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Recruitment and retention for chronic pain clinical trials: a narrative review

Kennedy, Nana; Nelson, Saraha; Jerome, Rebecca N.a; Edwards, Terri L.a; Stroud, Marya; Wilkins, Consuelo H.a,b,c,d; Harris, Paul A.a,e,*

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doi: 10.1097/PR9.0000000000001007
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1. Introduction

Opioid use disorder is a public health crisis. The U.S. Centers for Disease Control (CDC) reports that in 2014, 4.3 million Americans used opioids for nonmedical reasons in a given month,37 and 130 Americans, on average, died each day from overdose involving an opioid in 2017.21 An estimated 5 to 8 million adults in the United States use prescription opioids to manage their chronic pain,113 and although relatively few become addicted as a result, the increased risk of harms, including misuse and overdose, is substantial.23,131,132 Moreover, the disparity in the number of opioid overdose deaths among non-Hispanic Black individuals compared with Whites has continued to widen.30

Well-designed human trials of pain treatments with adequate sample sizes are needed to enable meaningful analyses and define evidence-based recommendations. Pain studies can be particularly difficult to design and recruit for, however, because of challenges in experimental treatment, study protocols and execution, inclusion criteria, analysis, and dissemination of results into clinical practice. A National Institutes of Health initiative—the Helping to End Addiction Long-term (HEAL) Pain Management Effectiveness Research Network—was created with the goal of improving pain care by deepening scientific understanding of how chronic pain emerges, evaluating the efficacy of current pain strategies through clinical trials, and accelerating the development and implementation of new preventions and treatments to reduce pain and improve function.4,98 The initial cohort of awarded HEAL Pain Management studies includes investigations of the effectiveness of nonpharmacological pain treatments such as cognitive behavioral and psychosocial interventions, and combinations of cognitive and drug treatments, to reduce pain associated with surgery, cancer treatment, osteoarthritis, and caesarean section.106

The Trial Innovation Network (TIN) is a partnership between 3 Trial Innovation Centers, the Recruitment Innovation Center (RIC)139 and the Clinical and Translational Science Award institutions, sponsored by the National Center for Advancing Translational Sciences, to develop and test innovations for conducting clinical trials.7 These national initiatives have received supplemental funding to provide expertise and coordination to the HEAL Pain Effectiveness Research Network. The work of the TIN dovetails with the needs of the HEAL Pain studies in developing an evidence base of proven alternatives to opioids in the treatment of chronic pain.

One of the RIC's aims is to catalyze enrollment by developing and disseminating novel strategies, methods, and tools to support researchers in recruiting participants. Together, the RIC's transdisciplinary team of experts in clinical trial recruitment, community engagement, and informatics methods creates new approaches for increasing awareness of and enrollment in clinical trials. A recent in-depth review of clinical trials methodology in chronic pain provided an overview of recruitment and retention issues.73 In this narrative review, we build on this discussion with a qualitative exploration of recruitment and retention in chronic pain trials through the lenses of both the researcher and participant. We studied the current literature to examine methods currently being used by pain researchers for recruitment and retention and detail the strategies that have been found effective. We summarize the key challenges to recruitment and retention that informed the RIC's pragmatic recommendations to the HEAL Pain studies and describe the generalizable resources we are providing to them. By gathering these strategies, methods, and resources into one place, we hope that other pain treatment researchers can use them to enhance the effectiveness and efficiency of their own chronic pain study recruitment and retention practices.

2. Methods

Because the design of a pain study can itself have a major impact on participant accrual, we considered articles in which protocol elements were selected or modified to maximize recruitment. Of note, we considered study design only in terms of how it relates to participant recruitment and engagement; broader design issues in the pain trial literature are well addressed in other reviews.33,38,51,73,75,93,94,114,141 We also identified pain studies that reported comparisons of different recruitment strategies or that reported success with novel retention methods. Our primary PubMed search used the following terms: pain[mh] AND (clinical trials as topic[mh] OR clinical trial[pt]) AND (recruitment[tiab] OR retention[tiab]) AND humans[mh]. The search included publications dated 2000 to October 1, 2021. To complement this approach, we conducted Google Scholar searches using keywords similar to the terms above and evaluated references from relevant publications to identify any additional relevant articles. This review should not be considered exhaustive but rather an attempt to locate and identify a range of ideas and methods to improve participant recruitment and retention in pain studies.

We have organized the relevant literature into 3 main themes: (1) study design considerations affecting recruitment, along with potential solutions; (2) recruitment and retention results from selected pain studies; and (3) novel engagement and retention strategies from successful studies. After our report on these findings, we describe strategies the RIC has developed in response to address recruitment and retention for the HEAL Pain studies.

3. Results

Although many publications report on recruitment and retention methods generally, we found very few that reported evidence of the success of such methods for studies of chronic pain. Among those that did, the wide variability in study objectives, design, and recruitment methods renders them difficult to compare quantitatively. For this reason, we report results in a qualitative format, citing recruitment issues that are especially relevant to pain research and noting novel solutions.

3.1. Study design considerations affecting recruitment—problems and solutions

According to a 2015 assessment, nearly 1 in 5 studies (19%) fail to meet enrollment goals.19 Although to date there has been no systematic analysis of failure rates in pain studies in particular, our search found that difficulties in recruiting a sufficient sample size were common. Few randomized controlled trials have been conducted that specifically test methods for increasing recruitment or reducing attrition rates in studies of chronic pain.2

Every population study has its own context and requirements for successful study participation. In this article, we consider the specific characteristics of the research experience of patients with pain that may have an impact on recruitment and retention, and how awareness of these issues may inform recruitment approaches and study procedures from the outset. Understanding these issues can help investigators design protocols that work more effectively in addressing challenges. Figure 1 provides a summary of design issues affecting pain studies and some potential solutions.

F1
Figure 1.:
Pain study design considerations affecting recruitment. EERW, enriched enrollment randomized withdrawal; EHR, electronic health record; RCT, randomized controlled trial.

3.2. Type of pain to be studied

The literature suggests that the type of chronic pain population targeted in a study will affect its recruitment success. A systematic review of 96 studies on the use of opioids in the treatment of chronic pain found that most focused on a specific type of chronic pain, with the most common being osteoarthritis, low back pain, and diabetic neuropathy.13 Only 12 of the 96 studies examined multiple pain populations. Thus, many potential participants are eliminated, not only hampering recruitment but also rendering the results less generalizable to the larger chronic pain population. Widening the scope of the targeted pain population can help mitigate these problems, although increased heterogeneity of the sample has an impact on both sample size estimation and statistical analyses and needs to be taken into consideration.38

3.3. Eligibility criteria and participant burden

Investigators need to develop realistic eligibility criteria in the design phase and eliminate those introducing bias or compromising patient safety. Researchers sometimes discover that a criterion which seems non-negotiable at the beginning of a study can be loosened when enrollment goals are not being met, thus facilitating study success without harming its primary goals. For example, in a study to evaluate whether opioid use could be tapered among chronic pain sufferers, Sullivan et al.121 reduced a requirement of no psychiatric hospitalizations within the previous 10 years, to none in the previous 1 year. Heapy et al.,61 in a study of chronic back pain, removed a walking ability requirement. Both studies reduced participant burden by eliminating urine drug screening, a requirement that did not influence study validity. Results of such alterations confirm that limiting the number of burdensome, nonessential assessments can improve recruitment to pain studies.48,75,87,125

3.4. Cohort identification and characterization

Estimating the number of potential participants can pose a challenge in studies of chronic pain because characterization of pain symptoms in health records can be inconsistent.137 Pain is a personal experience that does not lend itself well to objective measurement.28 Unfortunately, subjective measures of pain, including severity, intensity, duration, triggers, and lifestyle impact, are not readily captured in electronic health records (EHRs), making recruitment for pain studies through EHRs challenging. Accurate feasibility assessment thus requires multifaceted approaches that combine informatics tools and contextual data sources and systems, such as EHRs, to guide comprehensive cohort identification and characterization.

Although new diagnostic codes encompassing a range of chronic musculoskeletal pain conditions are now available in the International Classification of Diseases and Related Health Problems (ICD-11, 2019 release),68 these codes have not yet been implemented internationally in EHR systems. Their eventual adoption will provide investigators with a menu of options for pain study cohort recruitment. However, because no overarching diagnostic code is currently in use that can encapsulate the wide range of types of chronic musculoskeletal pain, several investigators have developed search strategies to more systematically capture patients with chronic pain in the EHR. Focusing on related domains, investigators have identified factors including repeat prescriptions of analgesics and low-dose antidepressants, as well as select terms for coding clinical conditions, that can be efficient indicators for identifying patients with pain.20,42,79 Others have developed informational models to capture concepts extracted from EHR flowsheets that are most likely to be related to pain, mapping these metadata to semantically similar concepts in the EHR.137 Still others have used machine learning to sift through clinical notes to locate pain assessments.41

Another solution to identifying the appropriate cohort is to deliver a targeted invite to patients within an EHR patient portal to request they complete a prescreen. A test case by Gold et al. used Research Electronic Data Capture (REDCap),59 a secure data management system, to capture patient-reported outcome measures through a patient EHR portal, with results deidentified and viewable by researchers.52 Although this case did not study pain specifically, the technical methods described in the article could easily be adapted using REDCap as a platform to prescreen potential study participants on pain measures of interest. Although an opt-out method of contacting patients such as described in this research can be ethically controversial and limited by government regulations in some jurisdictions, the literature shows that most patients consider it an acceptable approach.18,128

3.5. Sample size

Our review of chronic pain studies found small sample sizes to be problematic.92,93 Because only a minority of patients with pain are likely to benefit from any specific pain treatment, a larger sample is necessary to overcome random effects. In addition, smaller trials are likely to overestimate effects, possibly because of other quality deficits inherent in small studies. A third factor influencing the need for larger sample sizes is participant withdrawal in pain studies for reasons that are sometimes unavoidable, such as side effects from the study drug. These withdrawals are difficult to manage in statistical analysis and can compromise validity of the results.92,93 Despite this need for larger sample sizes, however, a systematic review of 383 low back pain trials over more than 3 decades found an average sample size of only 153, and a decline in average sample size in studies reported from 2005 to 2012.43

The literature indicates that, in general, the participant pool for studies will be larger when studying a type of pain for which an effective treatment does not exist. When treatments become available, future clinical trials are left with more treatment-refractory patients,38 causing any difference between intervention and control groups to be more difficult to detect.

Enrolling a larger sample is a potential solution, yet locating additional eligible participants can itself pose difficulties. One option is to use an enriched enrollment randomized withdrawal (EERW) design, which permits randomization to be performed after an initial open-label period to remove nonresponders and those unable to tolerate the experimental treatment.44,93 This design allows for smaller sample sizes that do not compromise the analysis. An EERW-designed study can produce findings on effectiveness during the open-label portion of the study, as well as efficacy results from the randomized control study following it.89 Trials of pain analgesics may especially benefit from this methodology because of requirements for dose titration and the larger placebo response typically detected in pain studies.74 Although some investigators find the EERW design problematic because of its potential to further obfuscate the heterogeneity of patient medication response,16 a review of chronic pain studies using this methodology found its use to be both feasible and useful, especially in terms of translation to clinical practice.94 Moreover, use of the EERW design in studies seeking regulatory approval of a drug treatment for pain has become commonplace.89

A variation on EERW is a sequential multiple assignment randomization trial with enrichment (SMARTER) design that performs sample enrichment with new patients in each stage who have already received the treatments assigned in the previous stages (naturalistically), while only being randomized in the current treatment phase. This plan can increase recruitment efficiency and minimize the effects of dropouts, resulting in a need for smaller sample sizes.85

3.6. Pain symptom instability

Evidence suggests that, unlike symptoms associated with many chronic diseases, chronic pain is frequently unstable,92,101 which adds a further challenge—study timing—to recruitment and retention efforts in pain studies.49,129 Lengthy delays from patient identification to recruitment to study initiation can cause dropout when an alleviation of pain symptoms (or simple regression to the mean) occurs during the waiting period or over the course of the trial because patients may no longer see the benefit in participating or continuing to participate.91,101,101,129

To mitigate timing issues, researchers in 1 study used dedicated staff not only for study enrollment (including recruitment, screening, and consenting) but also for actively connecting with healthcare providers weekly or even daily to identify eligible patients and follow-up immediately with those expressing interest in the study. Staff also scheduled and placed reminder calls.11

3.7. Effect of placebo

The literature indicates that recruiting participants for pain trials can sometimes be easier than recruiting for general conditions such as wellness studies60 because patients may be more likely to consent if they perceive a personal benefit (pain relief) from participating.136 That very motivation, however, may negatively affect recruitment and retention if the participant fears the possibility of landing in the placebo group or being assigned to a less desirable intervention arm.51,53 Although not unique to pain studies, an important consideration in designing a pain trial is the extent to which those patients with a strong treatment preference exhibit reluctance or refusal to participate or to continue participating.56,64,93,100

To overcome this reluctance, rescue medications (eg, acetaminophen, aspirin, or other nonsteroidal anti-inflammatory drugs, or weak opioids such as codeine, tramadol, dihydrocodeine, or dextropropoxyphene) can be tried.55 A balancing act exists, however, between providing sufficient rescue relief to retain participants in a study, but not so much that data noise invalidates the treatment effect estimate55 or contributes to false-negative results.115 In a study of patients with fibromyalgia, 72% said that allowing only acetaminophen for breakthrough pain in a clinical trial was a “very poor” idea.64 Although use of NSAIDs was later allowed in the control arm of that study, this option may still prove unacceptable to some prospective participants and could result in lower enrollment and more participant withdrawals. Likewise, the design decision to remove early on those patients with a high placebo response (in an effort to improve assay sensitivity) could have a significant negative impact on recruitment,38 in addition to reducing translatability to clinical practice.39,119,126 Investigators should consider that although there may be ethical considerations regarding placebo treatment when potentially effective treatments are available,38,115 increased use of rescue medication in the placebo group vs the drug treatment group may in itself provide evidence of a stronger response to the investigational drug.54

One solution, used in the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial, is to replace the placebo with some other form of pain treatment and compare the 2 groups.79 Although not as pure as a placebo-controlled trial, it may be a necessary compromise for achieving sufficient sample size in a pain study and avoiding the ethical concern of nontreatment. An alternative, used in the Integrated Treatment for Veterans with Co-Occurring Chronic Pain and Opioid Use Disorder (POSITIVE) HEAL Pain study,69 is to enroll individuals for the control and experimental groups who are already on a stable maintenance dose of pain medication (buprenorphine) and then compare effects of education sessions (control group) with psychosocial treatments (experimental group) in reducing pain interference and opioid misuse. Another solution is to use a waitlist control group or open extension phase.9,11,12 The FDA recently recognized that comparing an experimental treatment with an established drug in a noninferiority study, to mimic real-world scenarios, can sometimes be considered sufficient to determine the new treatment's efficacy.25

A crossover design, in which every participant receives the active treatment in sequence,31,73 can also assist in recruitment and retention. This design may be especially valuable when recruitment of large samples is not possible, as in studies of rare forms of chronic pain.33,50 Another possibility is to use an asymmetric allocation ratio of intervention to control (such as 1.33:1), anticipating that if potential participants are aware that they have a better chance of being assigned to the active treatment group, it may increase the likelihood of participating.20,123 Finally, providing the control group with a truncated version of the treatment received by the experimental group, as in a study on the effect of tai chi on osteoarthritis knee pain, can also help recruitment efforts.125

3.8. Study setting

Because of barriers to participation particularly salient in pain studies, such as limited mobility, comorbidities, and pain severity,111 study staff should consider addressing the needs of individual participants during the recruitment process by discussing the availability of convenient parking, wheelchair assistance, and being met by study staff at the door. It may also be desirable to use a different type of study setting or design. Our survey of the literature revealed the use of several variations in data collection or intervention settings to reduce participation barriers. For example, a recent clinical trial among low back pain sufferers compared a conventional with a decentralized site model. The decentralized arm, which studied patients in their homes and community through remote visits and monitoring, resulted in faster recruitment, enhanced convenience for patients, improved access to patients, and greater retention. In the decentralized arm, 89% of enrolled patients completed the study compared with 60% in the conventional arm. In addition, the decentralized arm included a more diverse population with increased participation from rural areas.120

Although remote monitoring proved attractive in the study above, clinical trial simulations found that a sizeable proportion of patients, some with chronic pain, would prefer to complete study visits at a clinic rather than have a nurse visit them, to avoid the stress from a perceived need to clean their living space.76 With the advent of COVID-19, however, virtual trials are being conducted more frequently, with study drugs delivered to patients' homes.81 This new methodology may prove useful in pain studies.

The Cooperative Pain Education and Self-Management (COPES) trial compared the efficacy of interactive voice response–based cognitive behavioral therapy delivered over the phone to in-person cognitive behavioral therapy in treating patients with chronic back pain.61 Both treatment modes evidenced improvements on several measures of functioning, with no statistical difference between the two. In a study of opioid therapy tapering for patients with chronic pain, researchers allowed up to half of the 17 study visits with the physician assistant to take place over the phone and also permitted participants to complete outcome assessments at home and mail them to the study team.121 The EMPOWER study, evaluating an eHealth self-help program for patients with chronic pain on opioid therapy, conducted its entire study remotely.141 The increase in sophistication and usage of telehealth technologies during the COVID-19 pandemic may inspire more researchers to conduct their studies virtually.

3.9. Alternative design approaches

Alternative approaches to overall study design may also be useful in facilitating the success of chronic pain trial recruitment without adverse effects on quality or safety. In addition to EERW and SMARTER designs mentioned earlier, several other approaches may be considered. Pragmatic trials, for example, seek to determine whether a treatment will work in usual care conditions135 and are thus practical for studying long-term therapeutic effectiveness of pain interventions in the primary care setting. Patients stay with their doctor, and a new intervention may be compared with usual care.25 Pragmatic trials are designed to capture the nuances of clinical expertise and patient preferences when comparing clinically relevant interventions within diverse populations over varied settings.17 Such trials, which can be included as part of the validation pathway, work under best-practice conditions, are flexible in terms of clinician judgment, have simple outcomes, and enable recruitment of a more diverse, heterogeneous population.83 In the SPACE trial, a pragmatic, randomized design of patients with chronic pain at primary care clinics was used to compare opioid vs nonopioid medications.78,79 Treatments were rolled out to individual patients in graduated steps and were adjusted based on patient response. Although such trials do have limitations,25,63,109 especially regarding randomization and blinding,32 it is noteworthy that the National Institutes of Health has recently expanded its portfolio of funded pragmatic clinical trials.90

Randomized N-of-1 studies, which are essentially multiple-period crossover trials that compare interventions in an individual, are especially salient for testing treatments that demonstrate significant variability in effectiveness from patient to patient, as treatments for pain often do. An N-of-1 study also addresses somewhat the problem of a placebo arm because every N-of-1 participant can receive every treatment under study, with only a variation in the treatment order.25 Moreover, enabling a low-burden, ongoing connection between providers and patients may help patients stay engaged in data collection while facilitating the sharing of real-world data with their providers to aid decision making. The Personalized Research for Monitoring Pain Treatment (PREEMPT) Study,5 for example, examined the use of an N-of-1 trial design to measure the utility of a mobile health smartphone app among patients with chronic pain being treated with analgesics.102 Retention and engagement levels were high; of the 108 participants randomized to the N-of-1 intervention, 95 completed the trial.

3.10. Community and stakeholder engagement

Our literature review suggests that the vulnerability of the pain population necessitates specific considerations regarding participation.111 These include not just increased difficulty traveling or participating when in pain110 but also psychosocial concerns about not being treated with compassion or fear of being labeled.24 The pain population tends to be older and may suffer from comorbidities that also need treatment, and which make trial participation more difficult.104,107

Study endorsements from trusted community professionals or physicians, especially when recruiting older or minority participants with pain,53,110 have been found to be effective, as have personal interactions with seniors at health fairs and at lectures on health care.53 Community Engagement Studios, described later in this article, can also be an effective strategy for obtaining potential participant feedback.

3.11. Role of clinicians

Our review of the literature yields valuable considerations regarding the challenges of involving clinicians in chronic pain trial recruitment efforts. Whether those clinicians are primary, treating, or front line, and whether located at an institution, at the clinic, or in the community, soliciting their input upfront can help define appropriate methods and instill a feeling of ownership.6,40 Communicating with clinicians on study methods and reinforcing the potential benefits of the clinical trial for them and their patients can also reinforce the study's value.6,40 Clarifying the relevance of the scientific question for clinicians and simplifying procedures are also helpful.66 The literature emphasizes the importance of providing clinicians with clear and comprehensive eligibility criteria, particularly with respect to comorbidities, so they can screen patients with greater confidence and ease.70 Promoting an inclusive approach when screening will discourage gatekeeping112 and the unintentional weeding out of eligible patients70 that may arise from therapeutic bias and underrecognition of pain among minority patients,62,88 thereby increasing the probability that all potential participants will have an equal opportunity to participate.84,97

In addition, it may be advisable to seek out—in advance—clinician attitudes and practices regarding analgesics. A recent study to compare methadone with morphine in the treatment of chronic neuropathic pain was shut down for low enrollment because some patients had already been prescribed opioids and were thus ineligible, whereas others declined to participate because their physician did not want them to take an opioid.86

Providing materials to providers that are concise and easy to understand and delegating tasks to research staff can also reduce clinician burden.6 Physicians may need reassurances that the study will not disrupt the doctor–patient relationship6,29 and that they will not lose their patients. Because clinicians have indicated that forgetfulness can factor into poor recruitment,6 maintaining frequent contact, integrating referrals into the clinical workflow, and adding reminders can be effective strategies. In addition, one study of low back pain treatments demonstrated that pharmacists, with proper preparation, may also be employed to help in recruitment.117

3.12. Recruitment of underrepresented minority populations

Individuals from racial or ethnic minority groups are just as likely as nonminorities to experience high-impact chronic pain,27 yet they may face additional barriers to study participation, including provider bias,40 lack of study translation into native languages,67 ineffective communication by researchers, mistrust of research and researchers,17,138 and proportionally more issues related to transportation, time, and financial burden.17 At the same time, these populations are at greater risk for undertreatment of their pain, and thus, investigators must take special care to ensure that they are adequately represented in pain research.17,36 For example, Hispanic and Black participants are greatly underrepresented in seminal studies on rheumatoid arthritis despite being at increased risk for this disease.77 At the same time, some investigators have found that minority patients express similar levels of interest as nonminorities in participating in pain-related research82 and are just as likely to consent as other groups.67,116 Note that some minority participants may be concerned about exposure of their immigration status because of government identification reporting requirements when studies provide compensation. Different countries will have different reporting requirements, but in some, it may be possible to avoid this problem. In the United States, for example, study teams can obtain a reporting waiver from the Social Security Administration.

From the literature, successful recruitment of underrepresented individuals for pain studies arises from using effective communication strategies for individuals with varying levels of educational attainment, giving support to those whose primary language is other than English, and using culturally relevant images in recruitment materials.17 Cultural differences with respect to clinical trial perceptions and needs should be examined and considered in trial design and recruitment materials. A survey of patients with rheumatoid arthritis pain, for example, found that Hispanics attached greater importance than non-Hispanic Whites to the increase in doctor visits and free laboratory tests that might be associated with a clinical trial.82

Taking the time to educate potential participants about the pain research, particularly when that education is provided by a trusted provider, can aid recruitment of underrepresented populations.110 Efforts to understand and involve the community can also increase minority recruitment into pain trials. These efforts need to be considered early, allowing sufficient time to identify community stakeholders, build trusting relationships, and create partnerships with cultural brokers who should serve as genuine members of the research team.17 Community consultation is most effective when it occurs as part of the initial stages of the research design and addresses barriers to enrollment, including ethnic and socioeconomic factors.56 In addition, participants from underrepresented groups are more trustful of researchers who provide them with research results.140 The RIC's recently conducted Return of Value survey,140 which found that participants value more than just the return of personal results, can be consulted for ideas on which study results are most valuable to specific minority populations. For example, Black and Hispanic/Latino individuals are more likely than Whites to value the opportunity to be connected to other study participants like them.

Another barrier particularly salient for recruiting diverse individuals to pain trials is insufficient clinician referrals. A study among women suffering from vulvodynia found that clinicians were not often referring African-American women, who were 13 times more likely than European-American women to be recruited to the trial through mass mailings as opposed to clinician referrals.3 One strategy to increase clinic recruitment is to hire additional study team members to recruit face to face in the clinic waiting room. In 1 cancer pain study, this technique was used to complement clinician referrals—students approached patients in clinic waiting rooms who appeared to be African American, introduced the study, and collected contact information from those indicating willingness to participate. (To address potential ethical concerns, team members asked patients how they self-identified on race/ethnicity and further explained that the study's purpose was to examine previously observed differences in pain experiences and pain control between African Americans and Whites.) This method helped screen significantly more participants than going strictly through clinicians.116

In addition, both decentralized studies and pragmatic trials, described earlier, can be more effective in recruiting and retaining a diverse, heterogeneous population134 and thus should be considered for increasing minority representation in pain studies. Other underrepresented populations, including veterans, rural populations, those living in poverty, and the elderly, also exhibit a higher prevalence of chronic pain, and thus, their needs and values should also be considered when recruiting for a pain study.27,47

3.13. Recruitment and retention results from selected pain studies

As part of our review, we examined results from chronic pain studies that reported data on the efficacy of their recruitment methods. We found relatively few such articles (Table 1), and of those, most confirm the efficacy of common recruitment practices, such as deploying multiple study awareness dissemination methods; obtaining referrals from clinicians, therapists, and specialized pain clinics; and promoting the study through pain support groups and pain conferences.111 Whichever methods are chosen, real-time tracking of recruitment and enrollment efficacy should be an ongoing concern, with adjustments made accordingly.65,111

Table 1 - Pain study recruitment results.
First author, year Population and pain type Recruitment methods studied Recruitment method results Recruitment and retention results
Bachour et al, 2016 3 Women with chronic pain from vulvodynia Mass mailing, media, clinician referrals, and community outreach Mass mailing was the most effective method, especially among Black women 868 were screened and 219 enrolled
Cambron et al, 2004 15 18–45-year-old women with chronic pelvic pain Newspaper ads, radio ads, direct mail, physician referral, and family/friend referral Direct mail (38%) and radio ads (34%) led to the most randomizations 355 women screened for eligibility; 153 were eligible—of these, 75 withdrew before in-person screening, and 33 dropped out before study completion; just 39 successfully completed the study
Carnes et al, 2013 20
 Taylor et al, 2016 123
Patients with chronic musculoskeletal pain in the United Kingdom Bulk mailout from EHR search results, ads in clinics and hospitals for self-referral, clinician referral, and used unbalanced sampling of intervention to control EHR search strategy based on repeat analgesic prescriptions, ‘read’ codes of clinical pain symptoms, and visit frequency was successful Randomized 703 participants; low attrition rate
Foell et al, 2014 42 Patients with chronic musculoskeletal pain EHR search used to identify potential participants, who were then sent an invitation letter; used unbalanced sample ratio Records were successfully searched for repeat mentions of prescription painkillers and classification codes for various types of chronic pain 8494 sent invitations and 703 enrolled; no mention of retention rate
Garland et al, 2014 46 Opioid users with chronic pain Posted flyers in primary care, pain, and neurology clinics; online classified ads NR 115 enrolled, 88 began treatment, 70 completed treatment, and 52 completed all follow-ups
Groupp et al, 2005 53 60+ year-olds with chronic low back pain Newspaper ads, senior email newsletters and listservs, ads in local community centers and businesses, in-person solicitations at health fairs, lectures in public and organizational meetings, and referrals from trusted professionals in the community Print and electronic media drew in no participants. Most effective method was study endorsement by a local trusted professional 120 seniors recruited, including 20 African Americans. Eleven withdrew when allocated to the control group
Hapca et al, 2014 57 Patients with osteoarthritis or rheumatoid arthritis Newspaper ads in Scotland Ads attracted few potential participants, many of whom were ineligible to participate 320 responded to the ads, of whom 36 were deemed eligible to participate. Only 15 enrolled, falling far short of expectations
Heapy et al, 2017 61 Patients with chronic back pain EHR search for back pain–related diagnoses and a recent primary care visit record of at least moderate pain intensity; potential participants received an opt-out recruitment letter; flyers were posted in the medical center Results not broken down by the recruitment method. Owing to low enrollment, eligibility criteria were changed, and urine toxicology screens were not conducted 125 were randomized, and 18 withdrew before treatment; 102 completed at least 3 treatment sessions. Fell far short of recruitment goal and had large amount of missing assessment data
Hondras et al, 2008 65 Patients with subacute and chronic low back pain Print, radio, and television ads; flyers and direct mail postcards, health fairs, and community-based focus groups Unable to break down results by the method because they overlapped, but direct mail yielded the most participants at the lowest cost 3789 screened for a total enrollment of 432. Took several months longer than anticipated to reach the goal, and recruitment costs were double what was anticipated. The retention rate was not reported
Krebs et al, 2017; Krebs et al, 2018 (SPACE trial) 78,79 21–80-year-old veterans with chronic back pain or hip/knee osteoarthritis pain EHR search for patients with chronic back pain or hip or knee osteoarthritis diagnosis with moderate severity pain despite analgesic use and screened by telephone after opt-out letter; primary care physician referrals No breakdown by the recruitment method 240 were randomized; 234 completed the trial
Ohrtman et al, 2019 103 Adults with moderate to severe pain and/or itching from burns Mailings sent to 1700 burn survivors; ads and flyers in inpatient and outpatient hospitals; Partners' Research Patient Data Registry Comparison of results by the recruitment group not stated No recruitment goal stated; 31 participants completed the study. Overall, 45.2% of participants dropped out before study conclusion
Park et al, 2021 108 Adults with fibromyalgia Newspaper ads, web ads, flyers, clinic referrals, direct mailing to patients in clinic database, and word of mouth, in the Boston area Ads in local commuter newspaper generated the most participants (113) but were the most expensive. Clinical referrals and web ads were least expensive and also least effective. Local ads and flyers resulted in the most racially diverse sample of any methods 651 were prescreened, 272 screened, and 226 participants were randomized
Pinto et al, 2016 111 Patients with chronic phantom limb pain Recruitment directly from limb loss clinics and other clinics and teaching hospitals in the Boston area Still recruiting as of report Aiming for 132 participants in 4 years
Sherman et al, 2009 118 Patients with low back pain who were members of Group Health in Seattle Mailed letter of invitation and placed ad in the health plan's magazine The proportion enrolling and completing treatment was similar for the ad vs magazine groups 859 responded to invitation letters and 410 to the magazine ad. Twelve of 150 in the mailed letter group withdrew early; 9 of 85 in the magazine ad group withdrew early
Sullivan et al, 2017 121 Patients using opioids long term for chronic pain who were interested in tapering down opioid usage Clinician referrals, originally from the University of Washington Medical Center for Pain Relief Owing to low enrollment, referrals expanded to other pain clinics and primary care clinics. Exclusion criteria were markedly curtailed Enrolled 35 out of original enrollment goal of 50. Thirteen of 18 patients attended 80% or more of the sessions
EHR, electronic health record; NR, not reported.

A caveat emerged in our literature review regarding recruitment bias in pain trials. Broad dissemination of recruitment advertisements can exacerbate placebo response rates,93 perhaps because of the increased motivation of those seeking out a trial vs those referred by clinician invitation. In addition, a study of whiplash-associated disorders found markedly different participant characteristics when recruiting from a patient support group vs a hospital emergency department, as did investigators studying osteoarthritis treatments, when comparing those recruited through physiotherapist referrals vs newspaper articles. Together, these findings suggest that to avoid participant bias, recruitment efforts should not be concentrated on a single recruitment source.99,127

3.14. Novel retention and engagement strategies from successful studies

In addition to our literature review of recruitment methods for pain studies, we also searched for articles that reported specifically on pain study engagement and retention strategies (Table 2). Retention success, like recruitment success, begins at the study design phase. Although retention is generally not as difficult as recruitment in randomized controlled trials overall,133 it can pose a significant problem in pain studies when participants suffer from problems of discomfort, mobility, and co-occurring conditions. Participant withdrawal from active treatment in a pain study (nonadherence) varies widely, with reports of dropout ranging from 5% to 60%.22,93,105 In a 2014 review of clinical trials of chronic pelvic pain, 8 of 13 studies were judged to be at high risk of attrition bias.22 Patients not seeing a positive treatment response or who experience side effects are more likely to drop out, and studies with high percentages of withdrawals can result in findings that overestimate treatment effects.22,51,93 Managing expectations for pain relief during the recruitment process could reduce the number of dropouts while also reducing expectation bias.48 A pain study is more “at risk” for potential patient dropout if it is one in which symptoms tend to disappear with treatment; in which the treatment, procedure, or timing differs substantially from standard of care; or in which there are many other treatment options available to the patient.35 A systematic review of studies following patients with long-term pain after hip or knee replacement found that follow-up loss ranged from 5.8% to 47.6%.8

Table 2 - Engagement and retention strategies in published pain studies.
First author, year Retention approach
Cutler et al, 2001 26 • Make special follow-up efforts with those patients most likely to drop out, eg, those with greater pain and lower functioning. Efforts could include collecting and updating alternate contact numbers, offering a small cash raffle, developing a staff–participant bond, minimizing the time between follow-ups, and informing participants about the purpose of the follow-up in advance.
Elvidge et al, 2010 35 (not a clinical trial but an interview with experts) • Develop retention messages to reward participants for steps already taken and to express gratitude for their continuing contribution.
• Reinforce their original reasons for taking part, including the opportunity to help evaluate a new pain treatment to improve quality of life and advance health care.
Heapy et al, 2017 61 • Use an interactive voice response method to deliver cognitive behavioral therapy treatment for patients with chronic back pain.
Jones et al, 2010 71 • Conduct detailed group orientation sessions with potential participants on study rationale, procedures, time commitment, and expected burden, and encourage questions to ensure a thorough understanding of the study before randomization.
Krebs et al, 2017, 2018 78,79 • Design study as a pragmatic trial to afford participants some treatment flexibility within their treatment group.
Ohrtman et al, 2019 103 • Allow treatments to take place at home (facilitated self-administration), in virtual visits, or at affiliated local settings.
• Offer psychiatric or psychological resources or care.
Sullivan et al, 2017 121 • Broaden inclusion criteria and curtail exclusion criteria wherever possible.
• Limit participation requirements, such as frequent urine screening.
• Offer a 2-step consent process to delay randomization until necessary.
• Allow some treatment sessions to take place over the telephone.
• Offer pain self-management for those on opioids long term with an option for tapering dose.
• Provide participants with an option to “pause” opioid tapering.
Winhusen et al, 2021 141 • In a pragmatic trial with primary outcomes obtained from the EHR, study staff can receive automatic updates of participant contact information to improve follow-up.
EHR, electronic health record.

Our literature review uncovered several strategies used by researchers to improve engagement and retention. A study of patients being treated for chronic low back pain found that patients with worse pain and those who were functioning at lower levels were more likely to be lost to follow-up, but that many could be retained using specialized techniques.26 These included study staff efforts to bond with the patient and to have the same staff member conduct follow-up interactions, to ensure that participants understood the purpose and importance of follow-ups, to keep intervals between follow-ups to a minimum, to update participant contact information at each point of contact, and to budget for staff follow-up time and for financial incentives such as random cash drawings to reward continuation.

Vetting the study protocol from the viewpoint of the participant can help retain participants. Investigators may consider eliminating unnecessary invasive procedures76 or tests such as urine toxicology screens,111,121 adding secondary endpoints, and increasing the spacing between procedures.76 Clear participant-facing recruitment materials should be provided with an explanation of requirements for participation.26 When working with pain sufferers, caring staff members should be employed to build solid relationships with individual participants that create a feeling of partnership that encourages retention.26

The burdens of trial participation can weigh especially heavy on those experiencing pain. Difficulty of travel can be somewhat alleviated by scheduling follow-up study visits at the same time as regularly scheduled medical appointments. The Sequenced Strategy for Improving Outcomes in People With Knee Osteoarthritis Pain (SKOAP)1 HEAL Pain study schedules some follow-up visits to take place electronically or over the phone. Providing treatment flexibility, including how medicines will be administered or tapered, can also increase participant motivation. The SKOAP trial, for example, allows participants the opportunity to cross over into a more aggressive treatment group if they so desire.

3.15. The Recruitment Innovation Center: translating recruitment and retention solutions into practice

The RIC has developed and implemented a wide range of strategies, techniques, templates, and platforms to strengthen participant recruitment and retention efforts. These strategies are informed by our analysis of the recruitment and retention literature and address a number of the challenges and gaps described above. Table 3 describes each of these resources, its potential to boost recruitment or retention, and an example of how the resource is being used to address recruitment challenges in the HEAL Pain studies.

Table 3 - Pain study recruitment and retention methods developed or refined by the Recruitment Innovation Center.
Innovation Capability HEAL Pain study example
ResearchMatch 58
 Spanish ResearchMatch 14
 ResearchMatch expert advice tool
ResearchMatch is the RIC's user-friendly, researcher–participant matching site. It can be queried by investigators to locate potential participants experiencing a specific type of chronic pain, with an email message about the study sent to potentially eligible participants. The expert advice feedback tool can solicit opinions of ResearchMatch volunteers on a study's proposed protocol, recruitment/engagement plan, and desired return of value. The RIC team worked closely with the ResearchMatch team to conduct an expert virtual consultative session for feedback on recruitment materials and messaging for the HEAL SKOAP study. 1 Specifically, experts were asked their initial reaction to images and printed advertisements as well as their understanding of the terminology and sentence structure in the ad.
EHR Cohort Characterization and Identification 96 Pain studies can face unique difficulties in identifying patients through EHRs because of diffuse diagnostic criteria. The RIC's EHR-based cohort assessment resource can develop and disseminate phenotype algorithms that define the pain population under study using diagnostic coding and other criteria, such as analgesic usage. The RIC is using ClinicalTrials.gov data to design and implement lists of conditions and medications that can be indicated as inclusion/exclusion criteria. For the HEAL SurgeryPal study, 34 the RIC developed a protocol-specific phenotype algorithm to evaluate the frequency and volume of specific types of spinal surgeries at each CTSA site. These data were used by the SurgeryPal study team to select study sites with a consistent volume of these types of surgeries.
To assess feasibility of recruitment for the SKOAP study, 1 the RIC reviewed available populations at study sites by using the NCATS-funded ACT platform 130 to capture KOA patient counts across sites and evaluate race/ethnicity/sex of these patients to ensure diversity across all SKOAP sites.
Community Engagement Studios 72 A Community Engagement (CE) Studio is a structured, facilitated forum that allows a small group of patients who represent the clinical trial population of interest to act as consultants, giving direct feedback and recommendations to a study team. For a pain study, a Studio allows investigators to better understand how the study design, procedures, and materials are viewed from the perspective of the patient with pain. The RIC conducted a CE Studio for the HEAL SKOAP study 1 among a population with knee osteoarthritis pain to solicit opinions on the use of mobile health (online or telephone) methods to inform recruitment material messaging. Resulting recommendations focused on clearly explaining randomization, improving usability of online study surveys, and implementing a multitiered social media campaign to reach a more age-diverse and ethnically diverse patient population. Study changes included recruitment and retention strategies, survey design, and data collection.
The RIC is planning 2 additional Studios in Fall 2021 for the HEAL RESOLVE study. 122 One studio will bring together a population of Asian American/Pacific Islanders living in Washington state and the second will include African American/Black individuals living in the state of Georgia. Both groups of studio participants are living with high-impact chronic pain.
Recruitment and Retention Plan Template 45 Pain studies can be particularly problematic for recruiting, so anticipating problems and vetting potential solutions beforehand enables the study team to more easily anticipate potential obstacles to recruiting to reduce such issues as selection bias or unrepresentative enrollment that can undermine the integrity of the data. 10 Templates for the NIH-required Recruitment and Retention Plan have been designed by the RIC and are currently being disseminated for use by any investigating team. For the HEAL studies, a revised recruitment and retention plan template was developed to reduce burden on the study investigative teams. This consolidated template has been implemented for use in other studies where funding is already secured or there are shorter timelines to work with.
Recruitment materials templates Templates allow for streamlined collaboration between designers, operational staff, and the study investigators. The RIC developed templates for printed recruitment materials such as brochures, posters, and flyers, which have been used widely across the HEAL Pain studies.
QR code The RIC has instituted the use of QR codes on printed recruitment materials, enabling potential participants to scan the code using their own mobile device and link directly to the study webpage. This enhancement minimizes public exposure and protects privacy when a study involves sensitive conditions such as opioid misuse. In addition, scanning a QR code to receive a digital version of study information is a “no-touch” method desirable during a pandemic such as COVID-19. A QR code was added to all recruitment materials for the HEAL POSITIVE, 69 SKOAP, 1 and SurgeryPal 34 pain studies. Potential participants can simply scan the QR code with a phone rather than pick up or ask for recruitment materials. This method is especially helpful for the POSITIVE trial, in which participants are U.S. Veterans who suffer from chronic pain and opioid use disorder.
MyCap—participation engagement platform Pain studies often require lengthy treatment and follow-up periods. MyCap, 95 a participant-friendly REDCap interface available on mobile devices, enables study teams to schedule appointments and send reminders, disseminate follow-up surveys and assessments, make general study announcements, and send messages to individual participants through secure server. The MyCap platform enhances participant engagement through continued awareness of participant obligations to the study while fostering a sense of ownership and satisfaction. MyCap is listed as retention strategy available for the HEAL POSITIVE study. 69 During the COVID-19 pandemic, the POSITIVE study revised their protocol to accommodate virtual delivery of the study intervention. With the addition of telehealth, MyCap will be a simple way to collect participant follow-up data through mobile devices while supporting remote participation.
Clinician Information Sheet and Clinician Study App The 1-page clinician information sheet concisely explains the study's purpose, benefits, eligibility criteria, and schedule of interventions and assessments, which can often be lengthy in a pain study. This same information can be placed into a clinician-facing mobile web page, also known as a “clinician study app” (CSA). This condensed information speeds time from potential participant identification to randomization, reducing dropout. A CSA is being used in the HEAL Pain SurgeryPal study, 34 a randomized controlled trial to test the effectiveness of a cognitive behavioral program to improve acute and chronic pain and health outcomes in youth undergoing spine surgery. The SurgeryPal study relies on most of its referrals to come from surgeons. With their already demanding schedule, the CSA allows these surgeons to easily access basic information about study participation as well as inclusion and exclusion criteria. A link enables clinicians to make a referral at the click of a button for a patient/family to be contacted. The streamlining and efficiency of this process reduces wait time from participant identification to randomization, potentially reducing dropout rates.
Competing Trials Tool Pain and opioid addiction are a highly prioritized area of research, which results in many concurrent open trials. Multiple pain studies at a single site may find themselves competing for participants with similar eligibility criteria. To mitigate this problem before site selection, the RIC developed a Competing Trials Tool using data retrieved daily from ClinicalTrials.gov. The tool enables a rapid search of keywords, eligibility criteria, medical conditions, and anticipated enrollment periods to produce a list of potentially competing trials that can be factored into the evaluation of site feasibility. A competing trials assessment was conducted for the POSITIVE study 69 to review other trials recruiting patients with chronic pain and opioid use disorder taking buprenorphine. With this information, the study team was able to collaborate with an investigator on a similar trial and strategize ways both of their trials would be able to enroll successfully.
FasterTogether 80 FasterTogether is a portfolio of strategies to accelerate and enhance minority recruitment and retention in clinical trials. These strategies include developing culturally tailored materials, creating guidelines for eliciting input from communities, and creating a massive open online course for minority recruitment. The training modules were designed to enhance skills and knowledge of clinical research staff and include lessons on engaging minority and underserved populations and improving trust. The FasterTogether course was included as a training option for each of the HEAL studies to ensure that site staff had skills and knowledge to engage minority populations.
ACT, Accrual to Clinical Trials; CDS, clinical decision support; CE, Community Engagement; CSA, Clinician Study Application; CTSA, Clinical and Translational Science Awards; EHR, electronic health record; HEAL, Helping to End Addiction Long term; NCATS, National Center for Advancing Translational Sciences; NIH, National Institutes of Health; POSITIVE, Integrated Treatment for Veterans with Co-Occurring Chronic Pain and Opioid Use Disorder; REDCap, Research Electronic Data Capture; RESOLVE, Tailored Non-Pharmacotherapy Services for Chronic Pain: Testing Scalable and Pragmatic Approaches; RIC, Recruitment Innovation Center; SKOAP, Pain Sequenced Strategy for Improving Outcomes in People with Knee Osteoarthritis Pain.

These methods and resources were designed to be generalizable and disseminated for wide use by investigators. Many of the RIC-developed tools and templates presented in the table are available online in the TIN Toolbox for free use by research teams.124 The MyCap mobile app platform, designed to enhance participant retention, is available free of charge to any institution with a REDCap installation. Some resources, including Community Engagement Studios and EHR Cohort Identification, can be pursued on the local level or potentially accessed by eligible institutions through the proposal submission portal on the TIN website. Other resources, such as the Competing Trials Tool, are not yet available for widespread use but are expected to be offered in the near future.

4. Discussion

In one sense, recruiting participants for chronic pain studies is much like recruitment for any clinical trial, in which tactics such as increasing study awareness through varied channels, obtaining clinician buy-in, supporting study staff, and offering incentives to potential participants are all beneficial. What makes recruitment and retention for pain trials different is the current suffering the patient is experiencing, their motivation to find robust and imminent relief, and the prevalence and role of opioids in society. The deep value of participants to this research cannot be overstated—without their interest in the study, their enrollment, and their ongoing engagement in study activities, successful studies would not be possible, especially in pain research in which treatment adherence and patient-reported outcomes play key roles.

Our review of the literature shows that one of the best ways to improve recruitment and retention is by designing the study well from the start—the inclusion/exclusion criteria, setting, scope, duration, visit requirements, and so on. Researchers often find that once a study begins and enrollment flags, they need to backtrack and rework their protocol to open up the study in ways they had not previously considered. Although more time-intensive upfront, thoughtful design choices and the development of a detailed recruitment and retention plan that anticipates risks and devises potential solutions will pay dividends later when fewer course corrections are needed. The RIC has created and refined multiple recruitment and retention techniques and tools and has customized and implemented them for the HEAL Pain studies. Other pain investigators can adopt or adapt many of these methods to their own studies.

A limitation of this review is that data on the success of pain study recruitment methods are rarely published and, in most cases, are probably not even collected. For this reason, the literature will never provide a full picture of what works. The lack of published evidence forms a major gap in our understanding of these issues. An evidence base can only be established when investigators heed the call to embed research on recruitment methods into studies. It is time to move recruitment methods from an art to a science.

5. Conclusion

Finding better methods and therapies to prevent, minimize, and manage pain while avoiding the known dangers of opioid addiction is a national priority. To find treatments, trials need to be conducted and people with chronic pain need to be recruited. These patients with pain bring their challenges to the clinical trial space—burdens that create obstacles, but that also provide opportunities to reach patients with pain where they are, to create recruitment and retention strategies that not only help locate and enroll eligible patients but engage them in ways that keep them actively participating and help them receive value from participation. We hope the information disseminated through this article will contribute to an increase in successful pain trial recruitment.

Disclosures

The authors have no conflict of interest to declare.

Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences, the National Library of Medicine, the National Institute of Neurological Disorders and Stroke, or the National Institutes of Health.

This project was supported by awards no. UL1 TR002243 from the National Center for Advancing Translational Sciences (NCATS), no. U24TR001579 from the NCATS and the U.S. National Library of Medicine, and no. 3U24 TR001579-05S2 from the NCATS and the National Institute of Neurological Disorders and Stroke.

Acknowledgments

The authors extend their sincere thanks to Jasmine Bell for her manuscript review and suggestions.

References

[1]. A sequenced strategy for improving outcomes in people with knee osteoarthritis pain. ClinicalTrials.gov, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04504812. Accessed August 30, 2021.
[2]. Adamson J, Hewitt CE, Torgerson DJ. Producing better evidence on how to improve randomised controlled trials. BMJ 2015;351:h4923.
[3]. Bachour CC, Bachmann GA, Foster DC, Wan JY, Rawlinson LA, Brown CS. Recruitment methods in a clinical trial of provoked vulvodynia: predictors of enrollment. Clin Trials 2017;14:103–8.
[4]. Baker RG, Koroshetz WJ, Volkow ND. The Helping to End Addiction Long-Term (HEAL) initiative of the National Institutes of Health. JAMA 2021;326:1005–6.
[5]. Barr C, Marois M, Sim I, Schmid CH, Wilsey B, Ward D, Duan N, Hays RD, Selsky J, Servadio J, Schwartz M, Dsouza C, Dhammi N, Holt Z, Baquero V, MacDonald S, Jerant A, Sprinkle R, Kravitz RL. The PREEMPT study—evaluating smartphone-assisted n-of-1 trials in patients with chronic pain: study protocol for a randomized controlled trial. Trials 2015;16:67.
[6]. Bell-Syer SEM, Thorpe LN, Thomas K, MacPherson H. GP participation and recruitment of patients to RCTs: lessons from trials of acupuncture and exercise for low back pain in primary care. Evid-Based Complement Altern Med 2011;2011:687349.
[7]. Bernard GR, Harris PA, Pulley JM, Benjamin DK, Michael J, Ford DE, Hanley DF, Selker HP, Wilkins CH. A collaborative, academic approach to optimizing the national clinical research infrastructure: the first year of the Trial Innovation Network. J Clin Transl Sci 2018;2:187–92.
[8]. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2012;2:e000435.
[9]. Bisla J, Ambler G, Frank B, Gulati S, Hocken P, James M, Kelly J, Keshet-Price J, McCabe C, McGylnn D, Padfield N, Pang D, Pout G, Sanders M, Serpell M, Shenker N, Shoukrey K, Wesley S, Weston M, White-Alao B, Wyatt L, Murphy C, Goebel A. Successful and unsuccessful recruitment and retainment strategies in a UK multicentre drug trial for a rare chronic pain condition which performed above target. Br J Pain 2020;14:171–9.
[10]. Blanton S, Morris DM, Prettyman MG, McCulloch K, Redmond S, Light KE, Wolf SL. Lessons learned in participant recruitment and retention: the EXCITE trial. Phys Ther 2006;86:1520–33.
[11]. Bradt J. Challenges related to conducting clinical studies in community healthcare settings. NEA Research Labs: NEA Research Labs, 2016. Available at: file:///C:/Users/kennedn/Downloads/ReflectionsBradt1NEA2418JB%20(5).pdf.
[12]. Bradt J, Norris M, Shim M, Gracely EJ, Gerrity P. Vocal music therapy for chronic pain management in inner city African Americans: a mixed methods feasibility study. J Music Ther 2016;53:178–206.
[13]. Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH. Opioids for chronic noncancer pain: a systematic review and meta-analysis. JAMA 2018;320:2448–60.
[14]. Byrne LM, Cook SK, Kennedy N, Russell M, Jerome RN, Tan J, Barajas C, Wilkins CH, Harris PA. Opening doors to clinical trial participation among Hispanics: lessons learned from the Spanish translation of ResearchMatch. J Clin Transl Sci 2020;5:e46.
[15]. Cambron JA, Hawk C, Evans R, Long CR. Recruitment and accrual of women in a placebo-controlled clinical pilot study on manual therapy. J Manipulative Physiol Ther 2004;27:299–305.
[16]. Campbell J, King NB. “Unsettling circularity”: clinical trial enrichment and the evidentiary politics of chronic pain. BioSocieties 2017;12:191–216.
[17]. Campbell LC, Robinson K, Meghani SH, Vallerand A, Schatman M, Sonty N. Challenges and opportunities in pain management disparities research: implications for clinical practice, advocacy, and policy. J Pain 2012;13:611–19.
[18]. Cardillo L, Cahill F, Wylie H, Williams A, Zylstra J, Davies AR, Fullwood L, Van Hemelrijck M. Patients' perspectives on opt-out consent for observational research: systematic review and focus group. Br J Nurs 2018;27:1321–9.
[19]. Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials. Clin Trials 2015;12:77–83.
[20]. Carnes D, Taylor SJ, Homer K, Eldridge S, Bremner S, Pincus T, Rahman A, Underwood M. Effectiveness and cost-effectiveness of a novel, group self-management course for adults with chronic musculoskeletal pain: study protocol for a multicentre, randomised controlled trial (COPERS). BMJ Open 2013;3:e002492.
[21]. Centers for Disease Control, National Center for Health Statistics, National Vital Statistics System. Drug overdose deaths in the United States, 1999-2017. Available at: https://www.cdc.gov/nchs/data/databriefs/db329_tables-508.pdf#page=4. Accessed February 17, 2021.
[22]. Cheong YC, Smotra G, Williams AC. Non‐surgical interventions for the management of chronic pelvic pain. Cochrane Database Syst Rev 2014;3:CD008797.
[23]. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health pathways to prevention workshop. Ann Intern Med 2015;162:276.
[24]. Cohen M, Quintner J, Buchanan D, Nielsen M, Guy L. Stigmatization of patients with chronic pain: the extinction of empathy. Pain Med 2011;12:1637–43.
[25]. Cohen SP, Wallace M, Rauck RL, Stacey BR. Unique aspects of clinical trials of invasive therapies for chronic pain. PAIN Rep 2019;4:e687.
[26]. Cutler RB, Fishbain DA, Cole B, Steele-Rosomoff R, Rosomoff HL. Identifying patients at risk for loss to follow-up after pain center treatment. Pain Med 2001;2:46–51.
[27]. Dahlhamer J. Prevalence of chronic pain and high-impact chronic pain among adults—United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:1001–6.
[28]. Dansie EJ, Turk DC. Assessment of patients with chronic pain. Br J Anaesth 2013;111:19–25.
[29]. De Hertogh W, Vaes P, Devroey D, Louis P, Carpay H, Truijen S, Duquet W, Oostendorp R. Preliminary results, methodological considerations and recruitment difficulties of a randomised clinical trial comparing two treatment regimens for patients with headache and neck pain. BMC Musculoskelet Disord 2009;10:115.
[30]. Disparities in opioid overdose deaths continue to worsen for Black people, study suggests. National Institute on Drug Abuse. 2021. Available at: https://www.drugabuse.gov/news-events/news-releases/2021/09/disparities-in-opioid-overdose-deaths-continue-to-worsen-for-black-people-study-suggests. Accessed October 6, 2021.
[31]. Dworkin RH, Evans SR, Mbowe O, McDermott MP. Essential statistical principles of clinical trials of pain treatments. PAIN Rep 2021;6:e863.
[32]. Dworkin RH, Kerns RD, McDermott MP, Turk DC, Veasley C. The ACTTION Guide to Clinical Trials of Pain Treatments, part II: mitigating bias, maximizing value. PAIN Rep 2021;6:e886.
[33]. Dworkin RH, Turk DC, Peirce-Sandner S, Baron R, Bellamy N, Burke LB, Chappell A, Chartier K, Cleeland CS, Costello A, Cowan P, Dimitrova R, Ellenberg S, Farrar JT, French JA, Gilron I, Hertz S, Jadad AR, Jay GW, Kalliomäki J, Katz NP, Kerns RD, Manning DC, McDermott MP, McGrath PJ, Narayana A, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Reeve BB, Rhodes T, Sampaio C, Simpson DM, Stauffer JW, Stucki G, Tobias J, White RE, Witter J. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. PAIN 2010;149:177–93.
[34]. Effectiveness of an mHealth psychosocial intervention to prevent transition from acute to chronic postsurgical pain in adolescents. ClinicalTrials.gov, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04637802. Accessed August 31, 2021.
    [35]. Elvidge S. The importance of patient-retention strategies, 2010. Available at: https://www.pharmaceuticalonline.com/doc/the-importance-of-patient-retention-0001. Accessed July 26, 2018.
    [36]. Ezenwa MO, Ameringer S, Ward SE, Serlin RC. Racial and ethnic disparities in pain management in the United States. J Nurs Scholarsh 2006;38:225–33.
    [37]. Factsheet. CDC guideline for prescribing opioids for chronic pain. Centers for Disease Control, 2016. Available at: https://www.cdc.gov/drugoverdose/pdf/Guidelines_At-A-Glance-508.pdf.
    [38]. Farrar JT. Advances in clinical research methodology for pain clinical trials. Nat Med 2010;16:1284–93.
    [39]. Finniss D, Nicholas M, Brooker C, Cousins M, Benedetti F. Magnitude, response, and psychological determinants of placebo effects in chronic low-back pain: a randomised, double-blinded, controlled trial. PAIN Rep 2019;4:e744.
    [40]. Fletcher B, Gheorghe A, Moore D, Wilson S, Damery S. Improving the recruitment activity of clinicians in randomised controlled trials: a systematic review. BMJ Open 2012;2:e000496.
    [41]. Fodeh SJ, Finch D, Bouayad L, Luther SL, Ling H, Kerns RD, Brandt C. Classifying clinical notes with pain assessment using machine learning. Med Biol Eng Comput 2018;56:1285–92.
    [42]. Foell J, Carnes D, Homer K, Taylor S. Developing and implementing electronic search strategies to recruit patients with chronic musculoskeletal pain in primary care databases. Prim Health Care Res Dev 2014;15:234–43.
    [43]. Froud R, Rajendran D, Patel S, Bright P, Bjørkli T, Eldridge S, Buchbinder R, Underwood M. The power of low back pain trials: a systematic review of power, sample size, and reporting of sample size calculations over time, in trials published between 1980 and 2012. Spine 2017;42:E680–6.
    [44]. Furlan AD, Chaparro LE, Irvin E, Mailis-Gagnon A. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Res Manag 2011;16:337–51.
    [45]. G.500—PHS human subjects and clinical trials information. Available at: https://grants.nih.gov/grants/how-to-apply-application-guide/forms-e/general/g.500-phs-human-subjects-and-clinical-trials-information.htm#2.5. Accessed November 26, 2019.
    [46]. Garland EL, Manusov EG, Froeliger B, Kelly A, Williams JM, Howard MO. Mindfulness-oriented recovery enhancement for chronic pain and prescription opioid misuse: results from an early stage randomized controlled trial. J Consult Clin Psychol 2014;82:448–59.
    [47]. Gauntlett-Gilbert J, Wilson S. Veterans and chronic pain. Br J Pain 2013;7:79–84.
    [48]. Gewandter JS, Dworkin RH, Turk DC, Devine EG, Hewitt D, Jensen MP, Katz NP, Kirkwood AA, Malamut R, Markman JD, Vrijens B, Burke L, Campbell JN, Carr DB, Conaghan PG, Cowan P, Doyle MK, Edwards RR, Evans SR, Farrar JT, Freeman R, Gilron I, Juge D, Kerns RD, Kopecky EA, McDermott MP, Niebler G, Patel KV, Rauck R, Rice ASC, Rowbotham M, Sessler NE, Simon LS, Singla N, Skljarevski V, Tockarshewsky T, Vanhove GF, Wasan AD, Witter J. Improving study conduct and data quality in clinical trials of chronic pain treatments: IMMPACT recommendations. J Pain 2020;21:931–42.
    [49]. Gewandter JS, Dworkin RH, Turk DC, Farrar JT, Fillingim RB, Gilron I, Markman JD, Oaklander AL, Polydefkis MJ, Raja SN, Robinson JP, Woolf CJ, Ziegler D, Ashburn MA, Burke LB, Cowan P, George SZ, Goli V, Graff OX, Iyengar S, Jay GW, Katz J, Kehlet H, Kitt RA, Kopecky EA, Malamut R, McDermott MP, Palmer P, Rappaport BA, Rauschkolb C, Steigerwald I, Tobias J, Walco GA. Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations. PAIN Rep 2021;6:e895.
    [50]. Gewandter JS, Dworkin RH, Turk DC, McDermott MP, Baron R, Gastonguay MR, Gilron I, Katz NP, Mehta C, Raja SN, Senn S, Taylor C, Cowan P, Desjardins P, Dimitrova R, Dionne R, Farrar JT, Hewitt DJ, Iyengar S, Jay GW, Kalso E, Kerns RD, Leff R, Leong M, Petersen KL, Ravina BM, Rauschkolb C, Rice ASC, Rowbotham MC, Sampaio C, Sindrup SH, Stauffer JW, Steigerwald I, Stewart J, Tobias J, Treede R-D, Wallace M, White RE. Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations. PAIN 2014;155:1683–95.
    [51]. Gilron I. Methodological issues associated with clinical trials in neuropathic pain. Expert Rev Clin Pharmacol 2016;9:1399–402.
    [52]. Gold HT, Karia RJ, Link A, Lebwohl R, Zuckerman JD, Errico TJ, Slover JD, Buckland AJ, Mann DM, Cantor MN. Implementation and early adaptation of patient-reported outcome measures into an electronic health record: a technical report. Health Informatics J 2020;26:129–40.
    [53]. Groupp E, Haas M, Fairweather A, Ganger B, Attwood M. Recruiting seniors with chronic low back pain for a randomized controlled trial of a self-management program. J Manipulative Physiol Ther 2005;28:97–102.
    [54]. Grøvle L, Hasvik E, Haugen AJ. Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain. PAIN 2022;163:e417.
    [55]. Grøvle L, Hasvik E, Haugen AJ. Rescue and concomitant analgesics in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain. PAIN 2020;161:3–10.
    [56]. Gul RB, Ali PA. Clinical trials: the challenge of recruitment and retention of participants. J Clin Nurs 2009;19:227–33.
    [57]. Hapca A, Jennings CG, Wei L, Wilson A, MacDonald TM, Mackenzie IS. Effectiveness of newspaper advertising for patient recruitment into a clinical trial. Br J Clin Pharmacol 2014;77:1064–72.
    [58]. Harris PA, Scott KW, Lebo L, Hassan N, Lightner C, Pulley J. ResearchMatch: a national registry to recruit volunteers for clinical research. Acad Med 2012;87:66–73.
    [59]. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81.
    [60]. HCSRN. Recruitment best practices guide a guide to optimizing recruitment and data collection in multi-site studies, 2006. Available at: http://www.hcsrn.org/en/Tools%20&%20Materials/Plan_Field/HCSRN_Recruitment&DataCollection.pdf.
    [61]. Heapy AA, Higgins DM, Goulet JL, LaChappelle KM, Driscoll MA, Czlapinski RA, Buta E, Piette JD, Krein SL, Kerns RD. Interactive voice response–based self-management for chronic back pain. JAMA Intern Med 2017;177:765–73.
    [62]. Hoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proc Natl Acad Sci U S A 2016;113:4296–301.
    [63]. Hohenschurz-Schmidt D, Kleykamp BA, Draper-Rodi J, Vollert J, Chan J, Ferguson M, McNicol E, Phalip J, Evans SR, Turk DC, Dworkin RH, Rice ASC. Pragmatic trials of pain therapies: a systematic review of methods. PAIN 2022;63:21–46.
    [64]. Holman AJ, Neradilek MB, Dryland DD, Neiman RA, Brown PB, Ettlinger RE. Patient-derived determinants for participation in placebo-controlled clinical trials for fibromyalgia. Curr Pain Headache Rep 2010;14:470–6.
    [65]. Hondras MA, Long CR, Haan AG, Spencer LB, Meeker WC. Recruitment and enrollment for the simultaneous conduct of 2 randomized controlled trials for patients with subacute and chronic low back pain at a CAM Research Center. J Altern Complement Med 2008;14:983–92.
    [66]. Huang GD, Bull J, Johnston McKee K, Mahon E, Harper B, Roberts JN. Clinical trials recruitment planning: a proposed framework from the Clinical Trials Transformation Initiative. Contemp Clin Trials 2018;66:74–9.
    [67]. Huang HY, Ezenwa MO, Wilkie DJ, Judge MK. ResearchTracking: monitoring gender and ethnic minority recruitment and retention in cancer symptom studies., ResearchTracking: monitoring gender and ethnic minority recruitment and retention in cancer symptom studies. Cancer Nurs 2013;36:E1–6.
    [68]. ICD-11. Available at: https://icd.who.int/en. Accessed March 15, 2022.
    [69]. Integrated treatment for veterans with co-occurring chronic pain and opioid use disorder. ClinicalTrials.gov, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04648228. Accessed August 31, 2021.
    [70]. Jenkinson CE, Winder RE, Sugg HVR, Roberts MJ, Ridgway N, Kuyken W, Wiles N, Kessler D, Campbell J. Why do GPs exclude patients from participating in research? An exploration of adherence to and divergence from trial criteria. Fam Pract 2014;31:364–70.
    [71]. Jones KD, Reiner AC. A multistep recruitment strategy to a participant-intensive clinical trial. Appl Nurs Res 2010;23:227–32.
    [72]. Joosten YA, Israel TL, Williams NA, Boone LR, Schlundt DG, Mouton CP, Dittus RS, Bernard GR, Wilkins CH. Community engagement studios: a structured approach to obtaining meaningful input from stakeholders to inform research. Acad Med 2015;90:1646–50.
    [73]. Katz N. Design and conduct of confirmatory chronic pain clinical trials. Pain Rep 2020;6:e845.
    [74]. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: focus on methodology. Clin J Pain 2009;25:797–807.
    [75]. Katz N, Dworkin RH, North R, Thomson S, Eldabe S, Hayek SM, Kopell BH, Markman J, Rezai A, Taylor RS, Turk DC, Buchser E, Fields H, Fiore G, Ferguson M, Gewandter J, Hilker C, Jain R, Leitner A, Loeser J, McNicol E, Nurmikko T, Shipley J, Singh R, Trescot A, van Dongen R, Venkatesan L. Research design considerations for randomized controlled trials of spinal cord stimulation for pain: initiative on methods, measurement, and pain assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations. PAIN 2021;162:1935–56.
    [76]. Kim J. What the patient voice taught Lilly about clinical trial design recruitment, 2019. Available at: https://www.clinicalleader.com/doc/what-the-patient-voice-taught-lilly-about-clinical-trial-design-recruitment-0001. Accessed January 30, 2020.
    [77]. Koehn CL. The role of ethnicity in willingness to participate in rheumatoid arthritis clinical trials. J Rheumatol 2005;32:2283–4.
    [78]. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA 2018;319:872–82.
    [79]. Krebs EE, Jensen AC, Nugent S, DeRonne B, Rutks I, Leverty D, Gravely A, Noorbaloochi S, Bair MJ, Kroenke K. Design, recruitment outcomes, and sample characteristics of the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial. Contemp Clin Trials 2017;62:130–9.
    [80]. Kusnoor SV, Villalta-Gil V, Michaels M, Joosten Y, Israel TL, Epelbaum MI, Lee P, Frakes ET, Cunningham-Erves J, Mayers SA, Stallings SC, Giuse NB, Harris PA, Wilkins CH. Design and implementation of a massive open online course on enhancing the recruitment of minorities in clinical trials—faster together. BMC Med Res Methodol 2021;21:44.
    [81]. Large clinical trial to study repurposed drugs to treat COVID-19 symptoms. National Institutes of Health, 2021. Available at: https://www.nih.gov/news-events/news-releases/large-clinical-trial-study-repurposed-drugs-treat-covid-19-symptoms. Accessed September 1, 2021.
    [82]. Lee SJ, Lenert L, Weisman S, Kavanaugh A. Factors affecting rheumatoid arthritis patients' decisions to participate in clinical trials. J Rheumatol 2005;32:2317–25.
    [83]. Lerman C. Randomized clinical trials versus practical clinical trials in pharmacogenomics. Institute of Medicine, 2009.
    [84]. Ling J, Rees E, Hardy J. What influences participation in clinical trials in palliative care in a cancer centre? Eur J Cancer 2000;36:621–6.
    [85]. Liu Y, Wang Y, Zeng D. Sequential multiple assignment randomization trials with enrichment design. Biometrics 2017;73:378–90.
    [86]. Lynch M, Moulin D, Perez J. Methadone vs. morphine SR for treatment of neuropathic pain: a randomized controlled trial and the challenges in recruitment. Can J Pain 2019;3:180–9.
    [87]. Madson TJ, Cieslak KR, Gay RE. Joint mobilization vs massage for chronic mechanical neck pain: a pilot study to assess recruitment strategies and estimate outcome measure variability. J Manipulative Physiol Ther 2010;33:644–51.
    [88]. Meints SM, Cortes A, Morais CA, Edwards RR. Racial and ethnic differences in the experience and treatment of noncancer pain. Pain Manag 2019;9:317.
    [89]. Meske DS, Lawal OD, Elder H, Langberg V, Paillard F, Katz N. Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials. J Pain Res 2018;11:923–34.
    [90]. Meyers C. NIH collaboratory expands its portfolio of pragmatic clinical trials. NCCIH, 2018. Available at: https://nccih.nih.gov/research/blog/Expands-Its-Portfolio-of-Pragmatic-Clinical-Trials. Accessed July 31, 2018.
    [91]. Michaleff ZA, Campbell P, Hay AD, Warburton L, Dunn KM. Child and adolescent musculoskeletal pain (CAM-Pain) feasibility study: testing a method of identifying, recruiting and collecting data from children and adolescents who consult about a musculoskeletal condition in UK general practice. BMJ Open 2018;8:e021116.
    [92]. Moore A, Eccleston C, Derry S, Wiffen P, Bell R, Straube S, McQuay H. “Evidence” in chronic pain—establishing best practice in the reporting of systematic reviews. PAIN 2010;150:386–9.
    [93]. Moore RA, Derry S, Wiffen PJ. Challenges in design and interpretation of chronic pain trials. Br J Anaesth 2013;111:38–45.
    [94]. Moore RA, Wiffen PJ, Eccleston C, Derry S, Baron R, Bell RF, Furlan AD, Gilron I, Haroutounian S, Katz NP, Lipman AG, Morley S, Peloso PM, Quessy SN, Seers K, Strassels SA, Straube S. Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting. PAIN 2015;156:1382–95.
    [95]. MyCap—mobilizing the participant voice. Available at: https://projectmycap.org/. Accessed September 1, 2021.
    [96]. Nelson SJ, Drury B, Hood D, Harper J, Bernard T, Weng C, Kennedy N, LaSalle B, Gouripeddi R, Wilkins CH, Harris P. EHR-based cohort assessment for multicenter RCTs: a fast and flexible model for identifying potential study sites. J Am Med Inform Assoc 2022;29:652–9.
    [97]. Newington L, Metcalfe A. Factors influencing recruitment to research: qualitative study of the experiences and perceptions of research teams. BMC Med Res Methodol 2014;14:10.
    [98]. NIH HEAL Pain Management ERN | Pain Consortium. Available at: https://www.painconsortium.nih.gov/funding-research/nih-heal-pain-management-ern?search-term=Funding%20Research%20NIH%20HEAL%20Effectiveness%20Research%20Program%20Pain. Accessed February 11, 2022.
    [99]. Nijs J, Inghelbrecht E, Daenen L, Hachimi-Idrissi S, Hens L, Willems B, Roussel N, Cras P, Wouters K, Bernheim J. Recruitment bias in chronic pain research: whiplash as a model. Clin Rheumatol 2011;30:1481.
    [100]. Nikles J, Keijzers G, Mitchell G, Farrell SF, Perez S, Schug S, Ware RS, McLean SA, Connelly LB, Sterling M. Pregabalin vs placebo to prevent chronic pain after whiplash injury in at-risk individuals: results of a feasibility study for a large randomised controlled trial. PAIN 2022;163:e274–84.
    [101]. Nothnagel H, Brown Menard M, Kvarstein G, Norheim A, Weiss T, Puta C, Mist S, Musial F. Recruitment and inclusion procedures as “pain killers” in clinical trials? J Pain Res 2019;12:2027–37.
    [102]. Odineal DD, Marois MT, Ward D, Schmid CH, Cabrera R, Sim I, Wang Y, Wilsey B, Duan N, Henry SG, Kravitz RL. Effect of mobile device-assisted N-of-1 trial participation on analgesic prescribing for chronic pain: randomized controlled trial. J Gen Intern Med 2020;35:102–11.
    [103]. Ohrtman EA, Zaninotto AL, Carvalho S, Shie VL, Leite J, Ianni CR, Kazis LE, Zafonte R, Ryan CM, Schneider JC, Fregni F. Longitudinal clinical trial recruitment and retention challenges in the burn population: lessons learned from a trial examining a novel intervention for chronic neuropathic symptoms. J Burn Care Res 2019;40:792–5.
    [104]. Paeck T, Ferreira ML, Sun C, Lin C-WC, Tiedemann A, Maher CG. Are older adults missing from low back pain clinical trials? A systematic review and meta-analysis: age of participants in clinical trials of LBP interventions. Arthritis Care Res 2014;66:1220–6.
    [105]. Pain management clinical trials—analgesia clinical trials | Rho. Available at: https://www.rhoworld.com/rho/services/therapeutic-expertise/analgesia. Accessed August 29, 2019.
    [106]. Pain Management Effectiveness Research Network. NIH HEAL Initiative, 2019. Available at: https://heal.nih.gov/research/clinical-research/pain-management-research. Accessed February 17, 2021.
    [107]. Park J, Lavin R. Risk factors associated with opioid medication misuse in community-dwelling older adults with chronic pain. Clin J Pain 2010;26:647–55.
    [108]. Park M, Bannuru RR, Price LL, Harvey WF, Driban JB, Wang C. Effective recruitment strategies in an exercise trial for patients with fibromyalgia. Trials 2021;22:557.
    [109]. Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci 2011;13:217–24.
    [110]. Peters-Lawrence MH, Bell MC, Hsu LL, Osunkwo I, Seaman P, Blackwood M, Guillaume E, Bellevue R, Krishnamurti L, Smith WR, Dampier CD, Minniti CP. Clinical trial implementation and recruitment: lessons learned from the early closure of a randomized clinical trial. Contemp Clin Trials 2012;33:291–7.
    [111]. Pinto CB, Vélez FGS, French MN, Zeng D, Crandell D, Bolognini N, Merabet LB, Fregni F. Strategies to enhance recruitment methods in phantom limb pain clinical trials. Int J Clin Trials 2017;4:72–9.
    [112]. Probstfield JL, Frye RL. Strategies for recruitment and retention of participants in clinical trials. JAMA 2011;306:1798–9.
    [113]. Reuben DB, Alvanzo AAH, Ashikaga T, Bogat GA, Callahan CM, Ruffing V, Steffens DC. National Institutes of Health pathways to prevention workshop: the role of opioids in the treatment of chronic pain. Ann Intern Med 2015;162:295.
    [114]. Rowbotham MC, Gilron I, Glazer C, Rice ASC, Smith BH, Stewart WF, Wasan AD. Can pragmatic trials help us better understand chronic pain and improve treatment? PAIN 2013;154:643–6.
    [115]. Rowbotham MC, McDermott MP. Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments. PAIN Rep 2019;4:e646.
    [116]. Schim SM, Vallerand AH, Hasenau SM, Robinson SG. Challenges to recruitment of urban African American patients with cancer pain. Palliat Med Care Open Access 2014;1:5.
    [117]. Shaheed CA, Maher CG, Williams KA, McLachlan AJ. Participation of pharmacists in clinical trial recruitment for low back pain. Int J Clin Pharm 2014;36:986–94.
    [118]. Sherman KJ, Hawkes RJ, Ichikawa L, Cherkin DC, Deyo RA, Avins AL, Khalsa PS. Comparing recruitment strategies in a study of acupuncture for chronic back pain. BMC Med Res Methodol 2009;9:69.
    [119]. Smith E. The case against excluding high placebo responders from clinical trials. Cognivia, 2019. Available at: https://cognivia.com/the-case-against-excluding-high-placebo-responders-from-clinical-trials-2/. Accessed January 26, 2022.
    [120]. Sommer C, Zuccolin D, Arnera V, Schmitz N, Adolfsson P, Colombo N, Gilg R, McDowell B. Building clinical trials around patients: evaluation and comparison of decentralized and conventional site models in patients with low back pain. Contemp Clin Trials Commun 2018;11:120–6.
    [121]. Sullivan MD, Turner JA, DiLodovico C, D'Appolonio A, Stephens K, Chan Y-F. Prescription opioid taper support for outpatients with chronic pain: a randomized controlled trial. J Pain 2017;18:308–18.
    [122]. Tailored non-pharmacotherapy services for chronic pain: testing scalable and pragmatic approaches. ClinicalTrials.gov, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04523714. Accessed August 31, 2021.
      [123]. Taylor SJC, Carnes D, Homer K, Kahan BC, Hounsome N, Eldridge S, Spencer A, Pincus T, Rahman A, Underwood M. Novel three-day, community-based, nonpharmacological group intervention for chronic musculoskeletal pain (COPERS): a randomised clinical trial. PLoS Med 2016;13:e1002040.
      [124]. TIN Toolbox—Trial Innovation Network. Available at: https://trialinnovationnetwork.org/recruitment-retention-toolkit/. Accessed September 1, 2021.
      [125]. Tsai P-F, Chang JY, Chowdhury N, Beck C, Roberson PK, Rosengren K. Enrolling older adults with cognitive impairment in research: lessons from A study of Tai Chi for osteoarthritis knee pain. Res Gerontol Nurs 2009;2:228–34.
      [126]. Vase L, Wartolowska K. Pain, placebo, and test of treatment efficacy: a narrative review. Br J Anaesth 2019;123:e254.
      [127]. Veenhof C, Dekker J, Bijlsma JWJ, van den Ende CHM. Influence of various recruitment strategies on the study population and outcome of a randomized controlled trial involving patients with osteoarthritis of the hip or knee. Arthritis Care Res 2005;53:375–82.
      [128]. Vellinga A, Cormican M, Hanahoe B, Bennett K, Murphy AW. Opt-out as an acceptable method of obtaining consent in medical research: a short report. BMC Med Res Methodol 2011;11:40.
      [129]. Vernon H, Jansz G, Goldsmith CH, McDermaid C. A randomized, placebo-controlled clinical trial of chiropractic and medical prophylactic treatment of adults with tension-type headache: results from a stopped trial. J Manipulative Physiol Ther 2009;32:344–51.
      [130]. Visweswaran S, Becich MJ, D'Itri VS, Sendro ER, MacFadden D, Anderson NR, Allen KA, Ranganathan D, Murphy SN, Morrato EH, Pincus HA, Toto R, Firestein GS, Nadler LM, Reis SE. Accrual to clinical trials (ACT): a Clinical and Translational Science Award Consortium Network. JAMIA Open 2018;1:147–52.
      [131]. Voon P, Karamouzian M, Kerr T. Chronic pain and opioid misuse: a review of reviews. Subst Abuse Treat Prev Pol 2017;12:36.
      [132]. Walsh SL, Long KQX. Deploying science to change hearts and minds: responding to the opioid crisis. Prev Med 2019:105780.
      [133]. Walters SJ, Bonacho Dos Anjos Henriques-Cadby I, Bortolami O, Flight L, Hind D, Jacques RM, Knox C, Nadin B, Rothwell J, Surtees M, Julious SA. Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme. BMJ Open 2017;7:e015276.
      [134]. Warner ET, Glasgow RE, Emmons KM, Bennett GG, Askew S, Rosner B, Colditz GA. Recruitment and retention of participants in a pragmatic randomized intervention trial at three community health clinics: results and lessons learned. BMC Public Health 2013;13:192.
      [135]. Wasan AD. Efficacy vs effectiveness and explanatory vs pragmatic: where is the balance point in pain medicine research? Pain Med 2014;15:539–40.
      [136]. Wasan AD, Taubenberger SP, Robinson WM. Reasons for participation in pain research: can they indicate a lack of informed consent? Pain Med Malden Mass 2009;10:111–19.
      [137]. Westra BL, Johnson SG, Ali S, Bavuso KM, Cruz CA, Collins S, Furukawa M, Hook ML, LaFlamme A, Lytle K, Pruinelli L, Rajchel T, Settergren TT, Westman KF, Whittenburg L. Validation and refinement of a pain information model from EHR flowsheet data. Appl Clin Inform 2018;9:185–98.
      [138]. Wilkins CH. Effective engagement requires trust and being trustworthy. Med Care 2018;56:S6.
      [139]. Wilkins CH, Edwards TL, Stroud M, Kennedy N, Jerome RN, Lawrence CE, Kusnoor SV, Nelson S, Byrne LM, Boone LR, Dunagan J, Israel T, Rodweller C, Drury B, Kost RG, Pulley JM, Bernard GR, Harris PA. The Recruitment Innovation Center: developing novel, person-centered strategies for clinical trial recruitment and retention. J Clin Transl Sci 2021;5:e194.
      [140]. Wilkins CH, Mapes BM, Jerome RN, Villalta-Gil V, Pulley JM, Harris PA. Understanding what information is valued by research participants, and why. Health Aff (Millwood) 2019;38:399–407.
      [141]. Winhusen T, Wilson M, Dolor RJ, Theobald J, Lewis D, Regan SL, Vonder Meulen MB. Design considerations for a remote randomized multi-site clinical trial evaluating an e-health self-management program for chronic pain patients receiving opioid therapy. Contemp Clin Trials 2021;101:106245.
      Keywords:

      Clinical trial recruitment, Participant retention, Chronic pain trial, Opioid use disorder, Helping to End Addiction Long-Term (HEAL)

      Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.