John D. Markman

Pain associated with multiple sclerosis : Systematic review and proposed classification

&NA; Pain is common in patients with multiple sclerosis (MS), but estimates of its prevalence have varied widely. The literature describing pain in MS patients spans four decades and has employed a range of different methodologies. We undertook a systematic review in order to summarize current understanding of the association between MS and pain and provide a basis for the design and interpretation of future studies. The point prevalence of pain in patients with MS is nearly 50%, and approximately 75% of patients report having had pain within one month of assessment. Pain adversely affects most aspects of health‐related quality of life, including functional domains such as the ability to work. The presence of pain in patients with MS is associated with increased age, duration of illness, depression, degree of functional impairment, and fatigue. Several different types of pain are found in patients with MS, including extremity pain, trigeminal neuralgia, Lhermitte’s sign, painful tonic spasms, back pain, and headache. Putative mechanisms of pain in patients with MS are discussed, and a classification of pain in MS is proposed. Few randomized clinical trials of treatments for MS pain have been conducted, and the limitations of current knowledge regarding approaches for treating MS pain are discussed. Suggestions for future studies that would increase understanding of the natural history, mechanisms, and treatment of pain in patients with MS are presented.

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.

An Outbreak of Yersinia enterocolitica O:8 Infections Associated with Pasteurized Milk

In October 1995, an outbreak of Yersinia enterocolitica O:8 infections occurred in the Upper Valley of Vermont and New Hampshire. Ten patients were identified, median age 9 years (range, 6 months-44 years). Three patients were hospitalized; 1 underwent an appendectomy. Consumption of bottled pasteurized milk from a local dairy was associated with illness (matched odds ratio undefined; lower 95% confidence interval, 1.9). No deficiencies in pasteurization procedures or equipment were detected. Y. enterocolitica O:8 was isolated from 1 raw-milk sample and from a fecal sample from 1 dairy pig. The route of contamination was not determined; this outbreak likely resulted from postpasteurization contamination of milk. Dairy pigs were the most likely source of contamination. Milk bottles were likely contaminated by rinsing with untreated well water prior to filling or by other environmental routes. Educating dairy owners about Y. enterocolitica and postpasteurization contamination is necessary to prevent further outbreaks.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations

Abstract Terminology related to prescription drug misuse and abuse is inconsistently defined. An expert panel developed consensus classifications and definitions for use in clinical trials. Abstract As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment’s abuse potential.

Traditional Acupuncture Triggers a Local Increase in Adenosine in Human Subjects

UNLABELLED Acupuncture is a form of Eastern medicine that has been practiced for centuries. Despite its long history and worldwide application, the biological mechanisms of acupuncture in relieving pain have been poorly defined. Recent studies in mice, however, demonstrate that acupuncture triggers increases in interstitial adenosine, which reduces the severity of chronic pain through adenosine A1 receptors, suggesting that adenosine-mediated antinociception contributes to the clinical benefits of acupuncture. We asked here whether acupuncture in human subjects is also linked to a local increase in interstitial adenosine concentration. We collected microdialysis samples of interstitial fluid before, during, and after delivering 30 minutes of conventional acupuncture in the Zusanli point in human subjects. The interstitial adenosine concentration increased significantly during acupuncture and remained elevated for 30 minutes after the acupuncture. Acupuncture-mediated adenosine release was not observed if acupuncture was not delivered in the Zusanli point or if the acupuncture needle was inserted, but not rotated. This study strengthens the role of adenosine in acupuncture-mediated antinociception by directly providing such evidence in humans. PERSPECTIVE This article presents further evidence of the role of adenosine in acupuncture-mediated antinociception by demonstrating that local adenosine concentrations increase in the acupoint in human subjects receiving traditional acupuncture.

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

Not so fast: the reformulation of fentanyl and breakthrough chronic non-cancer pain.

The US Food and Drug Administration is currently reviewing a supplemental new drug application seeking approval to market fentanyl for the management of breakthrough chronic non-cancer pain. The market opportunity for a new class of ultra fast, ultra short-acting potent opioids is clear, but the meaning of breakthrough in chronic non-cancer pain is not. The FDA has currently limited breakthrough pain as a treatment indication to patients with cancer, and significant debate already exists as to how to define it in this original context. Extending the ambiguous notion of breakthrough to noncancer pain stretches the indication beyond a clinically meaningful scope. Without appropriately conducted studies this new indication may lead to more opioid use in the patients most at risk for harm. The drive to broaden the market for drug reformulations appears to be propelling a redefinition of breakthrough for chronic non-cancer pain. Are the risks of wider availability justified? Most physicians agree that flares of pain compound the suffering of patients with cancer. Cross-sectional surveys of inpatients in the palliative care setting have associated these surges of pain intensity with advanced cancer [16]. As originally conceived, the underlying diagnosis of cancer and the concurrent use of long-acting opioid analgesics established breakthrough pain as a distinct therapeutic challenge [3,16]. Despite broad acceptance of this link, the report of the IASP task force on cancer pain found that the definition of breakthrough pain varies widely by country and specialty, even among a group of self-identified cancer pain specialists [11]. This finding prompted the task force to call for better and validated definitions of breakthrough pain terminology in this original clinical context [11]. The description of breakthrough pain, like so many compelling clinical observations in highly selected samples, has evolved to encompass many different phenomena. Breakthrough pain may be related not only to the progression of underlying cancer but also to drug-related phenomena such as under dosing of a long-acting opioid, end-of-dose failure of a long-acting opioid, or escalating tolerance to opioid analgesia. Recent indus-

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations

Abstract Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations.

Abstract Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.