Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update (April 16, 2020). Andrea C. Skelly, Ph.D., M.P.H., Roger Chou, M.D., Joseph R. Dettori, Ph.D., M.P.H., M.P.T., Judith A. Turner, Ph.D., et al. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 (Apr)

This section was compiled by Frank M. Painter, D.C.
Send all comments or additions to:   Frankp@chiro.org

Discussion

Key Findings and Strength of Evidence

Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64

This report updates the prior 2018 Agency for Healthcare Research and Quality (AHRQ) report. The key findings of this review, including strength of evidence (SOE) ratings, are summarized for each chronic pain condition in Tables 48–63 and reflect the totality of evidence from the 2018 review combined with new evidence from this update (interventions and comparators with no evidence for either function or pain outcomes are not shown). Changes to effect size or SOE based on integration of new trials with the 2018 evidence base are footnoted in the tables. Domains used to determine the overall SOE are shown in Appendix G. All outcomes were considered direct. The SOE was low or insufficient for many interventions and was limited by small numbers of trials for specific comparisons and for our specified time frames, particularly for long term. We focused on evaluating the persistence of effects for therapies beyond the course of treatment, using the following definitions for postintervention followup: short term (1 to <6 months), intermediate term (≥6 to <12 months) and long term (≥12 months). Evidence was particularly limited on effects for long-term outcomes; only two new trials contributed additional long-term data.

No trials in pregnant or breastfeeding women with pre-existing chronic pain or new trials comparing interventions with topical agents, medical cannabis or muscle relaxants were identified. No data were available to evaluate nociplasticity as a modifier to treatment effectiveness or safety.

The majority of trials compared interventions with usual care with very few trials employing pharmacological treatments or exercise as comparators; only three new trials of interventions versus active comparators were identified. In general, effect sizes for most interventions remained small, based on mean differences. Few trials reported on patients meeting clinically important differences. There tended to be more evidence for the effects of interventions on pain than for function, and the effects on function were generally smaller or not clearly present. Information on adherence to interventions was not well-reported; poor adherence may have impacted some of our findings.

No trials directly compared interventions with opioids and few trials reported effects of intervention on opioid use. In our concurrent review on opioid medications for chronic pain management, opioids were associated with small effects on pain and function during treatment compared with placebo (effects would not be expected to persist) but evidence is primarily from short-term (≤3 month) trials. [13, 19, 28, 284] There were no differences in pain, function or other outcomes for opioid compared with nonopioid medications.

Harms were poorly reported across interventions and reported harms varied in scope and specification. No serious intervention-related adverse events (e.g., leading to death, disability or requiring intensive medical attention) were identified; reported adverse events were generally minor (e.g., muscle soreness or increased pain with exercise, bruising or discomfort with acupuncture) and time-limited (e.g., temporary worsening of pain). Evidence was moderate for no differences between treatment groups for author-defined serious adverse events for spinal manipulation versus exercise (low back pain, 7 randomized controlled trials [RCTs]) or acupuncture versus sham, placebo, or usual care (neck pain, 6 RCTs; knee osteoarthritis, 9 RCTs; fibromyalgia, 4 RCTs). Evidence was low or insufficient for other adverse events. Table 64 summarizes reported adverse events for each intervention.

The findings below reflect integration of trials from the prior report (2018) with new trials for this update. Changes to SOE and/or effect size based on inclusion new trials are footnoted in the tables.

Low Back Pain.   For chronic low back pain (LBP), compared with usual care, attention control, sham, or placebo, there was moderate evidence of small improvement in function, at least in the short term, for exercise, massage, psychological therapies (cognitive-behavioral therapy [CBT]) and moderate improvement with yoga (SOE: moderate). There was low evidence of small functional improvement for acupuncture, low-level laser therapy, spinal manipulation, and multidisciplinary rehabilitation (MDR) (SOE: low). With the exception of spinal manipulation, these interventions also showed small improvement (acupuncture, massage, psychological therapies, MDR; SOE: low) or moderate improvements (exercise, yoga, low-level laser therapy, SOE: low) in pain short term. Interferential therapy did not improve function or pain short term (SOE: low). The small improvements in function compared with controls were sustained into the intermediate term for yoga, spinal manipulation, psychological therapies, and MDR, with low strength of evidence for all but the psychological therapies, for which SOE was moderate. No clear improvement in function was seen at intermediate term for exercise, acupuncture, massage or low-level laser therapy (SOE: low for all).

Improvements in pain were seen in the intermediate term for exercise, yoga and mindfulness-based stress reduction (MBSR) (small effects, SOE: low for all) as well as spinal manipulation, psychological therapies and MDR (small effects, SOE: moderate). Long-term evidence was available for four intervention categories: psychological therapies, MDR, exercise, and acupuncture. The strongest evidence was for psychological therapies (CBT primarily), which were associated with small improvements versus usual care or attention control in both function and pain at short, intermediate, and long term (SOE: moderate for all time frames). Neither exercise nor acupuncture was associated with improved function long term, even though both demonstrated continued pain improvement (SOE: low for all). For MDR, effects on function from earlier time frames were not sustained in the long term versus usual care (SOE: low). High intensity MDR (≥20 hours/week or >80 hours total) was not clearly better than nonhigh intensity programs. Short-term effects on function and pain were somewhat larger with high intensity MDR than with nonhigh intensity interventions but the tests for interaction were not statistically significant. At intermediate term, estimates were similar for high intensity and nonhigh intensity programs.

In people with chronic LBP, there were no clear differences in short-term function for comparisons of qigong, yoga, or spinal manipulation with exercise even though small improvements in pain were seen for yoga (SOE: low for all). MDR was associated with small effects on function short term as well as pain (SOE: moderate). For Qigong, results for intermediate-term function and short-term pain slightly favored exercise (SOE: low for all). Again, MDR was associated with small improvements in function and pain at intermediate term (SOE: moderate), but this was not sustained in the long term (SOE: low). Long-term data were only available for MDR.



Neck Pain.   For chronic neck pain, in the short term, moderate effects on function and pain were seen for low-level laser therapy (SOE: moderate). Massage conferred a small improvement in function and moderate improvement in pain short term; the functional improvement did not persist into intermediate term (SOE: low for all). In the short term and intermediate term, acupuncture and Alexander Technique were associated with a small improvement in function compared with usual care (both interventions), sham acupuncture or sham laser (SOE: low). The effect of acupuncture was not sustained long term (SOE: low) compared with sham acupuncture, sham laser, or usual care, and no improvement in pain was seen at any time frame (SOE: low). There were no clear improvements in function or pain at short or intermediate term across types of exercise or for psychological therapies (physical therapist–led relaxation training alone) compared with usual care, sham procedures, or attention controls (SOE: low for all). A small improvement in function was associated with exercise long term versus attention control (SOE: low). A subgroup of two trials of combination exercises (including 3 of the following 4 exercise categories: muscle performance, mobility, muscle re-education, aerobic) suggests a small benefit in function and pain versus waitlist or attention control over the short term. Exercise (Pilates) was associated with a small functional improvement and large improvement in pain short term compared with acetaminophen (SOE: low).



Knee Osteoarthritis Pain.   For knee osteoarthritis (OA), exercise was associated with small functional improvement in the short term compared with usual care, attention control, or sham procedure; the effect size was small for exercise (SOE: moderate). The small effects of exercise on function persisted into the intermediate term as moderate but were small at long term (SOE: low for both). A similar pattern for improvement in pain was observed; small effect (SOE: moderate) at short term, moderate at intermediate term and small at long term (SOE: low for intermediate and long term.) There were no clear benefits to ultrasound at short or intermediate term (SOE: low). With the exception of a small improvement in short term pain, no clear differences between psychological interventions (pain coping skills training, CBT) and usual care were observed (SOE low). There were no clear differences in function or pain associated with electromagnetic fields (short-term, SOE: low), or with acupuncture at short (SOE: moderate) or intermediate term (SOE: low) versus usual care, attention control, or sham procedure. There was no difference in function or pain between pain coping skills training and exercise at short term or intermediate term in one trial (SOE: low). There was no intermediate term improvement in function or pain with exercise versus acetaminophen and nonsteroidal anti-inflammatory drugs (SOE: low).



Hip and Hand Osteoarthritis Pain.   Evidence was sparse on interventions for hip and hand OA. Exercise was associated with small improvements in function compared with usual care at short and intermediate-term (SOE: low), but data were insufficient to determine long-term effects. For pain, a small effect was seen only at short term; no differences were seen at the other time points (SOE: low for short term and intermediate term, insufficient for long term). Compared with exercise, a small effect on function was seen with manual therapy in the short and intermediate term, and small improvement in pain short term (SOE: low for all). For hand OA, no clear differences were seen for low-level laser therapy versus sham or for MDR versus waitlist control at short term for either function or pain (SOE: low).



Fibromyalgia.   Short term, in patients with fibromyalgia (FM), there was low-quality evidence of small improvements in function were associated with exercise, MDR, and mind-body practices of tai chi and qigong (SOE: low for all) compared with wait list and attention control, and moderate-quality evidence with acupuncture compared with sham acupuncture (SOE: moderate). Small improvements in short-term pain were seen with exercise (SOE: moderate) and CBT (SOE: low) and moderate improvements with mind body practices (SOE: low), but not with acupuncture. No clear differences in function or pain outcomes were seen for mindfulness practices short term (SOE: moderate), but small improvements in both were noted at intermediate term (SOE: low). Intermediate term, small improvements in function continued for acupuncture and exercise (SOE: moderate). CBT was associated with moderate functional improvement (SOE: low) and small improvements were seen for mindfulness practices, myofascial release massage and MDR; there was no clear effect of magnetic mattress pads versus sham pad (SOE: low for all). Small improvements in pain intermediate term were seen for mindfulness practices and MDR (SOE: low) and for exercise (SOE: moderate), but not for CBT, acupuncture, or magnetic mattress pads (SOE: low). Long term, small improvements in function continued for MDR but not for massage (SOE: low); while massage conferred a small improvement in pain long term, MDR did not (SOE: low). There was no clear long-term impact on function or pain for exercise (SOE: moderate). No clear differences were seen between MDR and exercise for the long term on function or pain (SOE: low). Tai chi was associated improved function compared with exercise at short and intermediate terms but this did not persist long term (SOE: low). CBT was associated with a small benefit for function but not for pain compared with pregabalin at intermediate term (SOE: low).



Chronic Tension Headache.   Only nine trials of nonpharmacological treatments for chronic tension headache met the inclusion criteria and all but one was considered poor quality, resulting in a rating of insufficient evidence for comparisons of psychological therapies with waitlist or attention control, electrical stimulation versus sham, and acupuncture versus sham. One fair-quality trial of laser acupuncture versus sham suggested moderate improvement in pain short term (SOE: low), and another fair-quality trial of spinal manipulation versus usual care suggested a small effect on short-term function based on the Headache Impact Test (SOE: low). Approximately 25 percent of the patients in the trial had comorbid migraine headache.



Usual Care/Waitlist and Nonactive Comparators.   For comparisons involving usual care/waitlist or nonactive comparators (placebo, sham, attention control), there were some differences depending on the specific comparator evaluated. For some interventions results different by control type. For example, in some analyses, acupuncture was associated with greater effects on pain in patients with chronic low back pain or OA when compared with usual care than when compared with sham acupuncture, suggesting that much of the benefit may be due to placebo or other nonspecific effect.



Harms.   Harms were poorly reported across interventions. No serious intervention-related adverse events (e.g., death, disability or those requiring intensive medical attention were identified; reported adverse events were generally minor (e.g., muscle soreness with exercise, bruising with acupuncture) and time-limited (e.g., temporary worsening of pain). Evidence was moderate for no differences between treatment groups for author-defined serious adverse events spinal manipulation versus exercise (LBP, 7 RCTs) or acupuncture versus sham, placebo, usual care (neck pain, 6 RCTs; knee OA, 9 RCTs; FM, 4 RCTs). Evidence across some conditions and interventions was insufficient to draw meaningful conclusions regarding harms and adverse events. Table 64 above provides an overview of treatment-related adverse events reported in included trials. Many trials stated that there were no adverse events. Adverse events were not always well-defined or described. Detailed information on reported events is contained in the data abstraction. Harms and adverse events, including SOE, are discussed by condition and intervention in the report; SOE is detailed in Appendix G.



Medication Use.   Few trials compared opioid use pre- and postintervention, and medication use in general was not well reported across trials.



Subgroups.   One fair-quality trial in people with knee OA formally examined factors that might modify the effect of exercise on disability; the effect of exercise on activities of daily living disability did not appear to be modified by age, sex, baseline disability, knee pain score, body mass index, or race. [57] The few trials that reported subgroup analyses either did not provide sufficient data to assess modification by demographic or other factors or did not formally test for modification; trials were generally too small to effectively evaluate outcomes in subgroups.

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Findings in Relationship to What Is Already Known

The updated evidence in this systematic review provides some additional support for the effectiveness of selected nonpharmacological treatments presented in the 2018 review. New trials filled evidence gaps identified in the previous report in a few areas. There is now evidence for benefits of massage therapy on short-term pain and for exercise versus acetaminophen on function and pain for chronic neck pain, for CBT on short-term pain in knee OA, and for mindfulness practices on intermediate term function and pain and for tai chi versus exercise on short and intermediate term function in persons with fibromyalgia. Conclusions regarding effect sizes and SOE remained the same for the addition of trials for many interventions. As noted in the summary tables, some additions led to changes in effect size. For example, new trials of exercise versus nonactive comparators in chronic low back pain and knee OA resulted in different conclusions in some instances. For chronic low back pain, short term SOE was upgraded from low to moderate for small improvement in function and for pain improvement the effect size was upgraded to moderate, but the strength of evidence downgraded to low. For knee OA, effect sizes were upgraded for functional improvement to moderate at intermediate term function, and the addition of the only two trials with long-term data led to upgrading effect size to small where no difference was noted in the previous report; however, SOE remained low.

Many reviews have addressed the effects of interventions for chronic pain management during or immediately following treatments. We focused on evaluating the sustainability of effects for at least 1 month postintervention.

This review provides additional updates to our previous review on low back pain. [28] Consistent with the prior review, we again found exercise, yoga, various psychological interventions (primarily CBT), acupuncture, spinal manipulation, and low-level laser therapy with small to moderate effects on function and/or pain. This report differs from the prior low back pain review by focusing on durability of treatment effects 1 month or longer after completion of a course of treatment and basing estimates on meta-analyses when poolable data were available, and conducting stratified and sensitivity analyses to evaluate sources of heterogeneity and robustness of findings. Although we found some evidence that beneficial effects of some nonpharmacological therapies persist for up to 12 months following the end of a course of a treatment, data on longer-term (>1 year) outcomes were very sparse in previous reports and remain so.

A recent Institute for Clinical and Economic Review (ICER) review [285] on chronic low back pain and neck pain used relevant portions of our previous review for chronic low back pain and updated it with new publications so the findings are generally consistent with our review for this condition. For chronic neck pain, this report and the ICER report both suggest a small benefit for acupuncture. The ICER report focuses on evaluating comparative value for interventions and suggests that cognitive and mind-body therapies for treatment of chronic low back pain and chronic neck pain would be cost-effective, would meet value-based price benchmarks, and may result in only a small increase ($0.75) per member per month for a hypothetical payer plan covering 1 million members, compared with approximately $4.46 per member per month for pain medication.

Our findings indicate that a number of nonpharmacological treatments improve pain and/or function for specific chronic pain conditions included in this review. This is consistent with other reviews, including recent reviews on exercise [286] acupuncture, [287] and complementary health approaches [288] for chronic pain management across various conditions, an AHRQ report on knee OA treatment, [289] and a review of chronic pain treatment guidelines on the use of manual and physical therapies. [290]

The protocol for a systematic review and network meta-analysis of interventions for fibromyalgia was identified; [291] no publication timeline for this review is currently available.

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Applicability

New trials included for this update did not provide additional clarity on applicability. The applicability of our findings continues to be impacted by a number of factors. Symptom duration, clinical characteristics, comorbid conditions, the presence of overlapping chronic pain conditions or psychosocial factors and concomitant treatments were rarely reported. In addition, with the exception of fibromyalgia, information regarding diagnostic criteria for the pain condition of interest was limited. Information related to centralization of pain was not described. Thus, it is difficult to evaluate the extent to which populations represented in the included RCTs are reflective of those in primary care clinical practice. The majority of trial participants were female. The age of included populations generally reflected the ages impacted by the conditions. Our review did not include children or adolescents or people with other chronic pain conditions not included in our specified populations. Evidence to evaluate how effectiveness varies by age was limited. Duration of chronic pain, severity of pain (most trials enrolled patients with at least moderate pain at baseline), as well as other factors (e.g., use of medications, medical and psychological comorbidities), varied across trials. Our findings are generally most applicable to people without such comorbidities who have moderate or severe intensity pain that has persisted for more than 12 months. The heterogeneity in populations across included trials likely is consistent with the heterogeneity seen in clinical practice, so our findings may be applicable to most primary care clinical settings.

Heterogeneity in interventions, comparators and co-interventions may impact applicability. Substantial variability in the numbers of sessions, length of sessions, duration of treatment, methods of delivering the intervention and the experience and training of those providing the interventions present a challenge to assessing applicability. To address heterogeneity within intervention categories we abstracted details of techniques or methods used, (e.g., specific type of psychological intervention or yoga) and attempted to stratify by them, however in most cases, data were insufficient to do so. In general, there were no clear differences in effects based on intervention factors or comparators (e.g., sham acupuncture, usual care); however analyses were quite limited by small numbers of trials. In clinical practice, most chronic pain patients likely use a combination of therapies and may continue to receive some types of therapies if benefit is perceived. We included only RCTs focused on a single intervention; it is unclear to what extent our findings represent the conditions under which the various interventions are currently delivered.

To facilitate interpretation of results across trials and interventions, we categorized the magnitude of effects for function and pain outcomes using the system described in our previous review. [28] Using this system, beneficial effects identified were generally in the small or moderate range. We recognize that effects that we classified as small (e.g., 5 to 10 points on a 0 to 100 scale for pain or function) may be below some proposed thresholds for minimum clinically important differences for some measures. However, our classification provides some consistent and objective benchmarks to assess magnitude of smaller effects across trials and interventions. Interpretation of clinically important differences in mean change for continuous variables is challenging. If data were provided we also evaluated the proportion of patients who experienced a clinically important improvement in pain or function. This provides valuable insight regarding clinically important improvement.

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Limitations of the Evidence Base

Evidence remains sparse for most interventions, particularly long term. There were also limited data on outcomes other than pain and function and particularly for harms. The Visual Analog Scale for pain was the most commonly reported pain measure and does not adequately characterize or categorize pain. In addition, mean changes in outcomes measures between treatment groups describe how groups respond to treatment on average, but do not capture individuals’ response or achievement of clinically important differences which may be more clinically intuitive. For example, one trial [104] of MBSR versus usual care in low back pain reported a small improvement in function on a modified Roland Morris Disability questionnaire (1.87, 95% confidence interval [CI] –3.14 to –0.60 on 0-23 scale); however, absolute difference between MBSR and usual care on the percentage of participants (20%) achieving a minimally clinically meaningful (≥30%) improvement from baseline (68.8% to 48.6%, risk ratio 1.56, 95% CI 1.14 to 2.14) suggests that the benefits may be more substantial. Few trials directly compared an included intervention versus pharmacological therapy or the specified active comparator (exercise or biofeedback). Only 5 percent of included trials across conditions were considered to be of good quality; the majority were considered fair (61%). No trial of treatment for chronic tension headache was considered to be of good quality. For some interventions, it may not be possible to effectively blind participants and providers (e.g., CBT, MDR, exercise); thus, observed effects may be due in part to placebo, attention, or other nonspecific effects and results may have been susceptible to performance and other biases. Many included trials were small (<70 participants) and only few or single trials were available for some interventions (e.g., some physical modalities). The combination of these factors led to a determination that evidence was insufficient. There was no or little includable evidence for a number of interventions, including electromuscular simulation, traction, superficial heat or cold, bracing, use of magnets, interferential therapy, transcutaneous electrical nerve stimulation, and manual therapies (other than for low back pain). For most conditions, evidence was also sparse for mindfulness and mind-body practices. Evidence on interventions for hip and hand OA and chronic tension headache was very limited.

Heterogeneity in clinical diagnosis and presentation was present for most of the conditions, with the exception of fibromyalgia. It is likely that included patients may have additional conditions and/or psychological comorbidities that were not described in the trials. Details provided by trials were insufficient to conduct meaningful subanalyses.

Some of the limitations described for the review process reflect limitations of the evidence base, including those related to heterogeneity within and across interventions and heterogeneity within a given condition. Details of concurrent interventions and components of usual care were generally not reported or poorly reported. Additionally, it is assumed that most patients with chronic pain likely continued medications and other therapies or practices during the trials. These factors may have resulted in substantial mixing of effects of the intervention and cointerventions. These factors possibly attenuated observed effects.

Data on potential harms is sparse, although serious harms are not generally expected with the interventions included in this review. Serious treatment-related adverse events were not reported in any of the trials.

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Implications for Clinical and Policy Decision Making

Our review provides updated evidence that an array of nonpharmacological treatments provide small to moderate benefits function and/or pain that are durable for more than 1 month for the five common chronic pain conditions addressed in this review. Musculoskeletal pain, particularly back and joint pain, is the most common single type of chronic pain. Age-adjusted rates of adults reporting pain in the last three months were highest for low back pain (28%), neck pain (15%), knee pain (19.5%) and severe headache or migraine (16%). [3, 17]

The evidence synthesized in this review may help inform guidelines and healthcare policy (including reimbursement policy) related to use of noninvasive nonpharmacological treatments, and inform policy decisions regarding funding priorities for future research.

Recent guidelines [15] from the Centers for Disease Control and Prevention (CDC) in the United States and the Canadian Guideline for Opioid Use in Chronic Non-Cancer Pain [290] recommend nonopioid treatment as the preferred treatment for chronic pain. Further, guidelines from the American College of Physicians recommend nonpharmacological therapies over medications for chronic back pain. [19] Our findings support the feasibility of such guidelines by presenting evidence of sustained effectiveness after the completion of therapy for a number of nonpharmacological treatments. Importantly, interventions such as exercise, CBT, MDR, mind-body interventions, and some complementary and integrative medicine therapies, such as acupuncture and spinal manipulation, were associated with some sustained effects on function, although evidence beyond 12 months remains sparse. There was no evidence suggesting serious harms from these interventions, although harms data were limited.

Our report reviewed evidence that may also help inform decisions regarding prioritization of nonpharmacological therapies by clinicians selecting therapy and facilitate shared decision making between providers and patients. Exercise and CBT are considered routine first-line treatments in many guidelines, with many of the nonpharmacological treatments in this review including spinal manipulation, acupuncture, mindfulness practices, and MDR considered adjunctive or second line treatment for chronic low back pain [292] Our report provides indirect support for the adoption of integrated, multimodal management of chronic pain. While the CDC guidelines suggest use of a multi-modal approach to pain management, data on clinical pathways and optimal integration of nonpharmacological pain management as well as utilization are sparse, contributing to challenges on how to best implement evidence-based strategies into practice. [292, 293] Consistent with a biopsychosocial understanding of chronic pain, [3, 9] evidence was somewhat more robust for “active” interventions that engage patients in movement and address psychological contributors to pain, particularly at longer-term followup, versus more “passive” treatments focused on symptom relief such as massage. Active interventions include exercise, MDR, psychological interventions (particularly CBT), and mind-body interventions. This provides some support for clinical strategies that focus on “active” interventions as primary therapies, with “passive” interventions used in a more adjunctive or supplementary role. Research is needed to compare “active” vs. “passive” strategies.

Our review also has policy implications related to access to treatment and reimbursement. Given heterogeneity in chronic pain, variability in patient preferences for treatments, [3, 9] and differential responses to specific therapies in patients with a given chronic pain condition, policies that broaden access to a wider array of effective nonpharmacological treatments may have greater impact than those that focus on one or a few therapies. Several considerations could inform policy decisions regarding access to and coverage of nonpharmacological therapies. Policymakers could prioritize access to interventions with evidence of persistent effectiveness across different pain conditions, such as exercise, MDR, mind-body interventions, and acupuncture. Because the level of supporting evidence varies from condition to condition, policymakers may need to consider the degree to which evidence may be reasonably extrapolated across conditions (e.g., effectiveness of psychological therapies for chronic low back pain may not necessarily be extrapolated to OA). There is substantial variability in reimbursement and authorization procedures remain a potential barrier. [292–294] Although evidence supports the use of MDR over exercise therapy or usual care, primarily for low back pain, cost and availability remain important barriers particularly in rural areas. Our report suggests that less-intensive MDR may be similarly effective to high-intensity MDR, which could inform decisions about more efficient methods for delivering this intervention. Not all patients may require MDR. [295] Policy efforts that focus on use of MDR in individuals more likely to benefit (e.g., severe functional deficits, failure to improve on standard nonmultidisciplinary therapies, significant psychosocial contributors to pain) could also inform efforts to deliver this modality efficiently.

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Limitations of the Systematic Review Process

There were limitations in the systematic review process. Our analysis was restricted to trials that reported outcomes after at least 1 month following the end of therapy (except when therapy lasted at least 6 months; in these cases, we included assessments made immediately post-treatment). We did not include trials of patients with chronic pain conditions other than those specified and excluded trials of patients with diffuse or mixed pain conditions. Some noninvasive nonpharamcological interventions (e.g., self-management education) were excluded, and we did not address invasive therapies. The strict definition of chronic tension headache may have limited the number of trials identified. Trials that evaluated active comparators other than biofeedback (for headache) or exercise (all other conditions) or interventions as adjunctive treatment were excluded. Some meta-analyses were based on two or three trials; findings based on such meta-analyses must be interpreted with caution.

The interventions were grouped a priori to provide an organizational framework for the report. There is some overlap between categories and there a many other methods of grouping interventions. We performed separate or stratified analyses to the extent possible to evaluate specific techniques/methods within broader categories (e.g., we looked at different types of psychological therapies and mind-body practices). We also performed stratified analyses by comparator type where data were available. Sparse literature for many of the interventions precluded extensive examination specific types of intervention within a given category.

We excluded non-English-language articles; however, we did not identify large numbers of non-English-language articles in our review of bibliographies. We searched ClinicalTrials.gov and identified some potentially relevant studies, but none had results available. We did not search conference proceedings or other sources. We were unable to assess for publication bias using graphical or statistical methods to evaluate any potential impact of small samples, methodological limitations in trials, or heterogeneity in interventions, populations or outcomes. Based on hand searches of reference lists, searches of ClinicalTrials.gov, and suggestions from technical experts, we did not find evidence indicating the presence of unpublished literature sufficient to impact conclusions.

The frequency and scope of harms was poorly reported in included RCTs. RCTs may not be adequately powered or have sufficient length of followup to identify rare or long-term adverse events. RCTs assess benefits and harms under ideal circumstances in homogenous populations and specific settings which may limit the applicability of harms reported to more wide-spread use in general clinical practice. [296] Intervention-related serious adverse events resulting in death, disability or requiring intensive medical intensive attention were not seen across included RCTs; no differences between interventions and comparators were identified for serious events. Most reported events were minor and transient and SOE was low or insufficient for most. In general, serious adverse events are considered very rare for the interventions evaluated in this report and likely depend on patient factors (e.g., comorbid conditions) and provider skill and qualifications as well as characteristics of the intervention and how it is delivered. [286, 297–302]

Exhaustive listing, evaluation of explicit linkage to an intervention and appraisal of evidence quality for adverse events reported in the general medical literature are beyond the scope of this review. Examples of serious adverse events reported in the medical literature for acupuncture include vascular injuries, cardiac tamponade, subarachnoid hemorrhage and infective endocarditis as described in case reports or case series. [302–304] For spinal manipulation (including the neck), systematic reviews primarily report increases in nonserious AEs and that serious AEs are extremely rare and may include additional disc herniation, cauda equine syndrome, vertebral artery dissection, cerebral vascular accident or vertebrobasilar accident and death; reported frequencies ranged from < 1 per 10,000 patients to < 1 per millions of manipulations. [298] For interventions involving physical activity (including any form of exercise, yoga, tai chi, etc.), nonserious injuries (e.g., musculoskeletal strains and pains) are most common and resolve. [297, 301] More serious events such as falls, fractures, fibrocartilaginous injuries, cardiovascular events and worsening of pre-existing conditions, peripheral neuropathy, stroke, transient headache, pneumothorax and rectus sheath hematoma, lumbar disc damage, have been reported in the medical literature. Risk for adverse events depends on factors such as type, intensity, and duration of activity, whether it is done under the supervision of a qualified individual versus being home-based or self-practice, underlying patient health and the presence of concomitant clinical morbidities (e.g., cardiovascular disease).

Serious adverse events reported in the general literature may or may not be applicable to the interventions as applied in included studies or patient populations studied in this review.

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Research Recommendations

Table 65

Although new RCTs published subsequent to our 2018 report [16] provided additional support for many nonpharmacological interventions, evidence remains sparse for a number of interventions, particularly long-term and additional methodologic work is needed. New trials provided limited evidence to fill the gaps that continue across the common conditions we included (Table 65). Four primary issues relate to

(1)   the need to understand the longer-term sustainability of intervention effects;

(2)   the need for standardization of interventions for future trials;

(3)   the standardization of research protocols for collection of and reporting of outcomes including harms;

(4)   the need for comparisons of interventions with pharmacological interventions.

For many of these areas, future research would benefit from considering recommendations from organizations such as the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials, [305–310] the Analgesic, Anesthetic, and Addiction Clinical Trials Translations, Innovations, Opportunities, and Networks, [311, 312] the Report of the Task Force on Research Standards for Chronic Low Back Pain for the National Institutes of Health Pain Consortium [313] and the research priorities outlined in the recent Federal Pain Research Strategy. [314] Changes in conceptualization and terminology related to pain that reflect newer understandings of pain mechanisms are needed in future research. In addition, further research to evaluate differential effectiveness and safety of chronic pain treatments based on pain type/mechanism (e.g., nociplastic pain), age and social determinants of health are needed as are studies in pregnant and breastfeeding women with chronic pain. Evaluation of optimal delivery and integration of nonpharmacological strategies for chronic pain management is needed. Research funding for methodologically sound trials of nonpharmacological interventions is needed.

To understand the sustainability of effects, methodologically rigorous traditional (explanatory) trials with longer followup are needed to better understand whether benefits are sustained over time under ideal conditions. In addition, well-designed pragmatic trial designs with long-term followup could facilitate understanding of how interventions are delivered and continued in real-world settings as well as effect sustainability. Methods for enhancing recruitment, adherence and retention need to be incorporated for all trials. Education of researchers examining nonpharmacological approaches to pain management on clinical trial design, execution, and analysis may also assist with improving the quality of the evidence base for many of the interventions.

Research to identify optimal techniques and their delivery would help define more standardized interventions to evaluate in future trials is needed. In addition, there is a need to understand what combinations of interventions may be most logical for a given condition and standardization of methods to study adjunct therapies. Pragmatic trials may help provide insight into these questions.

Standardization of research protocols for reporting and outcomes measures and use of a standard set of measures would facilitate comparison of results across trials. Outcome measures such as the Visual Analog Scale or Numeric Rating Scale may not fully capture the impact of pain or allow for accurate classification or evaluation of changes in chronic pain. Inclusion of recommendations for pain assessment [315] that incorporate understanding of pathophysiological mechanisms and address multiple domains of pain, including temporal dimensions, sensory and affective qualities of pain and the location and bodily distribution of pain in trial planning and execution may facilitate more accurate classification and longitudinal tracking of response to interventions. Reporting the proportions of patients achieving a clinically meaningful improvement in pain, function, or quality of life as measures of “success” may provide important additional clinical information to complement data on average changes in continuous measures of pain, function, and quality of life for which there is difficulty describing clinically important effects. Routine collection of common or known harms associated with interventions is needed in future trials.

There is heterogeneity with regard to research design, execution, and outcomes reporting in trials of interventions included in this review compared with well-funded trials of devices or pharmacological agents. Lack of funding to design methodologically sound studies with reasonable sample size of nonpharmacological interventions may have contributed to the general low quality of evidence.

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