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

Educational Objective
To determine which of the most commonly prescribed medications is best tolerated and most effective for reducing pain in patients with cryptogenic sensory polyneuropathy.
1 Credit CME
Key Points

Question  Which of the most commonly prescribed medications (pregabalin, duloxetine, nortriptyline, and mexiletine) is best tolerated and most effective for reducing pain in patients with cryptogenic sensory polyneuropathy?

Findings  In a bayesian adaptive randomized clinical trial including 402 patients with cryptogenic sensory polyneuropathy, none of the 4 drugs were clearly superior in performance. However, nortriptyline and duloxetine performed better than pregabalin and mexiletine when efficacy and tolerability were both considered.

Meaning  Nortriptyline or duloxetine should be considered first for the treatment of pain among patients with cryptogenic sensory polyneuropathy.

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

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Article Information

Accepted for Publication: April 18, 2020.

Published Online: August 17, 2020. doi:10.1001/jamaneurol.2020.2590

Correction: This article was corrected on September 8, 2020, to fix errors in the Figure.

Corresponding Author: Alexandra Brown, MS, Department of Biostatistics & Data Science, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160 (abrown8@kumc.edu).

The PAIN-CONTRoLS Study Team Authors: Stanley Iyadurai, PhD, MD; Amro Stino, MD; John Kissel, MD; Robert Pascuzzi, MD; Thomas Brannagan, MD; Matthew Wicklund, MD; Aiesha Ahmed, MD; David Walk, MD; Gordon Smith, MD; Dianna Quan, MD; Darryl Heitzman, MD; Alejandro Tobon, MD; Shafeeq Ladha, MD; Gil Wolfe, MD; Michael Pulley, MD; Ghazala Hayat, MD; Yuebing Li, MD, PhD; Pariwat Thaisetthawatkul, MD; Richard Lewis, MD; Suur Biliciler, MD; Khema Sharma, MD; Kian Salajegheh, MD; Jaya Trivedi, MD; William Mallonee, MD; Ted Burns, MD; Mark Jacoby, MD; Vera Bril, MD; Tuan Vu, MD; Sindhu Ramchandren, MD; Mark Bazant, MD; Sara Austin, MD; Chafic Karam, MD; Yessar Hussain, MD; Christen Kutz, PhD, PA-C; Paul Twydell, DO; Stephen Scelsa, MD; Hani Kushlaf, MD; James Wymer, MD; Michael Hehir, MD; Noah Kolb, MD; Jeffrey Ralph, MD; Alexandru Barboi, MD; Navin Verma, MD; Moiz Ahmed, MD; Anza Memon, MD; David Saperstein, MD; Jau-Shin Lou, MD; Andrea Swenson, MD; Tiyonnoh Cash, MD.

Affiliations of The PAIN-CONTRoLS Study Team Authors: The Ohio State University, Columbus (Iyadurai, Stino, Kissel); Indiana University, Bloomington, Indiana (Pascuzzi); Columbia University Medical Center, New York, New York (Brannagan); Pennsylvania State University, Centre County (Wicklund, A. Ahmed); University of Minnesota, Minneapolis (Walk); University of Utah, Salt Lake City (Smith); University of Colorado–Denver, Denver (Quan); Texas Neurology, Dallas (Heitzman); UT Health Science–San Antonio, San Antonio, Texas (Tobon); Barrow Neurology, Phoenix, Arizona (Ladha); University at Buffalo, Buffalo, New York (Wolfe); University of Florida Jacksonville, Jacksonville (Pulley); Saint Louis University, St Louis, Missouri (Hayat); Cleveland Clinic, Cleveland, Ohio (Li); University of Nebraska Medical Center, Omaha (Thaisetthawatkul); Cedars-Sinai Medical Center, Los Angeles, California (Lewis); University of Texas Health Science Center at Houston (Biliciler); University of Miami, Miami, Florida (Sharma); Brigham and Women’s Hospital, Boston, Massachusetts (Salajegheh); UT Southwestern Medical Center, Dallas, Texas (Trivedi); Hutchinson Clinic, Hutchinson, Kansas (Mallonee); University of Virginia, Charlottesville (Burns); Mercy Medical Center, Des Moines, Iowa (Jacoby); University of Toronto, Toronto, Ontario, Canada (Bril); University of South Florida–Tampa, Tampa (Vu); University of Michigan, Ann Arbor (Ramchandren); Norton Neurology Services, Louisville, Kentucky (Bazant); Seton Brain and Spine, Austin, Texas (Austin); Oregon Health and Science University, Portland (Karam); Austin Neuromuscular Center, Austin, Texas (Hussain); Colorado Springs Neurological Associates, Colorado Springs (Kutz); Spectrum Health, Grand Rapids, Michigan (Twydell); Mt Sinai Beth Israel, New York, New York (Scelsa); University of Cincinnati, Cincinnati, Ohio (Kushlaf); University of Florida–Gainesville, Gainesville (Wymer); University of Vermont, Burlington (Hehir, Kolb); University of California, San Francisco (Ralph); NorthShore University Health System, Evanston, Illinois (Barboi); Neurological Services of Orlando Research, Orlando, Florida (Verma); Grand Medical Clinic, Katy, Texas (M. Ahmed); Henry Ford Hospital, Detroit, Michigan (Memon); Phoenix Neurological, Phoenix, Arizona (Saperstein); University of North Dakota, Grand Forks (Lou); University of Iowa Hospitals and Clinics, Iowa City (Swenson); University of California–Irvine, Irvine (Cash).

Author Contributions: Dr Barohn had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Barohn, Gajewski, Pasnoor, Herbelin, Kimminau, Jawdat, Dimachkie, Kissel, Sharma, Trivedi, Bril.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Barohn, Gajewski, Pasnoor, Brown, Herbelin, Kimminau, Iyadurai, A. Ahmed, Salajegheh, Burns, Scelsa, Kushlaf, M. Ahmed, Memon, Cash.

Critical revision of the manuscript for important intellectual content: Barohn, Pasnoor, Brown, Herbelin, Mudaranthakam, Jawdat, Dimachkie, Iyadurai, Stino, Kissel, Pascuzzi, Brannagan, Walk, Smith, Quan, Heitzman, Tobon, Ladha, Pulley, Wolfe, Hayat, Li, Swenson, Thaisetthawatkul, Lewis, Sharma, Biliciler, Trivedi, Salajegheh, Mallonee, Jacoby, Bril, Vu, Ramchandren, Bazant, Austin, Karam, Hussain, Kutz, Twydell, Wymer, Hehir, Kolb, Ralph, Barboi, Verma, Saperstein, Lou, Wicklund.

Statistical analysis: Barohn, Gajewski, Brown, Mudaranthakam, Salajegheh, Mallonee, Twydell.

Obtained funding: Barohn, Gajewski, Kimminau.

Administrative, technical, or material support: Barohn, Gajewski, Pasnoor, Herbelin, Kimminau, Mudaranthakam, Dimachkie, Stino, Kissel, Pascuzzi, Smith, Tobon, Thaisetthawatkul, Sharma, Salajegheh, Jacoby, Bril, Vu, Bazant, Karam, Hehir, Kolb, Barboi, Memon, Saperstein, Cash.

Supervision: Barohn, Pasnoor, Herbelin, Kimminau, Jawdat, Dimachkie, Smith, Heitzman, Ladha, Sharma, Hussain, Kushlaf, Wymer, Hehir, Ralph.

Conflict of Interest Disclosures: Dr Barohn reported receiving grants from Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study. Dr Gajewski reported receiving grants from PCORI during the conduct of the study; and grants from the National Institutes of Health (NIH) outside the submitted work. Dr Pasnoor reported receiving grants from PCORI during the conduct of the study; and personal fees from CSL Behring, Argenx, catalyst, and Momenta outside the submitted work. Ms Brown reported receiving grants from PCORI and the NIH during the conduct of the study. Dr Herbelin reported a patent issued. Dr Dimachkie reported receiving grants from PCORI during the conduct of the study. Dr A. Ahmed reported other from Biogen and other from Sanofi outside the submitted work. Dr Walk reported other from University of Kansas during the conduct of the study. Dr Quan reported receiving grants from PCORI during the conduct of the study; and grants from Pfizer outside the submitted work. Dr Pulley reported receiving personal fees from CSL Behring, Grifols, Stealth Biotherapeutcs, Bio Products Laboratory, Catalyst Pharmaceuticals, and Argenx outside the submitted work. Dr Lewis reported receiving personal fees from CSL Behring, Akcea, Alnylam, Annexon, Argenx, Biotest, Momenta, Pfizer, Sanofi, and Takeda outside the submitted work. Dr Salajegheh reported receiving grants from PCORI during the conduct of the study. Dr Bril reported receiving grants from PCORI during the conduct of the study. Dr Vu reported participating as the site principal investigator for clinical trials for CIDP, serving on the speaker bureau for CSL Behring, and serving as a consultant for BPL, Physicians Education Resource LLC, and Pharmacy Times. Dr Kushlaf reported receiving personal fees from Akcea, Sanofi Genzyme, Alexion, Catalyst Pharmaceuticals, and PTC Therapeutics outside the submitted work. Dr Wymer reported receiving grants from PCORI during the conduct of the study. Dr Hehir reported receiving grants from PCORI during the conduct of the study; and personal fees from Alexion Pharma, Argenx Pharma, and CSL Behring outside the submitted work. Dr Kolb reported receiving personal fees from Disarm Therapeutics outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by PCORI award: University of Kansas Medical Center CER-1306-02496 and NIH Clinical and Translational Science Award UL1TR002366.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The PAIN-CONTRoLS Study Team members: We thank the patients and site staff involved in the study: The University of Kansas Medical Center, Kansas City: Chad Parks and Tina Liu; The Ohio State University, Columbus: Adam Quick, MD, Carrie Blumenauer, and Kelly Neidert; Indiana University, Bloomington: Sandra Guingrich; Columbia University Medical Center, New York, New York: Allan Paras and Kim Arreum; Pennsylvania State University, Centre County: Max Lowden, MD, Heidi Runk, Anne Haulman, and Travis Haines; University of Minnesota, Minneapolis: Valerie Ferment, Rosanne Ferguson, and Muse Jama; University of Utah, Salt Lake City: Rob Singleton, MD, Angela Stonebraker, Brittany Thurgood, Cathy Revere, and Kami Grant; University of Colorado–Denver: Steven Ringel, MD, Vera Fridman, MD, and Brianna Blume; Texas Neurology, Dallas: Alan Martin, MD; UT Health Science–San Antonio, San Antonio, Texas: Pam Kitrell, and Amy Saklad; Barrow Neurology, Phoenix, Arizona: Gale Kittle, Ashley Reece, and Samantha Goins; University at Buffalo, Buffalo, New York: Nicholas Silvestri, MD, and Kara Patrick; University of Florida Jacksonville: Lisa Smith; Saint Louis University, Saint Louis, Missouri: Ayman Daoud; Cleveland Clinic, Cleveland, Ohio: John Anothony Morren, MD and Irys Caristo; University of Nebraska Medical Center, Omaha: Deb Heimes; Cedars-Sinai Medical Center, Los Angeles, California: Peggy Allred, Koral Wheeler, and Vy Nguyen; University of Texas Health Science Center at Houston: Carla Wilkerson; University of Miami, Miami, Florida: Monica Quesada; Brigham and Women’s Hospital, Boston, Massachusetts: Janice Wong, MD, Thomas Cochrane, MD, and Shirli Toska; UT Southwestern Medical Center, Dallas, Texas: Lindsay Cowell, PhD, Sharon Nations, MD, Steven Vernino, MD, Jeffrey Elliot, MD, PhD, Lauren Phillips, MD, Nina Gorham, Steve Hopkins, and Molly Michaels; Hutchinson Clinic, Hutchinson, Kansas: Juan Morales, Jennifer Gruver, Christina Sittler, and Jessica Chaney; University of Virginia, Charlottesville: Manish Kumar, MD, and Amruta Joshi; Mercy Medical Center, Des Moines, Iowa: Emily Froah; University of Toronto, Toronto, Ontario, Canada: Eduardo Ng; University of South Florida–Tampa: Brittany Harvey; University of Michigan, Ann Arbor: Stephanie Averills; Norton Neurology Services, Louisville, Kentucky: Robert Tillet Jr and Deborah Lockridge; Seton Brain and Spine, Austin, Texas: Krishna Saini; Oregon Health and Science University, Portland: Diana Dimitrova, PhD; Austin Neuromuscular Center, Austin, Texas: Ameel Husseini; Colorado Springs Neurological Associates, Colorado Springs: Laurence Adams, Jodi Ventimiglia, and Lisa Deschaine; Spectrum Health, Grand Rapids, Michigan: Jessica Gallavin and Nicole Walker; Mt. Sinai Beth Israel, New York, New York: Emily Ripps; University of Cincinnati, Cincinnati, Ohio: Alecia Boehl; University of Florida–Gainesville: Teri Green; University of Vermont, Burlington: Shannon Lucy; University of California San Francisco: Tu-Khan Duong; NorthShore University Health System, Evanston, Illinois: Julie Anderson, and Monika Szela; Neurological Services of Orlando Research, Orlando, Florida: Michele Cabrera; Grand Medical Clinic, Katy, Texas: Amna Ghouse; Henry Ford Hospital, Detroit, Michigan: Kara Steijlen, MD, Daniel Newman, MD, and Naganand Sripathi, MD; Phoenix Neurological, Phoenix, Arizona: Lynne Flynn; and Patient Advisory Committee: John Wyble, Maryanne Anderson, Patrick Peterson, Kathy Santora, Bob Giles, Carolyn Simmons, and Susan Burton.

Data Sharing Statement: See Supplement 2.

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