David J. Hewitt

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.

Topiramate vs placebo in painful diabetic neuropathy Analgesic and metabolic effects

Background: Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN. Methods: This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks. Results: Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (−2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control. Conclusions: Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.

Pain in ambulatory AIDS patients. I: Pain characteristics and medical correlates

&NA; The characteristics and impact of pain were evaluated in a prospective cross‐sectional survey of 438 ambulatory AIDS patients recruited from health care facilities in New York City. More than 60% of the patients reported ‘frequent or persistent pain’ during the 2 wks preceding the study. Patients with pain reported an average of 2.5 different pains. On the 0–10 numerical scale of the Brief Pain Inventory (BPI), mean pain intensity ‘on average’ was 5.4 (SD = 2.2; range = 0–10), and mean pain ‘at its worst’ was 7.4 (SD = 2.0; range = 1–10). The pain‐related functional interference index (sum of the seven item BPI subscale) was 42.6 (SD = 17.2; range = 0–70). Demographic variables were not associated with the presence of pain, but the number of current HIV‐related symptoms, treatment for HIV‐related infections, and the absence of antiretroviral medications were significantly associated with the presence of pain. Female gender, non‐Caucasian race, and number of HIV‐related physical symptoms were significantly associated with pain intensity. Presence of pain and increasing pain intensity were significantly associated with greater impairment in functional ability (Karnofsky Performance Status, BPI functional interference index) and physical symptom distress (Memorial Symptom Assessment Scale). Results demonstrate high levels of pain and pain‐related functional impairment among patients with AIDS. The presence and intensity of pain are associated with more advanced HIV disease and pain intensity is also associated with demographic factors (gender, race).

Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

The use of NMDA-receptor antagonists in the treatment of chronic pain.

Abstract: Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N‐methyl‐D‐aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose‐limiting side effects. Commercially available NMDA‐receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA‐receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA‐receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.

Sensory tics in Tourette's syndrome

Sensory tics are localized uncomfortable sensations for which patients attempt to obtain relief by producing movements or vocalizations. We report 3 patients with Tourettes syndrome (TS) and sensory tics to illustrate this poorly recognized symptom. A survey of 34 randomly selected TS patients indicates that sensory tics are common and should be considered part of a clinical spectrum of tics and associated sensory phenomena.

Fentanyl Iontophoretic Transdermal System for Acute-Pain Management After Orthopedic Surgery: A Comparative Study With Morphine Intravenous Patient-Controlled Analgesia

Background and Objectives: The fentanyl HCl iontophoretic transdermal system (ITS) has been demonstrated in clinical trials to be safe and effective for acute-pain management after several types of major surgery. The current study compared the efficacy, safety, and convenience of fentanyl ITS with morphine intravenous patient-controlled analgesia (IV PCA) for acute-pain management after unilateral total-hip replacement (THR). Methods: In this multicenter (52 sites), randomized, open-label, active-controlled, phase IIIb study, patients (n = 799) received fentanyl ITS (40 μg fentanyl [10-minute infusion/lockout], up to 6 doses/h) or morphine IV PCA (1-mg morphine bolus [5-minute lockout], up to 10 mg/h) after unilateral THR. The primary efficacy measure was success ratings (“excellent” or “good”) on the patient global assessment (PGA) of the method of pain control in the first 24 hours. Pain intensity and adverse events were also assessed. Results: The PGA success ratings (83.0% v 82.2%; difference = 0.9%; 95% CI: −4.4% to 6.1%) and the mean last pain-intensity scores (3.0 v 3.0; difference = 0.0; 95% CI: −0.33 to 0.33) in the first 24 hours were statistically equivalent between fentanyl ITS and morphine IV PCA groups, respectively. The incidence of adverse events was similar between the groups. Conclusions: Results of this study demonstrate fentanyl ITS and a standard regimen of morphine IV PCA were comparable methods of pain control for management of acute postoperative pain after THR, on the basis of the PGA success ratings and pain intensity in the first 24 hours of treatment.

Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy

ABSTRACT Objective: To examine the efficacy and safety of tramadol/acetaminophen (APAP) for the management of painful diabetic peripheral neuropathy (DPN). Methods: Adults with painful DPN involving the lower extremities received 37.5 mg tramadol/325 mg APAP or placebo, up to 1–2 tablets four times daily, for 66 days. Subjects rated average daily pain and sleep interference from 0 (‘none’) to 10 (‘pain as bad as you can imagine’ or ‘complete interference’) every night. Baseline values were recorded for 7 days before starting study medication. The primary endpoint was change in mean of average daily pain scores from baseline to final week. Secondary efficacy outcomes included pain intensity, sleep interference, quality of life, mood, and global impression of change. Potential study limitations included permission to use serotonin reuptake inhibitors concomitantly (except venlafaxine or duloxetine) and the lack of a tramadol-alone or APAP-alone control group. Results: A total of 160 subjects received tramadol/APAP and 153 received placebo. Tramadol/APAP reduced average daily pain significantly compared to placebo from baseline to the final week (–2.71 vs. –1.83, p = 0.001). Tramadol/APAP was associated with significantly greater improvement than placebo ( p ≤ 0.05) for all measures of pain intensity, sleep interference, and global impression, as well as several measures of quality of life and mood. The only adverse event reported by > 10% of subjects in either the tramadol/APAP or placebo group was nausea (11.9% and 3.3%, respectively). Adverse events resulted in early study discontinuation for 8.1% and 6.5% of subjects in the tramadol/APAP and placebo groups, respectively. Conclusion: Tramadol/APAP was more effective than placebo and was well tolerated in the management of painful DPN.

A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain.

&NA; The objective of this study was to compare the analgesic efficacy of tramadol/acetaminophen (APAP) (total dose 75 mg/650 mg) and tramadol (total dose 100 mg) for the control of pain after oral surgery. A total of 456 patients with moderate‐to‐severe pain within 5 h after extraction of two or more third molars were randomized to receive two identical encapsulated tablets containing tramadol/APAP 37.5 mg/325 mg, tramadol 50 mg, or placebo. Tramadol/APAP was superior to tramadol (P<0.001) or placebo (P<0.001) on all efficacy measures: total pain relief (PAR) over 6 h (7.4, 2.5, and 1.5, respectively, on a scale of 0–24); sum of pain intensity differences (PIDs) (3.1, 0.6, and 0.1, respectively, on a scale of −6 to 18); and sum of PAR and PID (10.5, 3.1, and 1.6, respectively, on a scale of −6 to 42). Median times to onset of perceptible and meaningful PAR were 37.6 and 126.5 min, respectively, for the tramadol/APAP group (P<0.001 for each, compared with tramadol and placebo arms). The most common adverse events with active treatment were nausea, dizziness, and vomiting; these events occurred more frequently in the tramadol group than in the tramadol/APAP group. This study established the superiority of tramadol/APAP 75 mg/650 mg over tramadol 100 mg in the treatment of acute pain following oral surgery.