I. Background

Pain is a monumental public health challenge in the United States affecting millions of adults, leading to disability. Conservative estimates suggest costs of $560-635 billion annually.¹ Low back and neck pain accounted for the highest healthcare spending in 2016 across 154 conditions.² Low back pain prevalence estimates in elderly adults range from 21 percent to 75 percent.³ Estimates of chronic pain and high impact chronic pain prevalence in adults 65–84 years of age were 27.6 percent and 10.7 percent respectively, based on 2016 National Health Interview Survey Data.⁴ Estimates of acute pain in those ≥65 years range from 7 to 52 percent, varying by site with headache, joint, and neuropathic pain most commonly cited.⁵ Opioids are frequently prescribed for acute and chronic pain but there is growing concern for the safety and efficacy of opioid management of pain. In 2016, over 2 million Americans reported an opioid use disorder,⁶ and an estimated 17,087 deaths involved prescription opioid overdose.⁷ In adults ≥65 years, there were substantial increases in opioid-related hospitalizations (34%) and emergency department visits (74%) between 2010 and 2015,⁸ and a 53 percent increase in the proportion of older adults seeking treatment for opioid use disorder from 2013 to 2015.⁹ Across a sample of 1,776,790 Medicare enrollees under 65 years old who qualified for Medicare secondary to disability, 38.5 percent had a pain diagnosis. In the sample, opioid overdose deaths increased from 57.4 per 100,000 in 2012 to 77.6 per 100,000 in 2016.¹⁰

Pain is complex. It substantially impacts physical and mental function and is influenced by multiple factors (e.g., genetic, central nervous system, psychological, and environmental) and individual characteristics (e.g., age, sex, presence of comorbidities and psychosocial factors). The National Academy of Sciences workshop on Non-Pharmacological Approaches to Pain Management,¹¹ the recent Pain Management Best Practices Inter-Agency Task Force report,¹² the National Pain Strategy (NPS) report,¹³ and others recommend that pain management be integrated, multi-modal, interdisciplinary, evidence-based, and individualized in keeping with the biopsychosocial model of pain. There is substantial heterogeneity in the terminology used in the literature and in clinical practice to describe pain management programs that address this model. Conceptually, pain management programs that potentially address care consistent with the biopsychosocial model may fit into two general categories, namely, integrated pain management programs (IPMP), which are centered in and integrated with primary care which have embedded or easy access to multidisciplinary providers and services; and comprehensive pain management programs (CPMP) which are not centered in primary care but are based on referral from primary care or other sources (e.g., insurance) to a set of multidisciplinary services separate from primary care environment and involvement. Both types of programs usually include a medication review and/or management component as well as psychological care (mental health services), and physical rehabilitative methods such as physical therapy (PT) or occupational therapy (OT) and have some mechanism of care coordination or formal communication between multidisciplinary providers. Both types of programs may incorporate patient education and self-management components as well as various complementary and integrative health treatments or methods (e.g., chiropractic, acupuncture, yoga, massage).

Traditional multidisciplinary or interdisciplinary rehabilitation programs (MDR) are examples of CPMPs. While MDR has been associated with improved function and pain in some chronic pain conditions,^14,15 several factors may impact the applicability and accessibility of such programs to the Medicare population. CPMPs generally have an occupational focus and set components are intended to facilitate return to work in younger, working populations. In addition, CPMPs may be very intensive. For example, MDR programs in patients with chronic low back pain summarized in our recent systematic review were primarily in populations under 50 years old and some programs some required >20 hours per week,^14,15 an intensity which may be challenging for older adults and those with disability.

IPMPs may be more accessible and applicable to those eligible for Medicare due to age or disability. In theory, IPMPs involve a multidisciplinary team focused on coordinated and integrated patient care that is individually focused and involves primary care.¹⁶ In addition to the primary components described above, minimally invasive procedures (e.g., steroid injections) or surgical procedures may be used. The U.S. Department of Veteran's Affairs (VA) Whole Health System is an example of an integrated program for chronic pain management.^17-19 A stepped care model is used which involves primary care together with Patient Aligned Clinical Teams (PACTs)¹⁹ and provides a basis for patient assessment, medication management and referral to a range of multidisciplinary providers and services (e.g., behavioral pain management) and for advanced diagnostics and interventions as needed. A recent VA rapid review of chronic musculoskeletal pain management models found that models incorporating decision support with proactive treatment monitoring resulted in patients experiencing clinically relevant improvement (≥30%) in pain and function.¹⁹ Common model components included multidisciplinary case management, pharmacotherapy review algorithms, mental health services, proactive symptom monitoring, and patient self-management resources. Models varied substantially regarding care coordination and component content and delivery.¹⁹ Because acute pain tends to improve rapidly in the majority of patients, IPMPs may be most applicable for treatment of chronic pain. In the era of COVID-19, consideration of which intervention components and aspects of care coordination and patient monitoring that could be delivered by phone, virtually or via telemedicine may become increasingly important.

Given the high prevalence of pain in older adults eligible for Medicare and those under 65 years old who qualify for Medicare due to disability, use of effective, safe, and cost-effective pain management becomes imperative. Unique challenges in assessing and managing pain in older adults^5,20 include age-related changes in pain perception and thresholds and responses to medication, comorbidities (medical and psychological), polypharmacy, psychosocial concerns, and lack of care coordination. Older adults may also be predisposed to transitioning from acute to chronic, persistent pain.^21,22 In Medicare-eligible adults under 65 years old with disability, substance abuse, psychiatric disease and chronic pain have been associated with increased risk of opioid overdose death.¹⁰ Thus, an integrated, coordinated, and individualized approach may be particularly important in the Medicare population to assure optimal pain management.

The U.S. Department of Health and Human Services has been directed to evaluate ways to improve Medicare coverage and payment for treatment of acute and chronic pain, particularly through integrated pain management programs and multidisciplinary, multimodal treatment models that involve care coordination. Requisite to addressing this decisional dilemma is understanding the types/components and methods of care delivery as well as benefits, potential risks and costs related of such programs to Medicare Parts A and B beneficiaries with complex acute/subacute pain or chronic non-active cancer pain.

Purpose of the Review

This systematic review will evaluate the effectiveness and harms of integrated pain management programs and describe contextual, process and structural factors that may impact outcomes particularly in the Medicare population. The intended audiences for this review are the Centers for Medicare & Medicaid (CMS) and other stakeholders including clinicians, policy makers, patients, their caregivers and researchers. This review is part of the Dr. Todd Graham Pain Management Study and is sponsored by CMS.

II. Key Questions

An initial set of Key Questions (KQs) and contextual questions were updated with input from the project sponsor (CMS), Technical Expert Panel (TEP) and AHRQ Task Order Officer; and application of Evidence-based Practice Center (EPC) team expertise. The following KQs and inclusion criteria and logic conceptual framework reflect these discussions.

Key Questions:

KQ1: What are the effectiveness and harms of integrated or comprehensive pain management programs for Medicare beneficiaries with complex acute/subacute pain or chronic, non-active cancer pain? Population subgroups of interest include those with disabilities (including ESRD), prior substance use disorder, psychological co-morbidities (including suicidal behaviors), and degree of nociplasticity.

KQ2: Have any of the following factors been evaluated and/or shown to impact outcomes in studies of comprehensive or integrated pain management models?

1. Treatment delivery including session formats (group, one-on-one), duration, intensity and frequency of sessions, number of sessions; general structure and scope of sessions
2. Treatment components (e.g., medication review and/or management, including transition from opioid to nonopioid medications; psychological support or mental health services; physical reconditioning, such as physical therapy and occupational therapy; use of complementary and integrative medicine treatments; patient education; use of medical procedures or devices)
3. Care provision
   1. Care coordination methods or decision support
   2. Provider types involved
   3. Personalization, care pathways
4. Program characteristics
   1. Program emphasis/goals
   2. Target population
   3. Referral sources
   4. Staffing characteristics (e.g., turn over)

For this review, integrated pain management programs will be defined as programs centered in primary care, that have embedded or easy access to multidisciplinary providers and include, at a minimum, the availability of pharmacotherapy review and/or management, psychological care (mental health services), and physical reconditioning (e.g., PT, occupational therapy [OT]) as well as processes of care coordination, case management or other mechanisms of multidisciplinary (interdisciplinary) collaboration or formal communication. Comprehensive programs will be defined as those that are not based in primary care and provide components of medical therapy, psychological services, and physical rehabilitation (e.g., PT, OT) provided by professionals from multiple disciplines and have some degree of coordination between providers (e.g., primary care referral to traditional multidisciplinary/interdisciplinary rehabilitation programs). Both types of programs may also include other components such as patient education and self-management and complementary and integrative care modalities (e.g., chiropractic, acupuncture, massage).

Contextual Questions: Following the methods of the U.S. Preventive Services Task Force (USPSTF)²³ contextual questions represent issues in a review for which a valid, but not necessarily systematic, summary of current research is needed in order to provide context on the issue. See the Methods section below for more details.

CQ1: What different types of comprehensive, integrated approaches to complex acute/subacute pain or chronic, non-active cancer pain management have been proposed or used in clinical practice?

1. How are comprehensive and integrated pain management defined?
2. What are considered the most important components of integrated pain management programs?
3. What pain management models or mechanisms are most commonly used in clinical practice?
4. What types of programs/models may be most applicable to Medicare beneficiaries?
5. What theoretical advantages and disadvantages do various programs/models have compared with current practice?
6. Are there any potential safety issues?

CQ2: Is there information on the costs or cost-effectiveness of integrated pain management programs in the Medicare or general population?

III. Analytic Framework

Figure 1. Logic conceptual framework

Abbreviations: ED = emergency department; HRQOL = Health-related quality of life; LTC = long-term care; OT = occupational therapy; PT = physical therapy

IV. Methods

All methods used for this systematic review will be conducting in accordance with the Agency for Healthcare Research and Quality's Methods Guide for Effectiveness and Comparative Effectiveness Review,²⁴ developed for the Evidence-based Practice Centers. Comprehensive, integrated, coordinated pain management programs are considered complex interventions²⁵ with multiple components, care pathways, provider types, participants, and organizational levels. Their evaluation requires extension of usual SR methods to adequately define and reflect the scope and complexity of the intervention^26,27 and assure appropriate analysis and reporting.^28-31

Criteria for Inclusion/Exclusion of Studies in the Review

The criteria for inclusion and exclusion of studies for the systematic review will be based on the KQs and on the specific criteria for population, interventions, comparators, outcomes, timing, and settings (PICOTS), listed in Table 1.

Table 1. Inclusion and exclusion criteria: population, interventions, comparators, outcomes, timing, and settings

Abbreviations: ED = emergency department; ESDR = end stage renal disease; HRQOL = Health-related quality of life; OT = occupational therapy; OUD = opioid use disorder; PICOTS = population, intervention, comparator, outcomes, timing, study design; PT = physical therapy; RCT = randomized control trial; SUD = substance use disorder.
Table Notes:
a. Complex acute or subacute pain: Patients with acute pain (<6 weeks duration) or subacute pain (6 weeks to 12 weeks duration) who are at risk of developing chronic pain).
b. Chronic, nonactive cancer pain (based on Mersky 1994)³²: Pain that persists for at least three months and is not associated with [active] malignant disease; pain could, however, be resultant from a previous malignancy that is no longer active.
c. The term nociplasticity has been used to describe pain resulting from altered nociception without underlying tissue damage resulting in hypersensitivity (e.g., fibromyalgia).³³ Many pain conditions may have a nociplastic component. Some additional terms used in the literature include centralized pain and amplified pain.

Study Design: For all KQs, we will focus on randomized controlled trials (RCTs) as they will have the least risk of bias. In the absence of RCTs for a KQ or subquestion, comparative cohort studies that adjust for potential confounding factors will be evaluated. If comparative cohort studies which adjust for confounding are not available, those that do not adjust will be considered. Single arm studies (i.e., pre-post studies, case series) will be considered in the absence of comparative studies only if they are clearly relevant to the Medicare population (i.e. those ≥65 or those eligible based on disability. If a systematic review is recent enough to cover the majority of the available evidence for a given question or subquestion and evaluates a cohesive group of interventions and outcomes within the scope for this review, we will include the review as the primary evidence. If there are more than two studies published since the review, our approach will be to use the review only to identify eligible studies for this review.

Non-English-Language Studies: We will restrict to English-language articles, given the focus on Medicare eligible patients within the U.S. healthcare system.

Literature Search Strategies

Literature Databases: Given that complex, multicomponent interventions encompass numerous dimensions and terminology related to them may be inconsistently used, a broad search strategy across multiple data bases will be used.³⁴ Ovid^® MEDLINE^®, PsycINFO^®, CINAHL^®, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews will be searched. Appendix A contains our sample search strategy.

Publication Date Range: Searches will be conducted across all KQs, with study dates reaching back to 1989 for each database. This date corresponds to publication of the earliest RCTs relevant to this topic.^35,36 Searches will be deduplicated and screened for inclusion. Searches will be updated while the draft report is open to public comment, to capture any new publications. Literature identified during the updated search will be assessed by following the same process of dual review as all other studies considered for inclusion in the report. If any pertinent new literature is identified for inclusion in the report, it will be incorporated before the final submission of the report.

Supplemental Evidence and Data for Systematic review (SEADS): Manufacturers and other stakeholders of included drugs and devices will be informed about submitting information relevant to this review using a Federal Register notification. A portal about the opportunity to submit information will be made available on the AHRQ Effective Health Care website.

Hand Searching: Reference lists of included articles will also be reviewed for includable studies.

Process for Selecting Studies

In accordance with the Methods Guide for Effectiveness and Comparative Effectiveness Review,²⁴ we will use the pre-established criteria above to screen citations (titles and abstracts) identified through our searches or Federal Register notification submissions to determine eligibility for full-text review. To ensure accuracy, any citation deemed not relevant for full-text review will be reviewed by a second researcher. All citations deemed potentially eligible for inclusion by at least one of the reviewers will be retrieved for full-text screening. Each full-text article will be independently reviewed for eligibility by two team members. Any disagreements will be resolved by consensus. A record of studies excluded at the full-text level with reasons for exclusion will be maintained.

Data Abstraction and Data Management

After studies are selected for inclusion, given intervention complexity (i.e., pain management models have multiple components, care pathways, participants, organizational levels) and anticipated heterogeneity of model components and delivery, we will first construct a framework to organize key structural features (e.g., setting, locus of coordination, primary care provider involvement) of models and understand relationships between essential components of models (e.g., medications use, monitoring, nonpharmacologic care). For complex interventions, there is no consensus regarding any single best approach for organizing the evidence.³⁴ We will initially build on the framework from our Medication-Assisted Treatment Models for Opioid Use Disorder³⁷ technical brief, which organized models as practice-based (i.e., those implemented in an individual stand-alone clinic) and system-based (involving multiple levels of a healthcare system). We will consider whether the program/model is integrated (based in primary care) or comprehensive (not based in primary care).

Organization by key model components (e.g., pharmacologic therapy, physical function, care coordination, psychological services) will then be considered. Data abstraction will reflect these elements, keeping the template for intervention description and replication (TIDieR) checklist in mind.²⁹ Elements will include, but not be limited to: study design, year, setting, country, sample size, eligibility criteria, attrition, population and clinical characteristics (including age, sex, comorbidities such as medical or psychological disabilities), diagnostic classifications/information, pain characteristics (e.g., degree of nociplasticity), sociodemographic factors, intervention component characteristics (including the type, number, intensity, duration of and adherence to treatments), processes of care (e.g., provider types, roles, coordination, decision support, sequence of care components, modifications to treatment), comparator characteristics, program/model characteristics (e.g., goals, emphasis, target population, staffing), and results (including harms). Data on outcomes evaluated short term (1 to <6 months), intermediate term (≥6 to <12 months) and long term (≥12 months) following intervention will be abstracted. Information relevant for assessing applicability will be abstracted, including the characteristics of the population, interventions, and the number of patients enrolled relative to the number assessed for eligibility. All study data abstraction will be verified for accuracy and completeness by a second team member.

Assessment of Methodological Risk of Bias of Individual Studies

Methods from the Methods Guide for Effectiveness and Comparative Effectiveness Review²⁴ will be used in concordance with the approach recommended in the chapter, Assessing the Risk of Bias of Individual Studies When Comparing Medical Interventions.^24,38 RCTs will be assessed based on criteria established in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8.5 Risk of Bias Tool),³⁹ and instruments tailored to observational studies^40,41 will be used for non-randomized studies. If systematic reviews are included, we will use the AMSTAR-2 tool to appraise these reviews.⁴² Based on the risk of bias assessment, individual included studies will be rated as being "good," "fair," or "poor" quality as described below in Table 2:

Table 2. Criteria for grading the quality of individual studies

Data Synthesis

We will construct evidence tables based on the organizational framework to include study and model characteristics (as discussed above), results of interest, and quality ratings for all included studies, and summary tables to highlight the main findings. We will review and highlight studies by using a hierarchy-of-evidence approach, focusing our synthesis on the highest quality data for each KQ. Data will be qualitatively summarized in tables, using ranges and descriptive analysis and interpretation of the results.

Meta-analyses, using profile-likelihood random effects models, will be conducted to summarize data and obtain more precise estimates where there are at least three studies reporting outcomes that are homogeneous enough to provide a meaningful combined estimate.^43,44 Study designs will be pooled separately (RCTs vs. observational studies). We will employ meta-analytic techniques best suited to complex intervention analysis.³⁰ Techniques will be considered based on available data and final organizational framework. Sensitivity and subgroup analyses, including meta-regression, will be performed to explore statistical heterogeneity and differences by study quality, intervention differences, patient and model characteristics, and outcome measurement as data permit (e.g., at least six to ten studies for continuous variables and four studies for categorical variables). Consistent with our prior chronic pain report,^14,15 we plan to explore the impact of higher intensity programs (intensity (≥20 hours/week or >80 hours total) versus lower intensity programs (<20 hours/week) if data are available. We will classify the magnitude of effects for continuous measures of pain and function using the same system as in prior and in-progress AHRQ reviews on pain,^14,15,45-47 and where possible, will focus on the proportion of patients meeting thresholds for clinically important differences (e.g., >30% pain relief). Publication bias will be assessed using funnel plots and statistical methods when there are at least 10 RCTs that can be combined in meta-analysis.

Synthesis will focus on programs/models of pain management that are clearly most applicable to the Medicare population. Programs/models that are clearly not applicable to the Medicare population may be briefly referenced, but will not be extensively synthesized. Results will be presented as structured by the KQs, and any primary outcomes, as prioritized in Table 1, will be presented first.

Grading the Strength of Evidence for Major Comparisons and Outcomes

Outcomes to be assessed for strength of evidence were prioritized based on input from the Technical Expert Panel. Based on this prioritized list, the strength of evidence for comparison-outcome pairs within each KQ will be initially assessed by one researcher for each clinical outcome (see PICOTS) by using the approach described in the Methods Guide for Effectiveness and Comparative Effectiveness Review.²⁴ To ensure consistency and validity of the evaluation, the initial assessment will be independently reviewed by at least one other experienced investigator using the following criteria:

• Study limitations (low, medium, or high level of study limitations)
  • Rated as the degree to which studies for a given outcome are likely to reduce bias based on study design and conduct. The aggregate risk of bias across individual studies reporting an outcome is considered.
• Consistency (consistent, inconsistent, or unknown/not applicable)
  • Rated by degree to which studies find similar magnitude of effect (i.e., range sizes are similar) or same direction of effect (i.e., effect sizes have the same sign)
• Directness (direct or indirect)
  • Rated by degree to which the outcome is directly or indirectly related to health outcomes of interest. Patient centered outcomes are considered direct
• Precision (precise or imprecise)
  • Describes the level of certainty of the estimate of effect for a particular outcome with a precise estimate being on that allows a clinically useful conclusion. This may be based on sufficiency of sample size and number of events, and if these are adequate, the interpretation of the confidence interval. When quantitative synthesis is not possible, sample size and assessment of variance within individual studies will be considered.
• Reporting bias (suspected or undetected)
  • Publication bias, selective outcome reporting, and selective analysis reporting are types of reporting bias. Reporting bias is difficult to assess as systematic identification of unpublished evidence is challenging. If sufficient numbers of RCTs (>10) are available, quantitative funnel plot analysis may be done.

The strength of evidence will be assigned an overall grade of high, moderate, low, or insufficient according to a four-level scale by evaluating and weighing the combined results of the above domains.

Table 3. Description of the strength of evidence grades

Bodies of evidence consisting of RCTs are initially considered as high strength while bodies of comparative observational studies begin as low-strength evidence. The strength of the evidence may be downgraded based on the limitations described above. There are also situations where the observational evidence may be upgraded (e.g., large magnitude of effect, presence of dose-response relationship or existence of plausible unmeasured confounders) as described in the AHRQ Methods Guide.^24,38 Where both RCTs and observational studies are included for a given intervention-outcome pair, we follow the additional guidance on weighting RCTs over observational studies, assessing consistency across the two bodies of evidence, and determining a final rating.²⁴

Assessing Applicability

Applicability to the Medicare population, i.e. patients eligible for Medicare due to age ≥ 65 or disability (including ESRD), will be assessed based on the EPC Methods Guide,24 using the PICOTS framework. Applicability refers to the degree to which outcomes associated with the intervention from are likely to be similar across patients and settings relevant to the care of the Medicare population based on the populations, interventions comparisons and outcomes synthesized across included studies. Factors that may affect applicability which we have identified a priori generally reflect the contextual components outlined in the conceptual logic diagram (Figure 1) and include (1) patient factors (e.g., age and disability status, medical and psychiatric comorbidities, symptom severity, duration and underlying pain condition); (2) intervention factors such as program structure and goals (e.g., patient return to work or activities of daily living), delivery of program components (e.g., session or component types, duration, intensity (i.e., hours/week, total hours) and frequency, level of adherence, support and coordination); (3) comparators, including feasibility of comparisons between programs; (4) outcomes (e.g., use of nonstandardized or unvalidated outcomes); and (5) settings (e.g., outpatient versus residential). For example, intensive programs of consisting of multiple daily sessions for 8 weeks geared toward rehabilitation for return to work may have limited applicability to retired populations >65 years old with chronic pain. We will use information on the factors to assess the extent to which programs and their components are likely most relevant to real-world clinical practice in typical U.S. settings that include the Medicare population. We will provide a qualitative summary of our assessment.

Contextual Question

We plan to follow the methods of the U.S. Preventive Services Task Force to evaluate the contextual question.²³ A targeted search will be designed by a medical librarian with experience in searching for contextual question evidence for USPSTF reviews, including searching for systematic and narrative reviews. The team will also identify any information relevant to this question opportunistically, while reviewing comprehensive literature searches for KQs, and will incorporate relevant information from TEP calls. The information on the contextual questions will be summarized in the introduction of the report and discussed in relation to the systematic review evidence on the KQs in the Discussion section.

V. References

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VI. Definition of Terms

Table 4. Abbreviations

VII. Summary of Protocol Amendments

If needed, protocol amendments will be added in the future.

VIII. Review of Key Questions

Initial KQs were revised based on EPC discussions with the review sponsor and AHRQ. The Evidence-based Practice Center (EPC) refined and finalized the KQs after input from the TEP. This input is intended to ensure that the KQs are specific and relevant.

IX. Key Informants

Key Informants are the end-users of research; they can include patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of healthcare, and others with experience in making health care decisions. A Key Informant panel was not convened for this review.

X. Technical Experts

Technical Experts constitute a multi-disciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes and identify particular studies or databases to search. The Technical Expert Panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicting opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, study questions, design, and methodological approaches do not necessarily represent the views of individual technical and content experts. Technical Experts provide information to the EPC to identify literature search strategies and suggest approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind; neither do they contribute to the writing of the report. They do not review the report, except as given the opportunity to do so through the peer or public review mechanism.

Members of the TEP must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The AHRQ TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

XI. Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. The EPC considers all peer review comments on the draft report in preparing final report. Peer reviewers do not participate in writing or editing of the final report or other products. The final report does not necessarily represent the views of individual reviewers. The EPC will complete a disposition of all peer review comments. The disposition of comments for systematic reviews and technical briefs will be published 3 months after publication of the evidence report.

Potential Peer Reviewers must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers with any financial conflict of interest greater than $5,000 will be disqualified from peer review. Peer reviewers who disclose potential business or professional conflicts of interest can submit comments on draft reports through the public comment mechanism.

XII. EPC Team Disclosures

EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Direct financial conflicts of interest that cumulatively total more than $1,000 will usually disqualify EPC core team investigators.

XIII. Role of the Funder

This project was funded under Contract No. 75Q80120D00006 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The AHRQ Task Order Officer reviewed the EPC response to contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by either the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

XIV. Registration

This protocol will be registered in the international prospective register of systematic reviews (PROSPERO).

Appendix A. Search strategies: Integrated Pain Management Programs

The following data base was searched from 1990 through August, 2020.

Database: Ovid MEDLINE(R) ALL 1946 to August 26, 2020

1     exp Pain/

2     (pain or fibromyalgia or "chronic fatigue" or neuropath* or headache or migraine or neurogenic or psychogenic or arthriti* or osteoarthriti*).ti,ab,kf.

3     1 or 2

4     exp Patient Care Team/

5     Pain Clinics/

6     interdisciplinary communication/

7     Combined Modality Therapy/

8     Case Management/

9     ((integrated or comprehensive or multidisciplin* or multimod* or interdisciplin*or multicomponent or collaborat* or coordinat*) adj5 (intervention* or treatment* or therap* or care or program* or model*)).ti,ab,kf.

10     or/4-9

11     3 and 10

12     (random* or control* or trial or cohort or compar*).ti,ab,kf.

13     limit 11 to (comparative study or randomized controlled trial)

14     (11 and 12) or 13

15     limit 14 to english language

16     limit 15 to yr="1990 -Current"