Richard J Barohn1, Byron Gajewski2, Mamatha Pasnoor1, Alexandra Brown2, Laura L Herbelin1, Kim S Kimminau3, Dinesh Pal Mudaranthakam2, Omar Jawdat1, Mazen M Dimachkie1, Stanley Iyadurai4, Amro Stino4, John Kissel4, Robert Pascuzzi5, Thomas Brannagan6, Matthew Wicklund7, Aiesha Ahmed7, David Walk8, Gordon Smith9, Dianna Quan10, Darryl Heitzman11, Alejandro Tobon12, Shafeeq Ladha13, Gil Wolfe14, Michael Pulley15, Ghazala Hayat16, Yuebing Li17, Pariwat Thaisetthawatkul18, Richard Lewis19, Suur Biliciler20, Khema Sharma21, Kian Salajegheh22, Jaya Trivedi23, William Mallonee24, Ted Burns25, Mark Jacoby26, Vera Bril27, Tuan Vu28, Sindhu Ramchandren29, Mark Bazant30, Sara Austin31, Chafic Karam32, Yessar Hussain33, Christen Kutz34, Paul Twydell35, Stephen Scelsa36, Hani Kushlaf37, James Wymer38, Michael Hehir39, Noah Kolb39, Jeffrey Ralph40, Alexandru Barboi41, Navin Verma42, Moiz Ahmed43, Anza Memon44, David Saperstein45, Jau-Shin Lou46, Andrea Swenson47, Tiyonnoh Cash48. 1. Department of Neurology, The University of Kansas Medical Center, Kansas City. 2. Department of Biostatistics & Data Science, The University of Kansas Medical Center, Kansas City. 3. Department of Family Medicine, The University of Kansas Medical Center, Kansas City. 4. The Ohio State University, Columbus. 5. Indiana University, Bloomington, Indiana. 6. Columbia University Medical Center, New York, New York. 7. Pennsylvania State University, Centre County. 8. University of Minnesota, Minneapolis. 9. University of Utah, Salt Lake City. 10. University of Colorado-Denver, Denver. 11. Texas Neurology, Dallas. 12. UT Health Science-San Antonio, San Antonio, Texas. 13. Barrow Neurology, Phoenix, Arizona. 14. University at Buffalo, Buffalo, New York. 15. University of Florida Jacksonville, Jacksonville. 16. Saint Louis University, St Louis, Missouri. 17. Cleveland Clinic, Cleveland, Ohio. 18. University of Nebraska Medical Center, Omaha. 19. Cedars-Sinai Medical Center, Los Angeles, California. 20. University of Texas Health Science Center at Houston. 21. University of Miami, Miami, Florida. 22. Brigham and Women's Hospital, Boston, Massachusetts. 23. UT Southwestern Medical Center, Dallas, Texas. 24. Hutchinson Clinic, Hutchinson, Kansas. 25. University of Virginia, Charlottesville. 26. Mercy Medical Center, Des Moines, Iowa. 27. University of Toronto, Toronto, Ontario, Canada. 28. University of South Florida-Tampa, Tampa. 29. University of Michigan, Ann Arbor. 30. Norton Neurology Services, Louisville, Kentucky. 31. Seton Brain and Spine, Austin, Texas. 32. Oregon Health and Science University, Portland. 33. Austin Neuromuscular Center, Austin, Texas. 34. Colorado Springs Neurological Associates, Colorado Springs. 35. Spectrum Health, Grand Rapids, Michigan. 36. Mt Sinai Beth Israel, New York, New York. 37. University of Cincinnati, Cincinnati, Ohio. 38. University of Florida-Gainesville, Gainesville. 39. University of Vermont, Burlington. 40. University of California, San Francisco. 41. NorthShore University Health System, Evanston, Illinois. 42. Neurological Services of Orlando Research, Orlando, Florida. 43. Grand Medical Clinic, Katy, Texas. 44. Henry Ford Hospital, Detroit, Michigan. 45. Phoenix Neurological, Phoenix, Arizona. 46. University of North Dakota, Grand Forks. 47. University of Iowa Hospitals and Clinics, Iowa City. 48. University of California-Irvine, Irvine.
Abstract
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: ClinicalTrials.gov Identifier: NCT02260388.
RCT Entities:
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: ClinicalTrials.gov Identifier: NCT02260388.