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

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.

Challenges in the identification of cobalamin-deficiency polyneuropathy.

BACKGROUND: Diagnosing cobalamin (Cbl) deficiency as a cause of polyneuropathy (PN) is problematic, as the frequency of both disorders increases with age, and serum Cbl levels can be difficult to interpret. OBJECTIVES: To identify unique clinical or laboratory features among PN patients with Cbl deficiency and to examine the role of testing of serum metabolite levels in the identification of Cbl deficiency. DESIGN: Cohort survey comparing patients with Cbl deficiency and cryptogenic PN identified during a 2-year period. Cobalamin deficiency was diagnosed using low serum Cbl levels or elevated serum methylmalonic acid or homocysteine levels. SETTING: Academic neuromuscular clinic. RESULTS: Of 324 PN patients, 27 were diagnosed as having Cbl deficiency. Twelve had Cbl levels within the normal range, but elevated serum metabolite levels. Compared with patients with cryptogenic sensory/sensorimotor PN, those with Cbl deficiency were more likely to have concomitant involvement of the upper and lower extremities and experience symptom onset in the hands and a sudden onset of symptoms (P<.005). These differences were seen regardless of whether Cbl deficiency was defined using low Cbl levels or elevated serum metabolite levels. Autoimmune pernicious anemia was identified in 6 (50%) of 12 Cbl-deficient patients with normal serum Cbl levels. The patients with PN and Cbl deficiency showed little objective improvement after parenteral replacement therapy; however, progression occurred less often in these patients compared with those with cryptogenic sensory/sensorimotor PN (P =.02). CONCLUSIONS: This study highlights the challenges of proving that Cbl deficiency is the cause for PN and identifies clinical features that suggest Cbl-deficiency PN. Testing of serum metabolite levels may identify Cbl deficiency in some patients with normal serum Cbl levels.