Clinical Trials For Chronic Pain Research Articles

Covariate Adjustment in Chronic Pain Trials: An Oft-Missed Opportunity

Self-reported pain intensity, frequently used as an outcome in randomized clinical trials (RCTs) of chronic pain, is often highly variable and could be associated with multiple baseline factors. Thus, the assay sensitivity of pain trials (ie, the ability of the trial to detect a true treatment effect) could be improved by including prespecified baseline factors in the primary statistical model. The objective of this focus article was to characterize the baseline factors included in statistical analyses of chronic pain RCTs. Seventy-three RCTs published between 2016 and 2021 that investigated interventions for chronic pain were included. The majority of trials identified a single primary analysis (72.6%; n = 53). Of these, 60.4% (n = 32) included one or more covariates in the primary statistical model, most commonly baseline value of the primary outcome, study site, sex, and age. Only one of the trials reported information regarding associations between covariates and outcomes (ie, information that could inform prioritization of covariates for prespecification in future analyses). These findings demonstrate inconsistent use of covariates in the statistical models in chronic pain clinical trials. Prespecified adjustments for baseline covariates that could increase precision and assay sensitivity should be considered in future clinical trials of chronic pain treatments. PerspectiveThis review demonstrates inconsistent inclusion and potential underutilization of covariate adjustment in analyses of chronic pain RCTs. This article highlights areas for possible improvement in design and reporting related to covariate adjustment to improve efficiency in future RCTs.

Editorial: Enrollment and Adherence of Minorities in Clinical Trials for Chronic Pain

Editorial: Enrollment and Adherence of Minorities in Clinical Trials for Chronic Pain

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

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.

Effects of tanezumab on satellite glial cells in the cervicothoracic ganglion of cynomolgus monkeys: A 26-week toxicity study followed by an 8-week recovery period.

Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or tanezumab-treated cynomolgus monkeys. These findings suggest that tanezumab treatment does not result in a true gliosis in sympathetic ganglia.

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.

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy.

Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use. Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy. Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties. Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant. In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA). KA-induced epilepsy in rodents is assumed to resemble to different extents human temporal lobe epilepsy (TLE) depending on the route of KA administration; intracerebral (i.c.) injection was recently shown to most closely mimic human TLE, while systemic KA administration causes more widespread pathological damage, both in brain and periphery. To explore the potential of PEA to exert therapeutic effects both in brain and periphery, acute and subchronic administration of PEA by intraperitoneal (i.p.) injection was assessed on mice with systemically administered KA. Specifically, we investigated: (i) neuroprotective and anticonvulsant properties of acute and subchronic PEA treatment in KA-induced seizure models, and (ii) temporal dynamics of eCB and eicosanoid (eiC) levels in hippocampus and plasma over 180 min post seizure induction in PEA-treated and non-treated KA-injected mice vs. vehicle injected mice. Finally, we compared the systemic PEA treatment with, and in combination with, pharmacological blockade of fatty acid amide hydrolase (FAAH) in brain and periphery, in terms of anticonvulsant properties and modulation of eCBs and eiCs. Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice.

Identifying optimal dosage regimes under safety constraints: An application to long term opioid treatment of chronic pain.

There is growing interest and investment in precision medicine as a means to provide the best possible health care. A treatment regime formalizes precision medicine as a sequence of decision rules, one per clinical intervention period, that specify if, when and how current treatment should be adjusted in response to a patient's evolving health status. It is standard to define a regime as optimal if, when applied to a population of interest, it maximizes the mean of some desirable clinical outcome, such as efficacy. However, in many clinical settings, a high-quality treatment regime must balance multiple competing outcomes; eg, when a high dose is associated with substantial symptom reduction but a greater risk of an adverse event. We consider the problem of estimating the most efficacious treatment regime subject to constraints on the risk of adverse events. We combine nonparametric Q-learning with policy-search to estimate a high-quality yet parsimonious treatment regime. This estimator applies to both observational and randomized data, as well as settings with variable, outcome-dependent follow-up, mixed treatment types, and multiple time points. This work is motivated by and framed in the context of dosing for chronic pain; however, the proposed framework can be applied generally to estimate a treatment regime which maximizes the mean of one primary outcome subject to constraints on one or more secondary outcomes. We illustrate the proposed method using data pooled from 5 open-label flexible dosing clinical trials for chronic pain.

The effect of depression on the decision to join a clinical trial.

Clinical trials are necessary for evaluation of novel treatments. However, concerns have been raised about the vulnerability of depressed individuals when joining clinical trials, that is, about their abilities to make good decisions about clinical trial participation. The purpose of this study was to determine whether depression compromises decisions to join clinical trials, by comparing the decisions of 3 groups: depressed individuals, individuals suffering from chronic pain, and individuals with comorbid depression and chronic pain. Participants (depressed: n = 61; chronic pain: n = 60; comorbid: n = 58) completed, via a clinical interview, common decision-making tasks from the field of judgment and decision making (time trade-off and standard gamble). The rationality of decisions was defined as the concordance between the evaluations of their health and the amount of risk participants would accept to improve health. Depressed individuals made less rational decisions than individuals with chronic pain (partial η2 = 0.075, 90% confidence interval [CI] [0.009, 0.180]); however, the discrepancy was in the direction of risk aversion, suggesting that depressed individuals were overly cautious about clinical trial participation. Furthermore, this risk aversion was not limited to clinical trials for depression, but also extended to clinical trials for chronic pain (partial η2 = 0.041, 90% CI [0.002, 0.117]), suggesting that depressed individuals may be overly cautious in their health choices more broadly. Our findings suggest that concerns about depressed individuals making overly risky "desperate" decisions is likely unfounded, and it is more likely that depressed individuals may forgo valuable care options in an attempt to avoid risk. (PsycINFO Database Record

Durations of Opioid, Nonopioid Drug, and Behavioral Clinical Trials for Chronic Pain: Adequate or Inadequate?

A recent US federal review and clinical guideline on opioids for chronic pain asserted that the literature contributes no evidence on efficacy because all trials had "inadequate duration." To explore the evidence, we examined durations of studies on opioid, nonopioid drug, and behavioral therapies for chronic pain. We retrieved Cochrane reviews of anticonvulsants, antidepressants, NSAIDs, opioids, or behavioral interventions for chronic pain. We also examined all opioid treatment studies retrieved for the federal evidence report but excluded due to "inadequate duration." Of 378 Cochrane reviews retrieved, 72 evaluated one of the five therapies. Six of these 72 were excluded because they were proposals without data or investigated acute pain. Fourteen addressed multiple interventions, leaving 52 for analysis. We graphed numbers of trials vs duration for the five treatments reviewed in the Cochrane Library, compared with durations of opioid trials dropped from the federal evidence report. Most graphs were overdispersed Poisson distributions. Nearly all trials had active treatment durations of 12 weeks or less. No common nonopioid treatment for chronic pain has been studied in aggregate over longer intervals of active treatment than opioids. To dismiss trials as "inadequate" if their observation period is a year or less is inconsistent with current regulatory standards. The literature on major drug and nondrug treatments for chronic pain reveals similarly shaped distributions across modalities. Considering only duration of active treatment in efficacy or effectiveness trials, published evidence is no stronger for any major drug category or behavioral therapy than for opioids.

When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program.

Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program. The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.

Harmonizing Pain Outcome Measures: Results of the Pre-OMERACT Meeting on Partnerships for Consensus on Patient-important Pain Outcome Domains Between the Cochrane Musculoskeletal Group and OMERACT.

A variety of authorities in pain measurement and outcome methodology met prior to the Outcome Measures in Rheumatology (OMERACT) 12 meeting in May 2014 to develop partnerships for consensus on pain outcomes. Following overview presentations, discussion centered on pain-specific and global constructs in the domain of chronic pain. Practical issues for clinical trial implementation were also discussed. Breakout sessions were completed regarding additional details of domain constructs. A nominal group process involving all workshop participants confirmed that chronic pain outcome measures encompass a broad range of constructs and that existing scales may be inadequate for assessment in clinical trials. Participants endorsed that both pain intensity and pain interference are important constructs to be measured in clinical trials of chronic pain as it pertains to rheumatologic diagnoses. Further work is needed on inclusion of the patient perspective in the development of pain domains as well as Cochrane Collaboration summary of findings tables.

Interference with work in fibromyalgia - effect of treatment with pregabalin and relation to pain response

BackgroundClinical trials in chronic pain often collect information about interference with work as answers to component questions of commonly used questionnaires but these data are not normally analysed separately.MethodsWe performed a meta-analysis of individual patient data from four large trials of pregabalin for fibromyalgia lasting 8-14 weeks. We analysed data on interference with work, inferred from answers to component questions of Fibromyalgia Impact Questionnaire (FIQ), Short Form 36 Health Survey, Sheehan Disability Scale, and Multidimensional Assessment of Fatigue, including "How many days in the past week did you miss work, including housework, because of fibromyalgia?" from FIQ. Analyses were performed according to randomised treatment group (pregabalin 150-600 mg daily or placebo), pain improvement (0-10 numerical pain rating scale scores at trial beginning vs. end), and end of trial pain state (100 mm visual analogue pain scale [VAS]).ResultsComparing treatment group average outcomes revealed modest improvement over the duration of the trials, more so with active treatment than with placebo. For the 'work missed' question from FIQ the change for patients on placebo was from 2.2 (standard deviation [SD] 2.3) days of work lost per week at trial beginning to 1.9 (SD 2.1) days lost at trial end (p < 0.01). For patients on 600 mg pregabalin the change was from 2.1 (SD 2.2) days to 1.6 (SD 2.0) days (p < 0.001). However, the change in days of work lost was substantial in patients with a good pain response: from 2.0 (SD 2.2) days to 0.97 (SD 1.6) days (p < 0.0001) for those experiencing >/= 50% pain improvement and from 1.9 (SD 2.2) days to 0.73 (SD 1.4) days (p < 0.0001) for those achieving a low level of pain at trial end (<30 mm on the VAS). Patients achieving both >/= 50% pain improvement and a pain score <30 mm on the VAS had the largest improvement, from 2.0 (SD 2.2) days to 0.60 (SD 1.3) days (p < 0.0001). Analysing answers to the other questions yielded qualitatively similar results.ConclusionsEffective pain treatment goes along with benefit regarding work. A reduction in time off work >1 day per week can be achieved in patients with good pain responses.

The clinical meaningfulness of pain reduction: achieving ratings of “mild” pain -- &lt;4

In many clinical trials for chronic pain, one of the entry criteria is a pain rating of ≥4. The criterion of ≥4 is selected because pain <4 has been shown to characterize “mild pain” and ≥4 denotes “moderate-to-severe” pain. Clinical trials often report a statistically significant reduction in pain as their primary outcome, although post-treatment means and standard deviations often imply that a considerable percentage of patients who received treatment did not achieve pain levels <4. The implication is that these patients would be eligible for additional clinical trials since their pain was sufficiently high to permit them to be included in another treatment study.

Cellular Transplants, 20 Years Later: The Pharma Initiative

Cellular Transplants, 20 Years Later: The Pharma Initiative

NMDA receptor subtypes: Structure, function and therapeutics

The N -methyl- d -aspartate (NMDA) receptor is multi-subunit ligand-gated channel which is highly expressed in the mammalian and human central nervous system. Multiple subtypes of the NMDA receptor comprising distinct subunit combinations exist which subserve distinct roles in the brain and spinal cord, which offers new hope to develop, in a rationale fashion, subtype-targetted therapeutic agents. The NR2B subtype represents the most advanced in terms of drug development, with agents currently in clinical trials for chronic pain. Furthermore, memantine a new drug approved for use in Dementias is showing promise as a neuroprotective as well as pro-cognitive agent.

Placebo-Controlled Comparison of a Morphine/Dextromethorphan Combination With Morphine on Experimental Pain and Hyperalgesia in Healthy Volunteers

In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain. Perspective Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.

Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization.

The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers. The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin. Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest. The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.

Symptom distress and quality of life

Clinical trials in chronic pain have used various methods to assess the effect of medications. In addition to measuring symptom relief, researchers must also address adverse events (AEs) associated with the medication to evaluate overall therapeutic results. This paper reviews methods of measuring symptoms and AEs, including passive capture, scripted prompting, prospective assessments of side effects of interest, and prospective comprehensive symptom checklists. Methods of measuring therapeutic results have advantages and disadvantages. Although passive AE capture (unscripted, open-ended questions about symptoms) is not constrained by preconceptions of potential AEs, it sometimes fails to capture clinically significant AEs. Scripted prompting (prespecified, scripted, open-ended questions about symptoms) is likely to address the latter problem but preclude consistency across trials. Prospective assessments (prespecified symptom inventories) can offer greater sensitivity and consistency in detecting side effects of specific treatments. Comprehensive symptom distress inventories can be more sensitive measures of overall treatment benefit, which may be important when efficacy, passive AE capture, and comprehensive quality of life (QOL) batteries fail to differentiate between treatments. In cancer populations these inventories have been statistically correlated with survival and other important clinical outcomes, even after controlling for disease status, global QOL, psychological state, and performance status. Other important considerations are patient perceptions of the importance of symptoms, the correlations between QOL and symptom distress, and the usefulness of global ratings, in which patients integrate any perceived benefits of the medication with tolerability and other factors, such as convenience and cost.