Impact of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin on the neuropathic component of severe, chronic low back pain

Introduction: For patients with severe low back pain with a neuropathic component, combination of strong opioids and co-analgesics (eg, anticonvulsants)1 often provides better analgesic efficacy than monotherapy but may be associated with increasing side effects and related discontinuations.2 A recent study showed that tapentadol PR was effective and well-tolerated for managing severe, chronic low back pain with or without a neuropathic component.3 This randomized, double-blind phase 3b study (NCT01352741; approved by Ethics Committee) evaluated the effects of tapentadol PR monotherapy versus combination therapy with tapentadol PR and pregabalin on the neuropathic component of severe, chronic low back pain as a secondary endpoint. Methods: Eligible patients had painDETECT scores of “unclear” or “positive” and average baseline pain intensity ≥6 (11-point NRS-3 [average 3-day pain intensity]). Patients were titrated to tapentadol PR 300 mg/day over 3 weeks. At randomization, patients with ≥1-point decrease in NRS-3 from baseline and NRS-3 ≥4 were randomized to target doses of tapentadol PR monotherapy (500mg/day) or tapentadol PR/pregabalin combination therapy (300/300mg/day) during an 8-week comparative period. The neuropathic component of low back pain was evaluated using painDETECT scores and the Neuropathic Pain Symptom Inventory (NPSI). Treatment-emergent adverse events (TEAEs) were documented. Results: Observed-case analyses of painDETECT scores in the monotherapy and combination groups, respectively, included 150 and 157 patients at baseline and randomization and 111 and 123 patients at final evaluation; mean (SD) scores were 22.2 (5.69) and 23.4 (5.94) at baseline, 17.6 (6.11) and 18.3 (5.98) at randomization, and 12.0 (7.55) and 12.8 (7.18) at final evaluation of the comparative period; mean (SD) changes from randomization to final evaluation were -6.4 (8.69) and -6.3 (7.55; both P< 0.0001). NPSI overall feeling scores (Figure) and subscores (observed-case) improved significantly from randomization to final evaluation in both treatment groups (all P< 0.0001). In the monotherapy and combination groups, respectively, the percentage of patients reporting “no pain attacks during the last 24 hours” on the NPSI was 4.6% and 2.5% at baseline, 7.9% and 4.5% at randomization, and 25.7% and 18.5% at final evaluation. During the comparative period, the most common TEAEs (≥5%) for tapentadol PR monotherapy (n=154) and tapentadol PR/pregabalin combination (n=159), respectively, were dizziness (11.0% vs 17.6%), somnolence (8.4% vs 11.9%), hyperhidrosis (11.7% vs 6.3%), nausea (10.4% vs 9.4%), fatigue (8.4% vs 10.1%), constipation (7.1% vs 5.0%), headache (6.5% vs 8.2%), vomiting (5.8% vs 3.1%), and dry mouth (3.9% vs 5.0%). Discussion: Comparable significant, clinically relevant improvements in neuropathic pain measures were observed with tapentadol PR (500mg/day) monotherapy and tapentadol PR/pregabalin (300/300mg/day) combination therapy, with fewer CNS-related TEAEs in the monotherapy arm. The favorable effectiveness and tolerability profile suggests that monotherapy with tapentadol PR, with its 2 mechanisms of action, is a viable treatment option for managing severe low back pain with a neuropathic component.