Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial


Richard J. Barohn, University of Kansas Medical Center
Byron Gajewski, University of Kansas Medical Center
Mamatha Pasnoor, University of Kansas Medical Center
Alexandra Brown, University of Kansas Medical Center
Laura L. Herbelin, University of Kansas Medical Center
Kim S. Kimminau, University of Kansas Medical Center
Dinesh Pal Mudaranthakam, University of Kansas Medical Center
Omar Jawdat, University of Kansas Medical Center
Mazen M. Dimachkie, University of Kansas Medical Center
Stanley Iyadurai, The Ohio State University
Amro Stino, The Ohio State University
John Kissel, The Ohio State University
Robert Pascuzzi, Indiana University Bloomington
Thomas Brannagan, Columbia University Irving Medical Center
Matthew Wicklund, Pennsylvania State University
Aiesha Ahmed, Pennsylvania State University
David Walk, University of Minnesota Twin Cities
Gordon Smith, The University of Utah
Dianna Quan, University of Colorado Denver
Darryl Heitzman, Texas Neurology
Alejandro Tobon, UT Health Science Center at San Antonio
Shafeeq Ladha, Barrow Neurological Associates, Ltd.Follow
Gil Wolfe, University at Buffalo, The State University of New York
Michael Pulley, University of Florida
Ghazala Hayat, St. Louis University
Yuebing Li, Cleveland Clinic Foundation
Pariwat Thaisetthawatkul, University of Nebraska Medical Center
Richard Lewis, Cedars-Sinai Medical Center
Suur Biliciler, University of Texas Health Science Center at Houston
Khema Sharma, University of Miami
Kian Salajegheh, Brigham and Women's Hospital

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© 2020 American Medical Association. All rights reserved. Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment's sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration: Identifier: NCT02260388.

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JAMA Neurology









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