Is Pregabalin, Duloxetine, and Amitriptyline Combination Therapy Effective for Treating Diabetic Neuropathy?

Is Pregabalin, Duloxetine, and Amitriptyline Combination Therapy Effective for Treating Diabetic Neuropathy?

Diabetic neuropathy is one of the classic microvascular complications, along with retinopathy and nephropathy. This is a condition that can affect up to about 50% of patients with diabetes mellitus (DM) throughout their lives. Of these, half can develop neuropathic pain, which is often difficult to control and is associated with worsening quality of life. Pain in general can be characterized by symptoms such as burning, paresthesias that resemble electric shocks, preferentially affecting the lower limbs and later the upper limbs. It is well known that chronic hyperglycemia is an important risk factor, but there are also data showing that neuropathy can develop even in patients with near-ideal control (ie, 7% glycated hemoglobin). Therefore, the pathophysiology of this complication is not completely understood.

Currently, the guidelines recommend as first-line treatment for neuropathic pain the use of duloxetine, gabapentin, pregabalin or amitriptyline, with the aim of analgesia. Despite studies showing benefit in pain relief, unfortunately the results are not so expressive – there is an improvement in about 50% of pain in less than half of patients who are using any of these medications. Still, there are few data regarding the use of combination therapies. This motivated the performance of the OPTION-DM study, recently published in the Lancet (August/2022), a study crossovermulticenter and randomized study based on 13 centers in the United Kingdom, whose objective was precisely to compare the effect of the combination of three of the first-line medications (pregabalin, duloxetine and amitriptyline) versus monotherapy in the control of neuropathic pain secondary to diabetes.

The study

The study included participants with diabetes, older than 18 years, with distal symmetric polyneuropathy confirmed by Toronto Clinical Neuropathy Score (TCNS) – greater than or equal to 5 – with daily episodes of neuropathic pain confirmed by the Douleur Neuropathique 4 questionnaire (score ≥ 4) for at least 3 months. A numerical pain scale (END) was also needed ≥ 4 (in which zero was no pain and 10 the worst possible pain), TGO and TGP less than twice the reference limit, glomerular filtration rate greater than 30, stable diabetes control in the last three months, in addition to lower or equal to 12%.

Pregnant women, subjects with postural hypotension, cardiac arrhythmias, or conduction disturbances on baseline ECG, BPH, presence of lower limb injuries, or evidence of other causes for neuropathy were excluded from the study. Participants did not use other analgesics or antidepressants during the trial and were instructed to use only acetaminophen up to 1g every 6h to relieve pain if necessary.


At the end, 130 patients were randomized. The mean age was 61 years, 74% men, 17% DM1, with a mean of 15 years of diabetes and a mean of 8.2%. Participants started monotherapy for 6 weeks at the maximum tolerated dose (amitriptyline 75 mg/d, duloxetine 120 mg/d, or pregabalin 600 mg/d). If pain relief was suboptimal (intensity still ≥ 4), combination treatment was started. The predefined sequences of combinations were amitriptyline supplemented with pregabalin (A+P), pregabalin supplemented with amitriptyline (P+A) and duloxetine supplemented with pregabalin (D+P), lasting a total of 16 weeks (six weeks of monotherapy followed by ten of combination therapy). Participants were divided into six groups for crossover therapies, and at the end of 16 weeks, the A+P group could go to D+P or P+A, and so on, combining all possibilities, after one week. pre-set of washout of the drugs, which totaled a duration of approximately 50 weeks.


In general, the combinations had an interesting result. In the three combination sequences, there was success and improvement in neuropathic pain control compared to baseline, with an improvement in END from 6.6 at baseline (mean; SD: 1.5) to 3.3 (SD 1.8) at baseline. end of 16 weeks. The difference between the groups was not significant in any of the combinations.

Most importantly, there was a significant reduction in pain in the combination therapy vs. monotherapy. At the end of six weeks of monotherapy, the mean reduction in END was 2.6 and 3.4 at the end of 16 weeks. In those starting a combination therapy, there was an additional -1.0 point reduction (0.6 to 1.3; P < 0.001) in END. There was a response to monotherapy (ie, END <4) in 37% when initiating treatment with amitriptyline, 32% with duloxetine and 34% with pregabalin. There was pain control (END < 4) in 48% in the A+P sequence, 43% in the D+P sequence and 47% in the P+A sequence.

The main side effects observed were dizziness in the P+A sequence, nausea in the D+P and dry mouth in the A+P.

Read too: Does vitamin D supplementation benefit patients with diabetic neuropathy?

Considerations and practical message

The main idea of ​​the study was to evaluate the response in the treatment of neuropathic pain in a context close to that of clinical practice, where a patient is often already on treatment with some medication, looking at different scenarios and comparing the association with other first-line medications. . The results are not brilliant, but scientifically solidify that it is possible to combine two first-line medications with the aim of improving pain control, a symptom that significantly reduces the quality of life of patients with diabetes.

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