During the titration period, the mean weekly pain score in the ITT population decreased from 6.73 at screening to 2.32 at double-blind baseline. From randomization baseline to the end of treatment, the score in the ITT population increased by a least-squares mean (±SE) of 1.46 ± 0.11 points in the placebo group compared with 0.92 ± 0.11 points in the NKTR-181 group. The difference between groups (primary efficacy analysis) was a significantly greater maintenance of pain reduction among patients continuing to take NKTR-181 than among patients switched to placebo (treatment difference, 0.55; 95% confidence interval [CI], 0.23-0.86; P = 0.002). Among 12-week completers, maintenance of pain reduction was also significantly greater in the NKTR-181 group (treatment difference, 0.69; 95% CI, 0.40-0.98; P < 0.001). The time course of mean weekly pain scores during treatment is displayed by treatment group in Figure 3A. Maintenance of pain reduction was significantly greater in the NKTR-181 group than in the placebo group at week 1 and in all subsequent weeks (P < 0.001).
Throughout the study, COWS, Subjective Opiate Withdrawal Scale, and MADDERS findings for NKTR-181 showed a low potential for opioid withdrawal and an incidence of abuse or misuse events closely resembling that for placebo. Detailed results are to be reported in separate publications.
This study has several limitations that must be acknowledged. The main purpose of an EERW study design is to evaluate the magnitude of the true treatment effect in subjects that can tolerate a drug once they endorse relief following an initial, open-label period of exposure. Clinicians treating patients with CLBP are keenly interested in understanding the extent of pain relief in the subgroup of patients who can tolerate and choose to continue a given course of therapy. Consequently, confirmation that an initial perceived benefit in subjects who find a therapy tolerable is due to specific drug effects is a vital clinical question, one this study design helps to answer. However, it is important to note that the opioid analgesic effect observed in the randomized phase of an EERW study such as this one is not directly comparable with a traditional study with a prospective, parallel design. The generalizability of the efficacy results is diminished because the double-blind phase includes only patients who could tolerate the study drug and endorsed a prespecified threshold of relief in the open-label phase. In addition, to facilitate the conduct of the study, potential subjects were excluded if they had significant risk factors for aberrant drug-taking behavior. Therefore, the safety profile as observed in this study with respect to aberrant drug-taking behavior cannot be extrapolated to patients at higher risk of substance use disorder.
In recent years, the FDA has encouraged the development of abuse-deterrent formulations of opioid analgesics.2 To date, only formulations of “legacy” opioids using physical/chemical barriers or agonist/antagonist combinations as abuse-deterrent strategies have been approved. The use of these agents has been advocated as a way to impede drug tampering; however, most of the current strategies for abuse deterrence can be circumvented and have not succeeded in addressing the escalating opioid epidemic.4 Efforts to convert NKTR-181 into a more active mu-opioid receptor agonist or one that crosses the BBB at a faster rate using known chemical or physical methods have been unsuccessful.19 In summary, NKTR-181 provides effective analgesia in patients with moderate-to-severe CLBP, with low rate of CNS side effects.
J. Markman has participated in advisory boards or consultant (Editas Medicine, Flexion Therapeutics, Pfizer, Teva, Quark, Pacira, Inspirion, Delivery Sciences, Quartet, Pacira Egalet, Biogen, Nektar, Endo, Immune Pharma, Chromocell, Collegium, Purdue, Trigemina, Novartis, Sanofi, Convergence, Aptinyx, Daiichi Sankyo, Allergan, Plasmasurgical, and Grunenthal), received research funding (Depomed, Pfizer), and served on Data Safety Monitoring Boards (Allergan, Novartis). Jeffrey Gudin is a consultant to Nektar Therapeutics, R. Rauck received research funding from Nektar; S.K. Doberstein, M. Tagliaferri, L. Lu, and S. Siddhanti are employed by Nektar Therapeutics. The remaining authors have no conflicts of interest to declare.
Editorial support, funded by Nektar Therapeutics, was provided by Phillips Gilmore Oncology Communications, Inc, and The Curry Rockefeller Group, LLC.
Funding source: Nektar Therapeutics.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A754.
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