Effectiveness and tolerability of tapentadol prolonged release compared with prior opioid therapy for the management of severe, chronic osteoarthritis pain

Abstract

Background: Tapentadol prolonged release (PR; 100-250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment.

Objective: The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR (50-250 mg twice daily) after direct rotation from World Health Organization (WHO) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability.

Methods: This open-label, phase 3b study (NCT00982280) was conducted from October 2009 through June 2010 (prematurely terminated due to slow recruitment and study drug shortages) in clinical care settings in Europe and Australia. The study population included patients with severe, chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening, responded to therapy (average pain intensity [11-point numerical rating scale-3 (NRS-3)] ≤5 at screening), and reported opioid-related adverse effects as their reason for changing analgesics. Patients switched directly from WHO step III therapy to tapentadol. Patients received oral tapentadol PR (50-250 mg twice daily) during 5-week titration and 7-week maintenance periods. Oral tapentadol immediate release (IR) was permitted (≤twice/day, ≥4 h apart) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids (combined dose of tapentadol [PR and IR] ≤500 mg/day). This study was planned to evaluate conversion to tapentadol PR, based on responder rate 1 (percentage of patients with same/less pain [NRS-3] versus Week -1) at Week 6 (primary endpoint), adverse events (AEs), and discontinuation rates. Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids (PR and PR plus IR formulations).

Results: Of 82 patients enrolled, 63 received study medication. In the per-protocol population, responder rate 1 at Week 6 (last observation carried forward) was 94.3 % (50/53; P < 0.0001 vs. the null hypothesis rate [<60 %]). Mean (standard deviation) pain intensity scores were 4.7 (0.66) at baseline, 2.5 (1.46) at Week 6, and 1.8 (1.41) at Week 12 in the main analysis population (change from baseline at Weeks 6 and 12, P < 0.0001). Tapentadol to transdermal buprenorphine equianalgesic ratios (PR [n = 48], 262.9:1; PR plus IR [n = 48], 281.1:1) and tapentadol to oral oxycodone equianalgesic ratios (PR [n = 4], 4.3:1; PR plus IR [n = 6], 4.6:1) were calculated for the main analysis population. In the safety population, prevalence of AEs reported as associated with prior opioids at Week -1 (reasons for rotation) and related to tapentadol treatment at Week 12 decreased over time; the most common were nausea (46.0 vs. 24.1 %) and constipation (31.7 vs. 7.4 %). Overall, 14.3 % of patients discontinued the study early; reasons included AEs (9.5 %), lack of efficacy (3.2 %), and withdrawal of consent (1.6 %).

Conclusions: Significant improvements in effectiveness were observed for tapentadol PR (50-250 mg twice daily) versus WHO step III opioids in patients with severe, chronic osteoarthritis knee pain who previously responded to WHO step III therapy. Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies.

Fig. 1

Responder rates 1 and 2 over time (main analysis population; observed-case analysis)^a. WHO World Health Organization ^aResponder rate 1 was the percentage of patients with the same or less pain compared with Week −1 (on previous WHO step III analgesic); responder rate 2 was the percentage of patients with the same or less pain compared with Week −1 and an improvement of ≥1 category in subject satisfaction with treatment compared with baseline ^b P < 0.0001 for testing the hypothesis that the response is 50 % ^cThe interim visit occurred 3–4 days after the baseline visit

Fig. 2

Mean pain intensity (NRS-3) over time (main analysis population; observed-case analysis)^a. The vertical dotted line indicates start of tapentadol prolonged release. NRS-3 numerical rating scale-3, W week, WHO World Health Organization ^aStandard deviations: screening, 0.63; baseline, 0.66; interim, 1.03; W1, 1.33; W2, 1.40; W3, 1.02; W4, 1.14; W5, 1.20; W6, 1.46; W7, 1.47; W8, 1.40; W9, 1.37; W10, 1.60; W11, 1.45; W12, 1.41 ^bPreplanned statistical analyses of change from baseline were conducted at Weeks 6, 8, and 12; P < 0.0001 for the change from baseline at each timepoint ^cOn WHO step III analgesics ^dEnrollment to baseline (i.e., point of rotation to tapentadol prolonged release) ^eThe interim visit occurred 3–4 days after the baseline visit

Fig. 3

Subject satisfaction with treatment at baseline, Week 6, and Week 12 (main analysis population; observed-case analysis)

Fig. 4

Ratings on the a PGIC and b CGIC at Weeks 6 and 12 (main analysis population; observed-case analysis). PGIC Patient Global Impression of Change, CGIC Clinician Global Impression of Change

Fig. 5

Mean WOMAC subscale and global scores over time (main analysis population; observed-case analysis). WOMAC Western Ontario and McMaster Universities, SDs standard deviations, W week ^aSDs: baseline, 13.19; W6, 16.72; W8, 19.57; W12, 19.00 ^bSDs: baseline, 9.88; W6, 12.40; W8, 14.26; W12, 14.04 ^cSDs: baseline, 2.48; W6, 3.45; W8, 3.94; W12, 3.59 ^dSDs: baseline, 1.76; W6, 1.52; W8, 1.80; W12, 1.78 ^e P < 0.0001 for the change from baseline

Fig. 6

Mean (SD) changes in SF-36 domain scores from baseline to a Week 6^a and b Week 12^b (main analysis population; observed-case analysis)^c,d. SD standard deviation, SF-36 Short Form-36 ^aSD: physical functioning, 21.99; role-physical, 41.88; bodily pain, 20.67; general health, 13.25; vitality, 13.92; social functioning, 27.39; role-emotional, 29.99; mental health, 11.24 ^bSD: physical functioning, 27.49; role-physical, 48.84; bodily pain, 29.28; general health, 15.59; vitality, 15.75; social functioning, 27.79; role-emotional, 33.50; mental health, 12.12 ^cSee Electronic Supplementary Material Table S7 for mean total SF-36 scores at baseline, Week 6, and Week 12 ^dWeek 6, n = 55; Week 12, n = 53 ^e P ≤ 0.0005 for the change from baseline ^f n = 52

Fig. 7

Prevalence of AEs (≥2 %) associated with previous treatment at Week −1 and related to tapentadol treatment at Week 12 (safety population; n = 63)^a. AE adverse event, WHO World Health Organization ^aThe prevalence of these AEs were summarized during Week −1 (the week prior to titration when patients were still on WHO step III treatment) and during Week 12 (the final week of tapentadol prolonged release treatment) ^bNausea, constipation, dry mouth, fatigue, and dizziness were reported as the main reasons for switching to tapentadol prolonged release

Fig. 8

Incidence of TEAEs reported by ≥5 % of patients (safety population; n = 63) (percentages based on the number of individual TEAEs and TEAEs in each SOC). The horizontal dotted lines separate the TEAEs included in each SOC. TEAE treatment-emergent adverse event, SOC system organ class