomes from 459 unique primary studies published from January 1981 to November 2018 (Table 1 ). Reviews were most commonly conducted by researchers in Germany (24%, n ¼ 20) and the United Kingdom (18%, n ¼ 15). Thirtyfive (42%) reviews were conducted by six distinct groups of authors. Thirty-five (42%) reviews included depressive symptoms as a primary outcome. A total of 182 meta-analyses were extracted. Fibromyalgia (31%, n ¼ 56), and mixed or unspecified chronic pain (30%, n ¼ 55), inactive comparators (29%, n ¼ 53), and short outcome timeframes (36%, n ¼ 65), were most common. Sample sizes ranged from 24 to 6,478 participants (mean ¼ 646) as reported in 81% (n ¼ 147) of the meta-analyses. Forty-two percent of meta-analyses (n ¼ 77) were extracted from reviews funded by the government, 3% (n ¼ 5) were funded by industry, and 27% (n ¼ 49) did not report funding details. Reviews were rated high-(12%, n ¼ 10), moderate-(16%, n ¼ 13), low-(24%, n ¼ 20), and critically low quality (48%, n ¼ 40). The most common critical quality issues were: no list of reasons for excluded full-text articles (Question 7 [Q7]; 54%, n ¼ 45); no investigation of causes of heterogeneity (Q11; 28%, n ¼ 23); and no investigation of publication bias or discussion of its impacts (Q15; 28%, n ¼ 23). The most common noncritical quality issues included: no explanation of included study designs (Q3; 92%, n ¼ 76); no description of included study funding details (Q10; 83%, n ¼ 69); and no account for risk of bias in when interpreting/discussing results (Q12; 35%, n ¼ 29). We identified eight pain types. Since some reviews aggregated types of pain differently in their meta-analyses, some of these pain types overlap: 1 We identified 13 types of interventions (Table 2 ). Across the 83 reviews, fibromyalgia (35%, n ¼ 29), mixed CP (28%, n ¼ 23), and arthritis (16%, n ¼ 13) were the most common pain types evaluated, and psychological (45%, n ¼ 37), pharmacological (18%, n ¼ 15), and mind-body (15%, n ¼ 12) were the most common intervention types ( Figure 2 ). See Supplementary Data for detailed Network Visualization; Captions include instructions to view. The network visualization provides a representation of the current landscape surrounding interventions for depression in people with chronic pain. Many included reviews synthesized the same primary articles and this overlap created multiple networks of connected reviews. Within these networks, distinct subgroups formed based on both pain type and intervention type. The largest network included 37 (45%) reviews of psychological interventions with a variety of subtypes (Table 2 ). One high-quality review [77] comparing ACT in mixed chronic pain against inactive comparators over medium outcome timeframes reported the largest significant point estimate (SMD À0.71 [95% CI À1.09 to À0.33]); three RCTs; 109 participants. One synthesis of four RCTs with 437 participants from a moderatequality review [51] reported a significant medium effect of reducing depressive symptoms for web-based psychotherapy in fibromyalgia with mixed comparators across all timeframes (SMD À0.51 [95% CI À0.87 to À0.15]). This was larger than for in-person CBT where the only meta-analysis from a high-quality review [50] The reviews of mind-body interventions examined effects in fibromyalgia and mixed chronic pain, while three unconnected reviews evaluated arthritis and axial pain. The largest significant effect of reducing depressive symptoms was from a moderate quality review [82] of meditation with mixed comparators synthesizing six RCTs with 658 participants (SMD À0.49 [95% CI À1.89 to À0.1]). Overall, mindful movement demonstrated small to medium effects with larger effects in axial pain than in fibromyalgia and also generally larger effects than meditation [31] . The exercise network only included reviews specific to fibromyalgia, arthritis, and musculoskeletal pain. The single meta-analysis of nine RCTs with 876 participants from a high-quality review [78] reported a small significant effect for exercise-based rehabilitation for arthritis (SMD À0. 16 [95% CI À0.29 to À0.02]). The single meta-analysis of 29 RCTs with 2,449 participants from a moderate-quality review of musculoskeletal pain [81] reported a small but significant effect for mixed exercise interventions against mixed comparators over medium/long timeframes (SMD À0.42 [95% CI À0.58 to À0.26]). Two low-and critically low-quality reviews [89, 124] investigated massage therapy in fibromyalgia. A moderate-quality review [98] investigated water-based interventions (balneotherapy and hydrotherapy) in fibromyalgia. The only meta-analysis here with a significant point estimate showed small effects on depressive symptoms for balneotherapy against inactive comparators at mixed medium/long outcome timeframes and included 205 participants from three RCTs (SMD À0.31 [95% CI À0.59 to À0.03]). There was no overlap between the main and pharmacological networks, meaning primary articles that were synthesized in the main network were not synthesized by any reviews in the pharmacological network and vice versa. The 16 reviews investigating pharmacotherapy showed a quality dichotomy: 53% were critically low, and 33% were high-quality. This network included the only three reviews reporting industry funding [70, 72, 110] . All pharmacological meta-analyses included only inactive comparators. Meta-analyses examined the Massage therapy that involved manipulation of the soft tissues in a systematic way-did not include Reiki or other manual therapy such as chiropractic, or spinal manipulation. Water therapy Therapies involving immersion in plain, mineral, or thermal water, sometimes with exercise components. Music therapy Listening to music, sounds, or rhythms, melodies, or chords. Included self-or instructorchosen recorded music, group music, and group music and guided imagery. Combined CAM and pharmacological One review synthesized trials investigating pharmacological interventions and herbal supplements together. Cannabinoids Cannabis extracts and synthetic cannabinoids. A therapeutic method of traditional Chinese medicine using needles to stimulate specific body points. Yan 2020 *Interventions not investigated by entire reviews, but separated out in distinct meta-analyses within reviews, and cannot be displayed in the network visualization ( Figure 2 ). ACT ¼ acceptance and commitment therapy; CAM ¼ complementary alternative medicine; CBT ¼ cognitive behavioral therapy; SSRIs ¼ selective serotonin reuptake inhibitors; SNRIs ¼ selective norepinephrine reuptake inhibitors; TCAs ¼ tricyclic antidepressants. following medications (number of meta-analyses): antidepressants, including selective serotonin reuptake inhibitors (SSRIs; 3), selective serotonin-norepinephrine reuptake inhibitors (SNRIs; 9), tricyclic antidepressants (1), and mirtazapine (1); gabapentinoids (8) , and quetiapine (1). The three meta-analyses from high-quality reviews with the largest significant point estimates in reducing depressive symptoms evaluated fluoxetine (SMD À0.55 [95% CI À0.93 to À0.18]; three RCTs; 116 participants) [114] , all SSRIs (SMD À0.39 [95% CI À0.65 to À0.14]; six RCTs; 244 participants) [114] , and quetiapine (SMD À0.39 [95% CI À0.74 to À0.04]; three RCTs; 206 participants) [113] in fibromyalgia at short timeframes. Gabapentinoids demonstrated larger effects in patients with neuropathic pain than in those with fibromyalgia, although the two meta-analyses from highquality reviews demonstrated trivial effects in both [100, 110] . All SSRI syntheses were conducted in fibromyalgia and had small to medium significant effect sizes. The SNRI syntheses demonstrated small to trivial significant effects. A variety of systematic reviews investigated brain stimulation [76, 83, 123] , music [64, 116] , complementary and alternative medicine (CAM; [52, 55, 62] ), acupuncture [121] , cannabis [108] and interventional therapy Figure 2 . Network visualization of reviews and synthesized primary articles. CAM ¼ complementary alternative medicine; BRAIN STIM ¼ brain stimulation; EDU ¼ education-based treatment; MDC ¼ multidisciplinary care; PHARM¼ pharmacological therapy; PSYCH ¼ psychotherapy; Self-Reg ¼ self-regulatory treatment; SNRIs ¼ selective-norepinephrine reuptake inhibitors; SSRIs ¼ selective serotonin reuptake inhibitors; WATER ¼ water-based therapy. [99] . The majority of these reviews were either of low-or critically low quality. One moderate-quality review [123] investigated the effects of brain stimulation in people with neuropathic pain and showed small to medium, nonsignificant effects on reducing depressive symptoms. The other moderate-quality review investigated the effects of herbal Chinese medicines combined with pharmacological interventions in people with arthritis [62] and reported small, non-significant effects. The majority of fibromyalgia meta-analyses investigated the effects of pharmacological (26%), mind-body (18%), and mixed psychological (9%) interventions (Figure 3 ; Supplementary Data for detailed figure and plot of Effect Size by Intervention Type and Quality). This was the only pain type that included meta-analyses of massage therapy, water therapies and CAM. Among the high-and moderate-quality reviews, the meta-analyses with the largest significant point estimates showed medium effects of reducing depressive symptoms for fluoxetine (SMD, À0.55 [95% CI À0.93, À0.18]; three RCTs; 116 participants) [114] , and web-based psychological therapies (SMD À0.51 [95% CI À0.87 to À0.15]; five RCTs; 437 participants) [51] . Meta-analyses specifically for gabapentinoids and milnacipran showed trivial effects. The large majority of mixed CP meta-analyses investigated the effects of psychological interventions, including ACT (20%), web-based psychotherapies (18%), and mixed psychological (16%). Mind-body and cognitive behavioral interventions were also prominently represented (13%, each). Among moderate-and high-quality reviews, ACT was the most effective therapy (SMD À0. 71 The majority of arthritis meta-analyses investigated psychoeducation (22%) and mixed psychological (17%) interventions. Mind-body interventions, exercise, CBT, and CAM combined with pharmacological interventions were also represented (11%, each). The single synthesis from a high-quality review [78] included nine RCTs with 876 participants and reported a significant but small effect (SMD À0.16 [95% CI À0.29 to À0.02]) for exercise. The largest significant point estimates from moderate-quality reviews were reported for psychoeducation (SMD À0.22 [95% CI À0.34 to À0.09]; three RCTs; 1,426 participants [63] and SMD À0.14 [95% CI À0.23 to À0.05] 18 RCTs; 1,770 participants [101] ). The majority of axial pain meta-analyses synthesized the effects of behavioral (31%), multidisciplinary (24%), and self-regulatory (17%) psychological, as well as mindbody (14%), interventions. No meta-analyses from highor moderate-quality reviews reported significant effects on depressive symptoms in axial pain. A number of meta-analyses (largely behavioral psychological therapy) against active comparators (exercise, self-regulatory, and physical interventions) had positive effect sizes, suggesting that the comparators were more effective in reducing depressive symptoms (see Supplementary Data) [73, 75, 80] . The 12 neuropathic pain meta-analyses investigated the effects of pharmacological interventions versus inactive comparators (83%) and brain stimulation (17%). Only one meta-analysis of four RCTs with 1,041 participants was from a high-quality review [100] and showed a trivial, nonsignificant effect for gabapentinoids (SMD À0.06 [95% CI À0.26 to 0.13]). Other syntheses of gabapentinoids from critically low-quality reviews found small to large non-significant effects. Meta-analyses of antidepressants from a moderate-quality review [57] found small effects. There were six musculoskeletal pain meta-analyses, all with mixed comparators, from three different systematic reviews. The only meta-analyses from a moderate-quality review [81] evaluated exercise across 29 RCTs with 2,449 participants and reported a significant small effect (SMD À0.42 [95% CI À0.58 to À0.26]). There were six meta-analyses of interventions studying chronic orofacial pain from two reviews examining psychological interventions, and one investigating local anesthetic injections. Small but significant effects were reported for the psychological interventions versus usual care, while the reports for injections were small and nonsignificant. The only meta-analysis extracted from a moderate-quality review demonstrated that psychologically-based multidisciplinary care over medium timeframes had small effects (SMD À0.21 [95% CI À0.41 to 0.00]; four RCTs; 510 participants [102] ). Two chronic headache meta-analyses were extracted from a critically low-quality systematic review [61] and both investigated the effects of web-based psychological interventions. Neither synthesis reported significant effects. ACT for general chronic pain, and fluoxetine and webbased psychotherapy for fibromyalgia were the only interventions for which there was at least a medium, significant improvement in depressive symptoms as synthesized in moderate-to high-quality reviews. Exercise for arthritis, pharmacotherapy for neuropathic pain, selfregulatory psychological therapy for axial pain, and music therapy, ACT, and mixed psychotherapy for general chronic pain showed large significant effects, but these were derived from low-or critically low-quality reviews. The distribution and magnitude of effects for depressive symptoms are comparable to those of other important outcomes for chronic pain conditions such as a pain severity [34, 35] and anxiety [39] . There were no interventions synthesized in moderate-or high-quality reviews that demonstrated a large, significant effect for reducing depressive symptoms in chronic pain. Only one meta- analysis examining long-term effects in a moderatequality review showed trivial effects in psychologically focused multidisciplinary care [80] . Interventions commonly employed for the management of chronic pain such as opioids, anti-inflammatories, and chiropractic have not been meta-analyzed for their effects on depressive symptoms and should be considered for future syntheses. Reports on acupuncture and cannabis were also very limited. For most pain types, the majority of syntheses showed trivial to small effects in reducing depressive symptoms. This trend appears to span across all quality levels and includes both significant and non-significant effects. One critically low-quality review from Iran [79] reported very large and significant effects for psychotherapy in mixed chronic pain, but suggested that cultural differences in pain perception and variations in study methods may have affected validity and observed magnitude of effect sizes which were out of keeping with the remainder of the reviews. In three reviews that investigated people with axial pain [73, 75, 80] , several syntheses of psychological interventions reported positive effect sizes, demonstrating that the comparators (exercise, physiotherapy, and self-regulatory interventions), were more effective in reducing depressive symptoms than psychotherapy. This is similar to the findings of another umbrella review of interventions for neck pain which found that psychosocial interventions including psychoeducation were not beneficial across a number of outcomes [35] . In this review of reviews, we found that meta-analyses with active comparators generally showed smaller effects. No trends were identified for reviews that included depressive symptoms as a primary versus secondary outcome. Three reviews of pharmacological interventions were the only ones to report industry funding and all reported trivial to small effects [70, 72, 110] . A broad range of interventions and methods of delivery have been investigated for addressing depressive symptoms in people with chronic pain. However, no single intervention type demonstrates substantial superiority across different pain populations. In fibromyalgia, fluoxetine and web-based psychotherapy show comparable medium effect sizes, and the latter can be prioritized in the context of physical distancing measures in response to the COVID-19 pandemic. In mixed chronic pain, ACT also showed medium effect sizes on depressive symptoms. For other pain types, this suggests that patients, clinicians and program planners should also consider other dimensions besides efficacy such as individual preference, intervention availability, safety, cost, and also efficacy for nondepressive outcomes when considering treatment and policy options. Nonspecific factors that are common across psychotherapies, such as warmth of the therapist, therapeutic alliance, and accurate empathy [126] may also play a role in reducing depressive symptoms when present in other interventions. This also points to a need for further investigation and synthesis of interventions for improving depressive symptoms in pain types other than fibromyalgia and mixed chronic pain. This is despite the comparable prevalence of comorbid depression across pain types [127] [128] [129] [130] . Likewise, the prevalence of axial and arthritic pain is significantly higher than fibromyalgia [131] [132] [133] , which strongly suggests a misalignment between population health and clinical epidemiology priorities. This may in part be due to biases about mental illness comorbidities in different kinds of pain, as well as differences in standardized instruments across different pain types and the inclusion of variable depression measures [134] . Within fibromyalgia and generalized chronic pain, there is an opportunity for formal estimates of comparative efficacy, such as through network meta-analysis, and a need for further synthesis of depressive symptom effects as a distinct and important outcome. Many existing reviews either do not synthesize this outcome or subsume depression outcomes within a catch-all mental health or quality of life outcome, exemplified in a recent synthesis of acupuncture [135] . Large bodies of research have investigated psychological interventions, as well as mind-body, and pharmacological interventions. Future research should aim to study and synthesize other intervention types including exercise and massage therapy which show reasonable efficacy in the few lower quality reviews completed to date. Exercise shows beneficial effects for a variety of other nondepression chronic pain outcomes together with few adverse effects [28] . Looking outside of chronic pain, there is evidence that the combination of psychotherapy and pharmacotherapy can lead to large depression improvements with effects lasting up to 2 years post-treatment, suggesting that a combination approach in chronic pain populations merits further investigation [136] . As demonstrated by the network visualization, there has so far been no overlap between pharmacological systematic reviews and reviews of other kinds of interventions. Depressive symptoms were the focus of this review of meta-analyses since much existing literature does not specifically focus on MDD. Indeed, clinical trials across various fields often exclude people with comorbid mental illnesses including specifically those with more severe depression [137, 138] . As such, when applying these findings to people living with chronic pain and comorbid MDD, it is important to consider that changes in depressive symptoms in individuals with subthreshold symptomology may differ from those with MDD. Given the very high comorbid prevalence of MDD in chronic pain, further study and synthesis of outcomes specifically in people with MDD is merited. Given identified challenges and controversies in translating standardized mean differences in depression outcomes to minimally important differences [139] , we have not made attempts to interpret effect sizes in terms of clinically significant effects. Intervention types were often not well-defined and often included overlapping components, making it challenging to aggregate meta-analyses by intervention type. We attempted to mitigate this by aggregating intervention types by review descriptions and augmenting this categorization using visual network analysis. However, these groupings may not perfectly distinguish between intervention types. Future systematic reviews in this area should provide detailed intervention descriptions, for example, by using recommended reporting checklists and guidelines [140, 141] . Pain types were grouped based on definitions provided by included reviews, which were inconsistent and varied in specificity. Some reviews included broader definitions of pain types compared to others, limiting our ability to create more distinct pain type groups in our evaluations. This heterogeneity was noted at the level of randomized controlled trials included in the meta-analyses, so disaggregation of the meta-analyses and then reaggregation based on specific pain types would be unlikely to resolve this challenge. Comparator types varied across as well as within reviews, and at other times were unreported. Generally, as is to be expected, analyses against active comparators showed smaller effect sizes, however, inconsistencies in comparator reporting limit our ability to draw firm conclusions about treatment effects. The AMSTAR 2 was used to appraise risk of bias, but the overall rating does not necessarily reflect the scientific rigor of the underlying primary evidence as AMSTAR 2 ratings are influenced by reporting practices of systematic reviewers. Given this, AMSTAR 2 ratings need to be taken into consideration when summarizing and interpreting results, but the evidence synthesized by reviews of low-or critically low quality should not be discounted altogether. The scope of this review of meta-analyses did not consider the effects on other pain-relevant outcomes such as pain intensity, function or quality of life, which are also important to investigate in relation to depression in chronic pain [142] . However, these have been widely analyzed in a variety of other systematic reviews and umbrella reviews [143] [144] [145] [146] . Finally, as a review of reviews, there may be important primary trials evidence that has not been captured in this synthesis. This would include primary trials published after the publication of the relevant review, trials that are studying unique interventions that are not easily synthesized with results of other trials, or trials that have otherwise not been captured by existing systematic reviews. For this and other reasons, it is important to note that an absence of evidence for a specific intervention does not imply an absence of effectiveness. A wide variety of interventions have been meta-analyzed for effects on depressive symptoms on different kinds of chronic pain. The most common pain types were fibromyalgia and mixed chronic pain, and psychological interventions were most often examined. Acceptance commitment therapy, fluoxetine and web-based psychotherapy were the most promising interventions and can be currently prioritized for implementation in clinical practice. The majority of interventions showed small to trivial effects, and the only negative effects were demonstrated when interventions were compared against active controls. Effects on depressive symptoms so far have been under-synthesized in common pain interventions such as opioids and acupuncture. There is also a need for more assessment and synthesis of depression outcomes in common pain conditions such as arthritis and axial pain. 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Supplementary data are available at Pain Medicine online .