Linda Porter

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

&NA; There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence‐based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Opioid Pharmacotherapy for Chronic Non-Cancer Pain in the United States: A Research Guideline for Developing an Evidence-Base

UNLABELLED This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence. PERSPECTIVE Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP.

Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

Background Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. Methods We conducted a randomized, double‐blind, placebo‐controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28‐day baseline period with the last 28 days of a 24‐week trial. Secondary outcomes were headache‐related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. Results A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between‐group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between‐group differences in headache‐related disability, headache days, or the percentage of patients who completed the 24‐week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. Conclusions There were no significant differences in reduction in headache frequency or headache‐related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

Abstract There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy

1. IntroductionEvidence of the efficacy of analgesic treatments is typicallybased on double-blind randomized clinical trials (RCTs) conductedin patients with a specific pain diagnosis, disease, or condition[1,2,9–11,40]. The results of these RCTs provide evidence of effi-cacy in the specific condition investigated, especially when thereis replication of the results. However, little attention has been de-voted to considering whether evidence of efficacy in one particularconditioncan be extrapolatedto otherswith a reasonabledegreeofconfidence that the treatment will be efficacious. For example, canit be assumed that the results of RCTs demonstrating that a medi-cation is efficacious for knee osteoarthritis (OA) pain indicate thatthis medication would also be efficacious for hip OA pain, or thatefficacy in postherpetic neuralgia (PHN) predicts efficacy in painfuldiabetic peripheral neuropathy (DPN)? In considering such gener-alization of efficacy, it would be important to specify the bound-aries of extrapolation, especially between pain conditions withdifferent neurobiological mechanisms, for example, neuropathicand musculoskeletal pain.The extrapolation of analgesic treatment efficacy to unstudiedconditions has broad implications. Most importantly, if efficacy isextrapolated to conditions in which treatments are truly not effec-tive, patients will be exposed to ineffective treatments that may beassociated with undesirable side effects, safety risks, and financialcosts. Conversely, if efficacy is not extrapolated to conditions inwhich treatments are truly efficacious but have not yet beenstudied, patients may be denied effective treatments that couldprovide meaningful relief. This is an important concern becausemany efficacious analgesics have been studied in relatively fewconditions, and there are numerous acute and chronic pain condi-tions for which effective treatments have not been identified.The United States Food and Drug Administration convened aworkshop to initiate discussion of the issues involved in consider-ingthe extrapolationof analgesic efficacy.The meetingincluded16pain specialists representing diverse disciplines and medical spe-cialties, all of whom are authors of this article. Participants wereasked to discuss the types of evidence that could provide the basisfor extrapolating efficacy to pain conditionsin which the treatmenthas not been studied. These discussions did not address the extrap-olation of safety, and also did not consider migraine headachegiven distinct regulatory and research design issues involving itsprevention and acute treatment [25].This article summarizes the conclusions from the workshop—which was held on December 2, 2009—and subsequent discussionsamong the participants. The considerations contained in thisarticle are not intended to serve as ‘‘consensus recommendations’’or to represent the views of the Food and Drug Administration orany other public or private agency or organization. Mostimportantly, given the major limitations of the evidence base forconsidering the extrapolation of analgesic efficacy, the material

The Childhood and Adolescent Migraine Prevention (CHAMP) Study: A Report on Baseline Characteristics of Participants

To describe baseline headache characteristics of children and adolescents participating in a multicenter, randomized, double‐blinded, placebo‐controlled, comparative effectiveness study of amitriptyline, topiramate, and placebo for the prevention of migraine (CHAMP Study).

Prescription Drug Coverage for Treatment of Low Back Pain Among US Medicaid, Medicare Advantage, and Commercial Insurers

Key Points Question Among US insurers, what are the coverage policies for pharmacologic treatments for low back pain? Findings In this cross-sectional study of 62 products used to treat low back pain examined across 50 Medicaid, Medicare Advantage, and commercial insurance plans, utilization management strategies were common for nonopioids and opioids alike. Key informant interviews with plan executives underscored the frequent absence of comprehensive strategies to improve chronic pain treatment and to better integrate pharmacologic and nonpharmacologic opioid alternatives. Meaning Our findings underscore important opportunities among insurers to redesign coverage policies to improve pain management and reduce opioid-related injuries and deaths.

Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers

Key Points Question Among US insurers, what are the coverage and utilization management policies for nonpharmacologic treatments for chronic, noncancer low back pain? Findings In this cross-sectional study of 45 Medicaid, commercial, and Medicare Advantage plans, most plans covered at least physical and occupational therapy and chiropractic care for chronic noncancer pain, but there was little evidence of coverage of acupuncture and psychological interventions. Utilization management strategies such as visit limits and prior authorization were common, but criteria varied widely across the plans examined. Meaning The lack of consistent coverage and utilization management policies underscores the need for best practices to improve comprehensive, multimodal coverage of treatments for chronic, noncancer low back pain.

Prevalence and profile of High Impact Chronic Pain in the United States

The multidimensional nature of chronic pain is not reflected by definitions based solely on pain duration, resulting in high prevalence estimates limiting effective policy development. The newly proposed concept of high-impact chronic pain (HICP) incorporates both disability and pain duration to identify a more severely impacted portion of the chronic pain population yet remains uncharacterized at the population level. As such, we used the 2011 National Health Interview Survey (N = 15,670) to 1) assess the likelihood of disability in the overall chronic pain population, 2) estimate the prevalence of HICP, and 3) characterize the disability, health status, and health care use profile of this population in the United States. Overall, chronic pain, defined as pain experienced on most days or every day in the previous 3 months, was strongly associated with an increased risk of disability after controlling for other chronic health conditions (odds ratio = 4.43; 95% confidence interval = 3.73-5.26), where disability was more likely in those with chronic pain than in those with stroke or kidney failure, among others. HICP affected 4.8% of the U.S. adult population, or approximately 10.6 million individuals, in 2011. The HICP population reported more severe pain and more mental health and cognitive impairments than persons with chronic pain without disability, and was also more likely to report worsening health, more difficulty with self-care, and greater health care use. HICP clearly represents a more severely impacted portion of the chronic pain population. Understanding this heterogeneity will contribute to developing more effective legislation promoting safe and cost-effective approaches to the prevention and treatment of chronic pain. PERSPECTIVE: HICP is a powerful new classification that differentiates those with debilitating chronic pain from those with less impactful chronic pain. By addressing the multidimensionality of chronic pain, this classification will improve clinical practice, research, and the development of effective health policy.