Nathaniel P. Katz

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations

AbstractObjective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of d

Core outcome domains for chronic pain clinical trials

&NA; Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Methods. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. Conclusions. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

Development and validation of the Current Opioid Misuse Measure

Abstract Clinicians recognize the importance of monitoring aberrant medication‐related behaviors of chronic pain patients while being prescribed opioid therapy. The purpose of this study was to develop and validate the Current Opioid Misuse Measure (COMM) for those pain patients already on long‐term opioid therapy. An initial pool of 177 items was developed with input from 26 pain management and addiction specialists. Concept mapping identified six primary concepts underlying medication misuse, which were used to develop an initial item pool. Twenty‐two pain and addiction specialists rated the items on importance and relevance, resulting in selection of a 40‐item alpha COMM. Final item selection was based on empirical evaluation of items with patients taking opioids for chronic, noncancer pain (N = 227). One‐week test–retest reliability was examined with 55 participants. All participants were administered the alpha version of the COMM, the Prescription Drug Use Questionnaire (PDUQ) interview, and submitted a urine sample for toxicology screening. Physician ratings of patient aberrant behaviors were also obtained. Of the 40 items, 17 items appeared to adequately measure aberrant behavior, demonstrating excellent internal consistency and test–retest reliability. Cutoff scores were examined using ROC curve analysis and reasonable sensitivity and specificity were established. To evaluate the COMM’s ability to capture change in patient status, it was tested on a subset of patients (N = 86) that were followed and reassessed three months later. The COMM was found to have promise as a brief, self‐report measure of current aberrant drug‐related behavior. Further cross‐validation and replication of these preliminary results is pending.

Opioid therapy for chronic noncancer back pain : a randomized prospective study

Study Design. A randomized, open, long‐term, repeated‐dose comparison of an anti‐inflammatory drug and two opioid regimens in 36 patients with back pain. Objectives. To examine the long‐term safety and efficacy of chronic opioid therapy in a randomized trial of patients with back pain. Methods. All participants underwent a 4‐week washout period of no opioid medication before being randomly assigned to one of three treatment regimens for 16 weeks: 1) naproxen only, 2) set‐dose oxycodone, or 3) titrated‐dose oxycodone and sustained‐release morphine sulfate. All patients then were assigned to a titrated dose of opioids for 16 weeks and then gradually tapered off their medication for 12 weeks. Finally, all participants were monitored for a 1‐month posttreatment washout period. Each patient was called once a week for a report on pain, activity, mood, medication, hours awake, and adverse effects and was monitored carefully for signs of abuse and noncompliance. Results. Weekly reports during the experimental phase showed the titrated‐dose group to have less pain (P < 0.001) and less emotional distress (P < 0.001) than the other two groups. Both opioid groups were significantly different from the naproxen‐only group. During the titration phase, patients also reported significantly less pain and improved mood. Few differences were found in activity or hours asleep, or between average pretreatment and posttreatment phone‐interview and questionnaire variables. No adverse events occurred and only one participant showed signs of abuse behavior. Conclusions. The results suggest that opioid therapy has a positive effect on pain and mood but little effect on activity and sleep. Opioid therapy for chronic back pain was used without significant risk of abuse. However, tapered‐off opioid treatment is palliative and without long‐term benefit.

Characteristics of methadone maintenance patients with chronic pain

Chronic pain patients who have limited access to opioids may be redirected to methadone maintenance centers for management of their pain. Unfortunately, little information exists on the incidence and characteristics of methadone maintenance patients with chronic pain. The aim of this study was to survey individuals at methadone maintenance centers in order to determine the prevalence of chronic pain and to explore differences between patients with and without pain in this treatment setting. Of 248 participants interviewed at three centers, 152 (61.3%) reported chronic pain. Compared with patients without pain, those with pain reported significantly more health problems (P < 0.001), more psychiatric disturbance (P < 0.05), more prescription and nonprescription medication use (P < 0.001), and greater belief that they were undertreated (P < 0.001); 44% of those with pain believed that opioids prescribed for their pain had led to an addiction problem. Most of the methadone maintenance patients stated that they had always required some substance (alcohol or opioids) to feel normal. These results raise many questions about chronic-pain treatment policies and resources for persons with a history of substance abuse. Further investigations are needed to define the needs of this population and to improve their access to effective pain management.

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.

Electronic diaries for monitoring chronic pain : 1-year validation study

&NA; Electronic data collection for monitoring pain has become increasingly popular in clinical research. However, no direct comparison has been made between electronic diaries and self‐report paper diaries or phone interviews. We asked 36 patients with chronic low back pain to monitor their pain for 1 year; 20 of them used both a palmtop computer and paper diaries, and 16 used paper diaries alone. All patients were called once a week and asked to rate their pain. Regression analyses with a measurement error model were run on hourly pain scores recorded by both palmtop computer and paper diaries. Ratings of pain intensity were highly reliable between data recorded with a palmtop computer and with data from paper diaries. Patients who monitored their pain with the palmtop computer entered data on average 6.75 times a week and were 89.9% compliant with daily monitoring throughout the year. Two‐way messaging available through the palmtop computer seemed to encourage continued use of the device. Internal consistency of reporting and correlations with phone reports and standardized measures were highly significant, suggesting that data from electronic diaries are both reliable and valid. Patients using electronic diaries preferred them to paper diaries and showed much higher rates of compliance and satisfaction over the 1‐year trial.

The Impact of Opioids on the Endocrine System

ObjectivesOpioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. MethodsA review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. ResultsLong-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. ConclusionsOpioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.

A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy.

BACKGROUND Opioid analgesics are the cornerstone of management for malignant pain. Their use in managing chronic, nonmalignant pain, albeit controversial, has increased in recent years. The decisions about whether to initiate opioid therapy or continue it over time should be guided by a comprehensive patient assessment. During long-term treatment, this assessment should focus on a broad range of outcomes, each of which should be documented in the medical record. OBJECTIVE The goal of this study was to develop an instrument, the Pain Assessment and Documentation Tool (PADT), to focus on key outcomes and provide a consistent way to document progress in pain management therapy over time. METHODS Items that assess 4 domains (pain relief, patient functioning, adverse events, and drug-related behaviors) were generated with input from a MEDLINE literature search and experts in pain and addiction management. The original tool was field tested by clinicians who applied it to the assessment of patients receiving long-term opioid therapy for the management of chronic, nonmalignant pain. Data analysis and debriefing telephone interviews with a formalized set of questions were then used to rephrase, delete, and refine items to create the final tool. RESULTS A 6-member expert panel contributed to the initial development of the PADT. Twenty-seven clinicians completed the preliminary version of PADT for 388 patients. The original 59-item tool was modified to create a 41-item tool. The revised PADT was formatted for use as a chart note designed to assist clinicians in assessing and documenting 4 main outcome domains during long-term opioid use. CONCLUSIONS In this study, the PADT appeared to be a useful tool for clinicians to guide the evaluation of several important outcomes during opioid therapy and provide a simple means of documenting patient care.

The Impact of Pain Management on Quality of Life

Although its inclusion in medical research is relatively recent and its interpretation is often variable, quality of life is increasingly being recognized as one of the most important parameters to be measured in the evaluation of medical therapies, including those for pain management. Pain, when it is not effectively treated and relieved, has a detrimental effect on all aspects of quality of life. This negative impact has been found to span every age and every type and source of pain in which it has been studied. Effective analgesic therapy has been shown to improve quality of life by relieving pain. Opioid analgesics, cyclooxygenase (COX)-2 inhibitors (or coxibs), and several adjuvant analgesics for neuropathic pain have been demonstrated to significantly improve quality-of-life scores in patients with pain. Coxibs provide effective, well-tolerated analgesia without some of the issues faced with opioids-benefits that should translate into improved quality of life. Recent studies have demonstrated that the COX-2 inhibitor rofecoxib significantly improves quality of life in patients with osteoarthritis and chronic, lower back pain. Quality-of-life measurements, especially symptom distress scales, can also be used as sensitive means of differentiating one agent from another in the same class. In future pharmacotherapeutic research, quality of life should be included as an outcome domain as are the traditionally measured variables of efficacy and safety. In particular, future studies of coxibs should include symptom distress scores as important quality-of-life measurements, to identify meaningful differences between this new class of analgesics and nonselective nonsteroidal anti-inflammatory drugs.