[Skip to Navigation]
Original Investigation
August 17, 2020

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

Richard J. Barohn, MD1; Byron Gajewski, PhD2; Mamatha Pasnoor, MD1; et al Alexandra Brown, MS2; Laura L. Herbelin, BS1; Kim S. Kimminau, PhD3; Dinesh Pal Mudaranthakam, MBA2; Omar Jawdat, MD1; Mazen M. Dimachkie, MD1; and the Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS) Study Team
Author Affiliations
  • 1Department of Neurology, The University of Kansas Medical Center, Kansas City
  • 2Department of Biostatistics & Data Science, The University of Kansas Medical Center, Kansas City
  • 3Department of Family Medicine, The University of Kansas Medical Center, Kansas City
JAMA Neurol. 2021;78(1):68-76. doi:10.1001/jamaneurol.2020.2590
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.


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

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    3 Comments for this article
    Suraj Rajan, MSc., MD. | OhioHealth & Johns Hopkins
    Can the authors clarify why gabapentin, the most commonly prescribed drug, was not included?
    RE: Gabapentin
    Alexandra Brown, MS | University of Kansas Medical Center
    In reply to Dr. Rajan's comment:

    It was a practical decision we had to make. The grant size was such that we could only choose 4 drugs. We had to make a decision to go with pregabalin or gabapentin. We chose pregabalin because that drug was FDA-approved for the treatment of diabetic neuropathy, a condition similar to CSPN. We ultimately chose four drugs with different mechanisms of action.

    If we get the opportunity to do a follow up PAINS-CONTRoLS 2, we plan to have gabapentin as one of the study drugs.
    Thank you
    Gary Murtaugh, BSN | Retired RN, Critical Care, PACU, Cardiac Care, Hospice Care
    You are commended for taking on a study of a heterogeneous yet large population as yet unstudied. Since my retirement due to bilateral idiopathic sensory axonal symmetric polyneuropathy, I am heartened to see something published on the approximately 50% of those with painful PN who aren't diabetic. I rely on pregabalin and duloxetine, with neither causing significant adverse reactions; I don't tolerate any of the tricyclics. Low dose methadone was actually very efficacious, but finding a prescriber became difficult when the realization of the opioid crisis became apparent. CNS drugs are a difficult study, especially with the genetic variability in any given individual's metabolism. I tolerate maximum doses of both pregabalin and duloxetine, yet 300 mgs of gabapentin makes me stuporous. Until genetic variation can be assessed in a cost effective and reimbursable manner, the issues of both drug metabolism and identification of "Idiopathic" types of neuropathy will remain difficult. At least someone took a first step. Thank You.