Both duloxetine and nortriptyline are effective and safe to treat diabetic neuropathic pain.

Diabetes mellitus, characterized by chronic hyperglycemic condition, is usually linked with various long-term complications, including neuropathy, which considerably impacts 70% of people with diabetes. It also results in resistance to insulin action and impaired quality of life.

The precise pathogenesis of diabetic neuropathic pain is not yet fully known. But, numerous theories concerning the pain associated with diabetic neuropathy have been suggested, including central and peripheral nervous system sensitization, alterations in calcium and sodium channel expressions, alterations in the blood vessels supplying the peripheral nerves, and defects in endogenous analgesic mechanisms via descending spinal pathways that suppress pain.

Tricyclic antidepressants like nortriptyline, imipramine, and amitriptyline have been utilized as a first-line treatment to alleviate neuropathic pain associated with diabetes for many years. However, these agents result in common side effects such as blurred vision, palpitations, constipation, dry mouth, and urinary retention, suggesting the need to explore novel drugs.

As per recent clinical trials, serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine have shown promising results in individuals suffering from diabetic peripheral neuropathy. Management of diabetic peripheral neuropathy is primarily focused on symptomatic pain relief and palliative therapy.  But, relieving symptoms using drug regimens is limited by adverse effects and tolerance development. Tricyclic antidepressants, gabapentin, duloxetine, pregabalin, and venlafaxine are the agents recommended for the first-line usage in the management of diabetic peripheral neuropathy.

Though the effect of nortryptiline in neuropathic pain has been illustrated in various studies, its broad spectrum of activity and possible side effects may limit its usage. Furthermore, duloxetine has been a safe and effective therapeutic choice in patients with diabetic neuropathic pain.

Rationale behind research

No study has compared the efficacy of duloxetine with nortryptiline in diabetic patients having neuropathic pain. Therefore, this study was performed.

Objective

This randomized, double-blind, parallel-group, placebo-controlled trial was carried out to investigate the pain-relieving efficacy of duloxetine and nortryptiline among diabetic patients suffering from neuropathic pain.

Study outcomes

• The primary outcome was the comparison of mean pain intensity between the treatment groups

Outcomes

Baseline: There were no significant differences reported at baseline.

Study outcomes

• A substantial decline was observed in the visual analogue scale (VAS) in both treatment groups compared to placebo (Fig.2)
• No considerable differences were found in the analgesic efficacy (or VAS scores), alterations in vital signs, laboratory evaluations, electrocardiograms and occurrence of severe adverse events between duloxetine and nortriptyline groups
• In the primary assessment and the by-visit assessment, a decline in the mean pain intensity was remarkably higher in the nortriptyline and duloxetine arm vs placebo arm

For managing diabetic neuropathic pain, both duloxetine and nortriptyline were found to be safe and effective. In this trial, no superiority of either drug was noted. An improvement in pain score was witnessed in 59% of individuals treated with duloxetine vs 55% of individuals treated with nortriptyline.

These findings are in concordance with the prior studies that reported the same range of pain assessment scores. The decline in pain severity noted in the present study was considerably maintained and persistent from week one through the end of week five. A therapeutic regimen consisted of an initial dose of nortriptyline (25 mg) and duloxetine (20 mg).

Prior trials had depicted an effective dose range of 25-150 mg and 60-120 mg for nortriptyline and duloxetine, respectively. Goldstein et al. investigated the effect of duloxetine (given at doses of 20 mg, 60 mg, or 120 mg) and placebo in minimizing pain in individuals suffering from diabetic peripheral neuropathy. Duloxetine 60 mg and 120 mg per day illustrated a considerably more significant decline in pain severity than placebo. However, the same effect was not witnessed with 20 mg/day duloxetine.

In this study, an improvement in pain was reported with relatively low doses of both drugs (25 mg nortriptyline, 20 mg duloxetine). It might be due to the possible effect of lower body size and weight of the patient population. Also, it might be due to the variability in the individual differences in drug metabolism. Overall, both the drugs were safely given and showed good tolerability. No significant adverse events were noted in this trial. The data is in agreement with prior trials illustrating that there were no vital differences in various other outcomes before and after therapy.

The strength of the study includes a randomized, placebo-control, double-blind trial design to explore the therapeutic effects of both nortriptyline and duloxetine to manage diabetic neuropathic pain. Furthermore, the presence of a placebo arm enhanced the sensitivity for recognizing the pain relief alterations with each drug in diabetic neuropathic pain.

The results of this trial illustrated the effectiveness and safety of both nortriptyline and duloxetine to treat diabetic neuropathic pain. Duloxetine 20 mg once daily showed non-superiority to nortriptyline 25 mg. Both the agents displayed a comparable magnitude in pain decline in individuals having diabetic neuropathic pain. Though duloxetine is relatively more expensive, it yields an effective and safe alternative to individuals who cannot tolerate nortriptyline. But, there is a requisition of more extensive, robust studies with longer follow-up duration.