The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non-neuropathic pain that can be used in studies of epidemiology, natural history, ...pathophysiologic mechanisms, and treatment response. We expanded and revised the Short-form McGill Pain Questionnaire1Copyright: SF-MPQ, R. Melzack; SF-MPQ-2, R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT).1 (SF-MPQ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0–10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials. The reliability, validity, and subscale structure of the revised SF-MPQ (SF-MPQ-21) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a randomized clinical trial. The data suggest that the SF-MPQ-2 has excellent reliability and validity, and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales—continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors. These results provide a basis for use of the SF-MPQ-2 in future clinical research, including clinical trials of treatments for neuropathic and non-neuropathic pain conditions.
An essential component of the interpretation of results of randomized clinical trials of treatments for chronic pain involves the determination of their clinical importance or meaningfulness. This ...involves two distinct processes—interpreting the clinical importance of individual patient improvements and the clinical importance of group differences—which are frequently misunderstood. In this article, we first describe the essential differences between the interpretation of the clinical importance of patient improvements and of group differences. We then discuss the factors to consider when evaluating the clinical importance of group differences, which include the results of responder analyses of the primary outcome measure, the treatment effect size compared to available therapies, analyses of secondary efficacy endpoints, the safety and tolerability of treatment, the rapidity of onset and durability of the treatment benefit, convenience, cost, limitations of existing treatments, and other factors. The clinical importance of individual patient improvements can be determined by assessing what patients themselves consider meaningful improvement using well-described methods. In contrast, the clinical meaningfulness of group differences must be determined by a multi-factorial evaluation of the benefits and risks of the treatment and of other available treatments for the condition in light of the primary goals of therapy. Such determinations must be conducted on a case-by-case basis, and are ideally informed by patients and their significant others, clinicians, researchers, statisticians, and representatives of society at large.
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.
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.
Multiparous Holstein cows at six universities were utilized to examine effects of ruminally protected methionine and lysine on lactational performance. Three hundred and four cows began the study; ...259 cows were included in the production analysis. Following a 21-d standardization period, cows received a basal diet of corn silage and ground corn supplemented with one of five dietary treatments, which were supplements of soybean meal or corn gluten meal, the latter with zero and three combinations of protected methionine and lysine (methionine; methionine and lysine; methionine and double (2×) lysine). Treatment effects were evaluated during early, mid, late, and total lactation (22 to 112, 113 to 224, 225 to 280, and 22 to 280 d post-partum respectively). On a DM basis, ratios of forage to concentrate (50:50, 60:40, and 70:30) increased, and dietary CP (16.0, 14.5, and 13.0%) decreased during the three periods of lactation. Amount of amino acid supplementation also decreased (15, 12, and 9 g/d methionine; 20, 16, and 12 g/d lysine; and 40, 32, and 24 g/d 2× lysine) with period of lactation. Actual and least squares means for milk, FCM, and milk protein yields were greater for soybean than for corn gluten meal during early, mid, and total lactation. In addition, these variables responded linearly to lysine in early lactation. Response to lysine was quadratic during mid and total lactation for these variables. Differences in nutrient intake explained production responses to protein sources but not to lysine. Serum amino acid responses primarily reflected differences in dietary protein source and rumen-protected amino acid.
A 3×3 factorial response surface design was used to study the effects of feeding rumen-protected methionine and lysine to dairy cows between 22 and 305 d of lactation. A total of 130 dairy cows at ...three universities were individually fed a corn silage and corn grain-based diet that contained either soybean meal or corn gluten meal and urea. An unsupplemented control diet plus nine treatment combinations of three amounts of rumen-protected DL-methionine (3.4, 7. 8, and 12.2g/d) and three amounts of rumen-protected L-lysine (5.9, 13.5, and 21.1g/d) were fed at all locations. Plasma concentrations of methionine and lysine were increased when rumen-protected methionine and lysine were supplemented to the diets. Rumen-protected methionine and lysine did not affect feed intake by cows fed either the soybean meal or corn gluten meal and urea based diets. Milk protein percentage was increased, but milk and milk protein yields were not improved when diets containing soybean meal were supplemented with rumen-protected methionine and lysine. In contrast, milk and milk protein yields were improved when a diet that contained corn gluten meal and urea was supplemented with rumen-protected methionine and lysine. Health and reproduction measurements were similar for cows receiving all treatments.
OBJECTIVE:Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials.
METHODS:We examined the associations between ...study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain.
RESULTS:There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant.
CONCLUSIONS:Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.
Research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties ...of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.
Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.
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