Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

ABSTRACT: Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

Pitfalls and Rewards of Setting Up a Liquid Biopsy Approach for the Detection of Driver Mutations in Circulating Tumor DNAs: Our Institutional Experience.

We describe our institutional experience of developing a liquid biopsy approach using circulating tumor DNA (ctDNA) analysis for personalized medicine in cancer patients, focusing on the hurdles encountered during the multistep process in order to benefit other investigators wishing to set up this type of study in their institution. Blood samples were collected at the time of cancer surgery from 209 patients with one of nine different cancer types. Extracted tumor DNA and circulating cell-free DNA were sequenced using cancer-specific panels and the Illumina MiSeq machine. Almost half of the pairs investigated were uninformative, mostly because there was no trackable pathogenic mutation detected in the original tumor. The pairs with interpretable data corresponded to 107 patients. Analysis of 48 gene sequences common to both panels was performed and revealed that about 40% of these pairs contained at least one driver mutation detected in the DNA extracted from plasma. Here, we describe the choice of our overall approach, the selection of the cancer panels, and the difficulties encountered during the multistep process, including the use of several tumor types and in the data analysis. We also describe some case reports using longitudinal samples, illustrating the potential advantages and rewards in performing ctDNA sequencing to monitor tumor burden or guide treatment for cancer patients.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

ABSTRACT: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Evolution of Analgesic Tolerance and Opioid-Induced Hyperalgesia Over 6 Months: Double-Blind Randomized Trial Incorporating Experimental Pain Models.

Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic nonmalignant pain patients entered a 6-month long, randomized, double-blind, dose-response, 2-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35 and 122 morphine equivalents. Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, brief pain inventory scores, and results of the brief thermal sensitization model at 5 opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14 to 300; average addition 105 morphine equivalents. After observed dosing, the brief thermal sensitization area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0 to 100 visual analog scale pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but 8 completed with higher visual analog scale ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. TRIAL REGISTRATION: NCT00275249 Evolution of Analgesic Tolerance With Opioids PERSPECTIVE: A double-blind, 6-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and OIH. Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic randomized controlled trial design.

Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments.

INTRODUCTION: In the field of pain research, clinical trials may randomize over 500 subjects and include more than 150 sites spanning over a dozen countries. METHODS: This review examines the ethical considerations affecting clinical trial design, execution, and analysis of trials for chronic pain. The Belmont Report has been the touchstone for human studies protection efforts since 1979. Commissioned by the U.S. government in response to ethical failures in medical research, such as the Tuskegee Syphilis Study, the report emphasizes 3 basic principles: respect for persons, beneficence, and justice. Trial design and sample size have important ethical implications. CONCLUSIONS: Measures to enhance trial transparency and combat publication and many other types of bias should be implemented.

The IASP classification of chronic pain for ICD-11: chronic neuropathic pain.

The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.

Evaluation of composite responder outcomes of pain intensity and physical function in neuropathic pain clinical trials: an ACTTION individual patient data analysis.

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.

Natural history of pain associated with melanoma surgery.

INTRODUCTION: After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed. OBJECTIVE: To determine the natural history of pain and sensory changes after MM surgery. METHODS: We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing. RESULTS: No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND (P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND (P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain (P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05). CONCLUSION: Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes.

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials. PERSPECTIVE: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.

Reporting of data monitoring boards in publications of randomized clinical trials is often deficient: ACTTION systematic review.

OBJECTIVE: To examine whether primary reports of randomized clinical trials (RCTs) in six high-impact, general medical journals reported (1) whether or not a Data Monitoring Committee/Data and Safety Monitoring Board (DMC/DSMB) was used and (2) the composition of the responsibilities of the reported DSMB/DMCs. STUDY DESIGN AND SETTING: Systematic review of RCTs published in 2014 in Annals of Internal Medicine, BMJ, NEJM, JAMA, JAMA Internal Medicine, and Lancet. RESULTS: Of the 294 articles identified, 174 (59%) mentioned using a DMC/DSMB. Of these 174, 126 (72%) indicated at least one responsibility of the DMC/DSMB, 26% listed the names of the DMC/DSMB members, and another 14% listed both their names and affiliations. Only one article stated that a DSMB was not used. The remaining 119 articles did not report whether or not a DMC/DSMB was used, although 59 had previously stated in a clinical trials registry entry or a published protocol that a DMC/DSMB was to be used. CONCLUSIONS: Considering the major role that DMC/DSMBs play in protecting participant safety, data quality, and interim analyses in RCTs, we recommend that authors of publications of RCTs report whether a DMC/DSMB was used and the responsibilities and members of DMC/DSMBs to increase transparency regarding study conduct.

Adverse Event Reporting in Clinical Trials of Intravenous and Invasive Pain Treatments: An ACTTION Systematic Review.

Thorough assessment and reporting of adverse events (AEs) facilitates a detailed understanding of a treatment's risk-benefit profile. Although the Consolidated Standards of Reporting Trials (CONSORT) 2004 statement provides recommendations regarding AE reporting, adherence to these standards is often inadequate. We investigated AE reporting in clinical trials of intravenous and invasive pain treatments published in 6 major anesthesiology and pain journals between 2000 to 2003 and 2006 to 2012. We examined whether AE reporting improved after publication of the 2004 CONSORT recommendations and also comprehensively reviewed AE assessment using the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting recommendations. No improvement was found overall in CONSORT harms reporting scores from pre- to postpublication of the CONSORT recommendations, with only 5 of 10 fulfilled on average. AE reporting assessed using the ACTTION coding manual was generally inadequate, and 8% of articles failed to report any AE information at all. Anesthesiology and pain journals were similar in AE reporting quality, although industry-sponsored trials reported more AE information than nonindustry sponsored trials. Improvement is needed in AE reporting in analgesic clinical trials. The CONSORT checklist and ACTTION AE recommendations can assist investigators and editors in improving clinical trial transparency and quality. PERSPECTIVE: This systematic review of AE reporting in intravenous and invasive pain treatment trials shows that little improvement has been made since the 2004 CONSORT harms reporting guidelines. Better assessment and reporting of treatment AEs is necessary to understand the full clinical effect of intravenous and invasive treatments.

Mitochondrial DNA Heteroplasmy Associations With Neurosensory and Mobility Function in Elderly Adults.

BACKGROUND: Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at specific mtDNA sites lead to inherited mitochondrial diseases with neurological, sensory, and movement impairments. Here we test the hypothesis that heteroplasmy levels in elderly adults are associated with impaired function resembling mild forms of mitochondrial disease. METHODS: We examined platelet mtDNA heteroplasmy at 20 disease-causing sites for associations with neurosensory and mobility function among 137 participants from the community-based Health, Aging, and Body Composition Study. RESULTS: Elevated mtDNA heteroplasmy at four mtDNA sites in complex I and tRNA genes was nominally associated with reduced cognition, vision, hearing, and mobility: m.10158T>C with Modified Mini-Mental State Examination score (p = .009); m.11778G>A with contrast sensitivity (p = .02); m.7445A>G with high-frequency hearing (p = .047); and m.5703G>A with 400 m walking speed (p = .007). CONCLUSIONS: These results indicate that increased mtDNA heteroplasmy at disease-causing sites is associated with neurosensory and mobility function in older persons. We propose the novel use of mtDNA heteroplasmy as a simple, noninvasive predictor of age-related neurologic, sensory, and movement impairments.

Results availability for analgesic device, complex regional pain syndrome, and post-stroke pain trials: comparing the RReADS, RReACT, and RReMiT databases.

Evidence-based medicine rests on the assumption that treatment recommendations are robust, free from bias, and include results of all randomized clinical trials. The Repository of Registered Analgesic Clinical Trials search and analysis methodology was applied to create databases of complex regional pain syndrome (CRPS) and central post-stroke pain (CPSP) trials and adapted to create the Repository of Registered Analgesic Device Studies databases for trials of spinal cord stimulation (SCS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). We identified 34 CRPS trials, 18 CPSP trials, 72 trials of SCS, and 92 trials of rTMS/tDCS. Irrespective of time since study completion, 45% of eligible CRPS and CPSP trials and 46% of eligible SCS and rTMS/tDCS trials had available results (peer-reviewed literature, results entered on registry, or gray literature); peer-reviewed publications could be found for 38% and 39%, respectively. Examining almost 1000 trials across a spectrum of painful disorders (fibromyalgia, diabetic painful neuropathy, post-herpetic neuralgia, migraine, CRPS, CPSP) and types of treatment, no single study characteristic consistently predicts unavailability of results. Results availability is higher 12 months after study completion but remains below 60% for peer-reviewed publications. Recommendations to increase results availability include supporting organizations advocating for transparency, enforcing existing results reporting regulations, enabling all primary registries to post results, stating trial registration numbers in all publication abstracts, and reducing barriers to publishing "negative" trials. For all diseases and treatment modalities, evidence-based medicine must rigorously adjust for the sheer magnitude of missing results in formulating treatment recommendations.