Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies

Abstract

Background: The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318–1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials.

Methods: Patients in both studies were randomized (2:1) to tapentadol ER (25–250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods).

Results: For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were −0.1 (−1.04, 0.80) in the OA/LBP study and −0.1 (−1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated.

Conclusions: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

Key words

tapentadol - chronic pain - Japanese - placebo-controlled - underpowered

• References

• 1 Chapman CR, Lipschitz DL, Angst MS et al. Opioid pharmacotherapy for chronic non-cancer pain in the United States: a research guideline for developing an evidence-base. J Pain 2010; 11: 807-829
• 2 Dworkin RH, Turk DC. Accelerating the Development of Improved Analgesic Treatments: The ACTION Public-Private Partnership. Pain Med 2011; 12 (Suppl. 03) S109-S117
• 3 Dworkin RH, Turk DC, Peirce-Sandner S et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010; 149: 177-193
• 4 Green CR, Ndao-Brumblay SK, Nagrant AM et al. Race, age, and gender influences among clusters of african american and white patients with chronic pain. J Pain 2004; 5: 171-182
• 5 Kim DH, Schwartz CE. The genetics of pain: implications for evaluation and treatment of spinal disease. Spine J 2010; 10: 827-840
• 6 Freynhagen R, Baron R, Gockel U et al. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006; 22: 1911-1920
• 7 Schmidt CO, Schweikert B, Wenig CM et al. Modelling the prevalence and cost of back pain with neuropathic components in the general population. Eur J Pain 2009; 13: 1030-1035
• 8 Farrar JT, Young Jr JP, LaMoreaux L et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94: 149-158
• 9 Hoffman GA, Harrington A, Fields HL. Pain and the placebo: what we have learned. Perspect Biol Med 2005; 48: 248-265
• 10 Quessy SN, Rowbotham MC. Placebo response in neuropathic pain trials. Pain 2008; 138: 479-483
• 11 Afilalo M, Etropolski MS, Kuperwasser B et al. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig 2010; 30: 489-505
• 12 Lange B, Kuperwasser B, Okamoto A et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010; 27: 381-399
• 13 Buynak R, Shapiro DY, Okamoto A et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010; 11: 1787-1804
• 14 Schwartz S, Etropolski M, Shapiro DY et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin 2011; 27: 151-162
• 15 Vinik AI, Shapiro DY, Rauschkolb C et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care 2014; 37: 2302-2309
• 16 Imanaka K, Tominaga Y, Etropolski M et al. Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Curr Med Res Opin 2013; 29: 1399-1409
• 17 Kress HG, Koch ED, Kosturski H et al. Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician 2014; 17: 329-343
• 18 Imanaka K, Tominaga Y, Etropolski M et al. Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor-related pain on other opioids to tapentadol extended release. Clin Drug Investig 2014; 34: 501-511
• 19 Nucynta Nucynta^® ER (tapentadol) extended-release oral tablets C-II [package insert]. Raritan, NJ: Janssen Pharmaceuticals, Inc.; 2014. 2014
• 20 Palexia Palexia^® SR 25 mg prolonged-release tablets (tapentadol) [summary of product characteristics]. Uxbridge, United Kingdom: Grünenthal Ltd; 2012. 2012
• 21 Bellamy N, Buchanan WW, Goldsmith CH et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988; 15: 1833-1840
• 22 Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003; 35: 253-259
• 23 Agbalaka A, Schwenke K, Litzenburger B. Tapentadol prolonged release for the treatment of severe chronic tumor pain in routine clinical practice. MMW Fortschr Med 2012; 154 (Suppl. 04) 123-130
• 24 Schwittay A, Schumann C, Litzenburger BC et al. Tapentadol prolonged release for severe chronic pain: results of a noninterventional study involving general practitioners and internists. J Pain Palliat Care Pharmacother 2013; 27: 225-234
• 25 Miaskowski C. Understanding the genetic determinants of pain and pain management. Semin Oncol Nurs 2009; 25: S1-S7
• 26 Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007; 81: 429-444
• 27 Hey SP, Kimmelman J. The questionable use of unequal allocation in confirmatory trials. Neurology 2014; 82: 77-79