Results from the largest and longest-running head-to-head, crossover trial indicate that amitriptyline (A), pregabalin (P), and duloxetine (D) as monotherapy and in combination had similar analgesic effects for patients with diabetic peripheral neuropathic pain (DPNP). These findings were published in The Lancet.
The OPTION-DM trial was a multicenter, randomized, double-blind trial conducted at 13 centers in the United Kingdom. Patients (N=130) with DPNP were randomly assigned to receive 3 sequences of combinations of A, P, and D: A-P followed by D-P followed by P-A (n=23); A-P, P-A, D-P (n=22); D-P, A-P, P-A (n=19); D-P, P-A, A-P (n=22); P-A, D-P, A-P (n=22); and P-A, A-P, D-P (n=22). For each of the combinatorial periods, patients started using monotherapy with a 2-week titration period followed by 6 weeks of treatment. At 6 weeks, patients were evaluated for efficacy of treatment. Responders (numeric rating scale [NRS] score ≤3) remained on monotherapy and nonresponders started the assigned combination therapy for 10 weeks, at which point the patients underwent a 1- to 2-week wash-out and switched to the next assigned drug combination.
Approximately three-quarters of the study population were men. Median age of study participants was 61.0 (interquartile range [IQR], 55-70) years, 94% were White, the average duration of diabetes was 15.1 (standard deviation [SD], 9.3) years, the average duration of neuropathic pain was 4.9 (SD, 4.1) years, 36% had previously tried an opioid medication, and mean NRS pain score was 6.6 (SD, 1.5) points.
After 6 weeks of monotherapy, NRS scores decreased from baseline by an average of 2.9 (SD, 2.0) points for A, by an average of 2.8 (SD, 2.0) points for D, and by an average of 2.5 (SD, 2.2) points for P (overall effect of monotherapy, P <.0001). The proportion of patients who responded to monotherapy was 37% for A, 32% for D, and 34% for P.
At week 16 of combination therapy, NRS scores decreased from baseline by an average of 3.4 (SD, 2.1) points for A-P, 3.5 (SD, 2.1) points for D-P, and 3.3 (SD, 2.1) points for P-A (overall effect of dual therapy, P <.0001). The response rates for combination therapy were 48%, 43%, and 47% for A-P, D-P, and P-A, respectively.
No significant differences were observed in the pair-wise comparison analyses of monotherapies and combination therapies.
Among patients receiving maximum tolerated doses, similar improvements in short form-36 (SF-36), Hospital Anxiety and Depression Scale (HADS), and Insomnia Severity Index (ISI) scores were reported.
Serious adverse event rates did not differ significantly between study groups. Dizziness was reported more frequently with P-A (P =.036), nausea was reported more frequently with D-P (P =.0011), and dry mouth was reported more frequently with A-P (P =.0003). Most instances of treatment discontinuation due to adverse events occurred during monotherapy and fewer discontinuations occurred during the P-A combination (5%; P =.031) compared with A-P (11%) or D-P (17%).
A major limitation of this study was its lack of a placebo control group.
In this largest and longest-running head-to-head comparison trial, 3 of the most frequently used medications for DPNP were found to have similar safety and efficacy outcomes when administered as monotherapy and in combination. The investigators concluded that “our study can give confidence that any of these drugs or drug combinations, if titrated carefully to maximum tolerated doses, can result in similar levels of pain relief.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Tesfaye S, Sloan G, Petrie J, et al; on behalf of the OPTION-DM trial group. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. Lancet. 2022;400(10353):680-690. doi:10.1016/S0140-6736(22)01472-6