Arvind Narayana

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.

Fentanyl Buccal Tablet Compared with Immediate-Release Oxycodone for the Management of Breakthrough Pain in Opioid-Tolerant Patients with Chronic Cancer and Noncancer Pain: A Randomized, Double-Blind, Crossover Study Followed by a 12-Week Open-Label Phase to Evaluate Patient Outcomes

OBJECTIVE Evaluate analgesic efficacy, functional benefit, and patient satisfaction with fentanyl buccal tablet vs immediate-release oxycodone for breakthrough pain (BTP). DESIGN Randomized, double-blind, active-controlled crossover trial and 12-week open-label extension. SETTING Forty-two U.S. sites. PATIENTS Opioid-tolerant patients with predominantly chronic noncancer pain experiencing BTP. INTERVENTION Patients were randomized to open-label titration periods with fentanyl buccal tablet followed by oxycodone or vice versa for BTP management. After titrating to a successful dose of both medications (single dose providing adequate analgesia without unacceptable adverse events), patients were re-randomized to treat 10 BTP episodes with one medication and 10 with the other. OUTCOME MEASURES The primary efficacy measure was pain intensity (PI) difference 15 minutes postdose. Secondary measures included PI difference 5, 10, 30, 45, and 60 minutes postdose; sum of PI differences 30 and 60 minutes postdose; ≥33% and ≥50% reduction in PI; and pain relief. Questionnaires assessed functional status/satisfaction. RESULTS Of 213 patients enrolled, 149 achieved a successful dose of both medications; 131 completed the double-blind phase and 112 the open-label phase. PI difference at 15 minutes (mean [standard deviation]) was greater with fentanyl buccal tablet (0.88 [1.20]) vs oxycodone (0.76 [1.13]; P < 0.001). Patients preferred fentanyl buccal tablet (47%) over oxycodone (35%); 18% had no preference. Patients and clinicians reported consistently better functional improvement and satisfaction with fentanyl buccal tablet vs short-acting opioids (P < 0.05). CONCLUSIONS Fentanyl buccal tablet was associated with rapid onset of analgesia and improvements in functional status and patient satisfaction compared with immediate-release oxycodone.

Aberrant Drug‐Related Behavior Observed During a 12‐Week Open‐Label Extension Period of a Study Involving Patients Taking Chronic Opioid Therapy for Persistent Pain and Fentanyl Buccal Tablet or Traditional Short‐Acting Opioid for Breakthrough Pain

OBJECTIVE Evaluate aberrant drug-related behaviors in patients administering fentanyl buccal tablet or traditional short-acting opioids for breakthrough pain. DESIGN Twelve-week open-label extension. SETTING Forty-two US sites. SUBJECTS Opioid-tolerant patients with chronic pain who completed the previous randomized, double-blind, crossover portion of a study comparing fentanyl buccal tablet and immediate-release oxycodone for treatment of breakthrough pain. METHODS Patients were rerandomized to continue treatment with fentanyl buccal tablet or begin any traditional short-acting opioid. Assessments included Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) at baseline and Addiction Behaviors Checklist and Current Opioid Misuse Measure at baseline and final visit. Case report forms were reviewed retrospectively to identify aberrant drug-related behaviors. RESULTS One hundred thirty patients entered the open-label extension (fentanyl buccal tablet, N = 65; traditional short-acting opioid, N = 65). SOAPP-R scores were <18 (low risk of aberrant drug-related behavior) in 74% of patients; no significant differences in SOAPP-R scores were observed between treatment groups. At the final visit, ≤14% of patients in each treatment group had scores indicating potential aberrant drug-related behavior (Addiction Behaviors Checklist ≥3, Current Opioid Misuse Measure ≥9); no significant differences in scores were observed between treatment groups. Baseline SOAPP-R score ≥18 was not predictive of Addiction Behaviors Checklist ≥3 but was predictive of Current Opioid Misuse Measure ≥9. Aberrant behaviors were identified in 12 (18%) fentanyl buccal tablet patients and 13 (20%) traditional short-acting opioid patients. CONCLUSIONS Incidence of aberrant drug-related behaviors was similar between patients taking fentanyl buccal tablet and traditional short-acting opioids over 12 weeks.

National Breakthrough Pain Study: prevalence, characteristics, and associations with health outcomes.

Abstract The National Breakthrough Pain Study is a large observational study that assessed breakthrough pain (BTP) in a population of commercially insured community-dwelling patients with opioid-treated chronic pain. Eligible patients were identified from an administrative claims database, and consenting patients were asked to complete a structured telephone interview and several validated questionnaires. Questionnaires assessed pain interference with function (Brief Pain Inventory-Short Form), health status (Short Form 12 [SF-12] Health Survey), disability (Sheehan Disability Scale), work performance (World Health Organization Health and Work Performance Questionnaire), and mood (Generalized Anxiety Disorder-7 Screener [GAD-7] and Patient Health Questionnaire-2 [PHQ-2]). Of 2198 patients interviewed, 1278 patients had persistent pain controlled with opioid therapy; 1023 (80%) of these patients reported BTP. Patients had a median of 2.0 episodes of BTP per day (range, 1-50) and a median duration of BTP of 45 minutes (range, 1-720). Compared with patients without BTP, patients with BTP had more pain-related interference in function (Brief Pain Inventory, mean ± SD: 34.2 ± 15.6 vs 25.0 ± 15.7 [P < 0.001]), worse physical health (SF-12 physical component score: 29.9 ± 9.6 vs 35.1 ± 10.4 [P < 0.001]) and mental health (SF-12 mental component score: 47.4 ± 11.3 vs 49.3 ± 10.4 [P < 0.001]), more disability (Sheehan Disability Scale global impairment score: 15.1 ± 9.1 vs 10.6 ± 8.5; World Health Organization Health and Work Performance Questionnaire absolute absenteeism: 12.4 ± 59.9 vs 7.7 ± 44.9 hours [both P < 0.001]), and worse mood (GAD-7 score: 7.4 ± 5.9 vs 5.9 ± 5.4; PHQ-2 anhedonia score: 1.2 ± 1.1 vs 0.9 ± 1.0 [both P < 0.001]). In this population of community-dwelling patients with opioid-treated chronic pain, BTP was highly prevalent and associated with negative outcomes. This burden of illness suggests the need for specific treatment plans.

Treatment of breakthrough pain with fentanyl buccal tablet in opioid-tolerant patients with chronic pain: appropriate patient selection and management.

BACKGROUND Opioids can be a safe and effective option for carefully selected patients with a structured treatment program that includes consistent monitoring. However, the benefits and risks of opioid therapy for patients with chronic pain, and society as a whole, have been sharply debated. A key component of this debate has involved the administration of rapid-onset opioids for the management of breakthrough pain. OBJECTIVE Review key aspects of breakthrough pain management with fentanyl buccal tablet, with a focus on minimizing risk to optimize therapeutic outcomes. Recommendations that apply broadly to all rapid-onset opioids are also discussed. DESIGN Available fentanyl buccal tablet clinical and post-marketing data were reviewed. RESULTS Like other schedule II controlled substances, and because fentanyl buccal tablet is a highly potent opioid, its use is associated with risk of overdose, misuse, and diversion. As with all rapid-onset opioids, particular attention to patient selection and risk assessment is warranted. The inclusion and exclusion criteria in fentanyl buccal tablet clinical studies represent patient selection standards that should be translated to clinical practice, most importantly, that patients are opioid-tolerant before fentanyl buccal tablet initiation. Titration of fentanyl buccal tablet from a low starting dose to a successful dose allows the safe identification of a dose that provides the greatest pain relief without unacceptable adverse events. After initiating fentanyl buccal tablet therapy, all patients should continue to be regularly monitored for response, including analgesia, functioning, tolerability, and aberrant behavior. CONCLUSIONS Fentanyl buccal tablet can be an effective and generally safe treatment for breakthrough pain when appropriate patient selection, administration, dosing, and monitoring are applied.