Comparative Safety and Tolerability of Duloxetine vs. Pregabalin vs. Duloxetine Plus Gabapentin in Patients With Diabetic Peripheral Neuropathic Pain

G. Irving; R. J. Tanenberg; J. Raskin; R. C. Risser; S. Malcolm


Int J Clin Pract. 2014;68(9):1130-1140. 

In This Article

Abstract and Introduction


Objective: The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared.

Methods: A 12-week, randomized, open-label study confirming the non-inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability.

Results: Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p= 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end-point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 ± 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (−2.39 ± 0.04 and −1.06 ± 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p= 0.01).

Conclusion: Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP.


Estimates suggest that 60–70% of people with diabetes have some form of neuropathy.[1] Patients who experience diabetic peripheral neuropathic pain (DPNP) report painful sensations in the extremities described as aching, burning, stabbing or tingling.[2–4]

There are currently two medications that have been approved by the FDA for the management of DPNP: duloxetine hydrochloride (here after referred to as duloxetine) and pregabalin. Duloxetine is a re-uptake inhibitor of both serotonin (5-HT) and norepinephrine in the central nervous system; it is believed that by increasing these neurotransmitters, duloxetine reduces the perception of pain by dampening pain signals ascending to the brain.[5,6] In contrast, pregabalin has been proposed to reduce pain by modulating the α-2-δ subunit of calcium channels in the central nervous system.[7] Both drugs have been shown to be efficacious, safe and well tolerated for the management of DPNP.[8–15]

Gabapentin is FDA-approved for postherpetic neuralgia. Although not FDA-approved for DPNP, gabapentin is widely used in clinical practice for the treatment of DPNP.[16,17] The proposed mechanism of action of gabapentin, similar to pregabalin, involves binding to the α-2-δ subunit of voltage-gated Ca2+ ion channels, which may account for its antinociceptive and antiseizure effects.[18]

While the safety and tolerability of duloxetine, pregabalin and gabapentin as treatments for DPNP has been established, no known report compares the safety and tolerability of duloxetine to pregabalin as well as to a combination of duloxetine plus gabapentin, which is often used in clinical practice. These three regimens were administered as part of a clinical trial assessing the non-inferiority of duloxetine vs. the other regimens as treatment for DPNP as the primary outcome, the results of which have been published.[19] The current study is a detailed report of safety and tolerability outcomes from that trial. The aim of this analysis was to examine any safety-related differences between these treatment groups, given the widespread clinical use of these treatment options. The current analysis includes assessments of vital signs, body weight, haemoglobin A1c (HbA1c), neurotoxicty, sleep and sexual function, all of which are clinically relevant to these therapeutic options. Our expanded analysis provides additional safety information that may be useful to both patients and clinicians when choosing a medication for DPNP.