PATIENTS AND METHODS: We performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥900 mg/d) and had an inadequate response (defined as a daily pain score of ≥4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of –0.8 unit.

RESULTS: The mean change in the pain rating at end point was –2.6 for duloxetine and –2.1 for pregabalin. The 97.5% lower confidence limit was a –0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin.

CONCLUSION: Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin.

Currently, 2 medications are approved by the US Food and Drug Administration for the management of DPNP: duloxetine hydrochloride and pregabalin. The proposed mechanism of action of duloxetine, an antidepressant, is reuptake inhibition of both serotonin and norepinephrine in the central nervous system, which increases the activity of these neurotransmitters and subsequently reduces the perception of pain by modulating the pain signals.^8,9 In contrast, pregabalin, an anticonvulsant agent, has a proposed analgesic mechanism of action that involves binding to the α₂-δ subunit of calcium channels in hyperexcited afferent neurons, which reduces the release of glutamate, norepinephrine, and substance P, thereby reducing pain signals transmitted from the periphery to the brain.¹⁰

When treatment with an analgesic does not provide satisfactory pain reduction or is not well tolerated, one option is to switch to or add another analgesic with a different mechanism of action. Selecting a medication to switch to is based on its efficacy and adverse event profile.¹¹ This study was undertaken to determine whether switching from gabapentin to duloxetine would provide a benefit similar to that of switching to pregabalin and to determine the benefit of adding duloxetine to gabapentin. Although TCAs are first-line therapies for DPNP, none were used as comparators in the current study because the therapeutic doses are associated with substantial adverse events.

This study used a noninferiority design that specifically examines whether a medication (in this case duloxetine) is no worse than (or as good as) a reference medication (pregabalin) for which efficacy has been established. Noninferiority compares the difference in improvement between 2 treatments to a predetermined margin of noninferiority (MoNI) for the treatment effect on the primary outcome. This margin represents the maximum treatment difference that is not considered clinically better or worse. The benefit of using a noninferiority study design is that fewer patients are required than for a head-to-head comparison trial between 2 efficacious medications. A head-to-head comparison trial between duloxetine and pregabalin would require large numbers of patients to achieve significance because the difference in efficacy between these analgesics would be small.

Because patients with diabetes generally have a high prevalence of comorbid illnesses and are often prescribed multiple medications, this was an open-label study that allowed more realistic disease management and the use of a broader range of concomitant medications. Thus, the results of this trial may be more generalizable to a clinical population.

The primary objective of this open-label, noninferiority study was to determine whether treatment with duloxetine was at least as good as pregabalin in reducing pain associated with diabetic neuropathy in patients who had an inadequate pain response to treatment with gabapentin.

Outpatients with type 1 or type 2 diabetes mellitus and a glycated hemoglobin (HbA_1c) level of 12% or lower were eligible for inclusion in the study if they were aged at least 18 years, presented with DPNP (confirmed by a score of at least 3 on section B of the Michigan Neuropathy Screening Instrument),¹² and had a daily pain score of 4 or higher based on a numerical rating scale (0-10 points). Also, patients had to be taking a stable dose of gabapentin (≥900 mg/d) for at least 5 weeks before randomization, had to be at least 80% adherent to gabapentin therapy, and had to agree not to change the dose of gabapentin between visits 1 and 2. In addition, the patient or physician had to have indicated a need to change from the current gabapentin therapy for pain management. Patients were excluded if they had a history or current diagnosis of mania, bipolar disorder, obsessive-compulsive disorder, or posttraumatic stress disorder or were judged before randomization to be at risk of suicide. Other exclusion criteria included historical exposure to drugs known to cause neuropathy, treatment with a monoamine oxidase inhibitor within 14 days, or treatment with fluoxetine within 30 days of randomization. Concomitant antidepressants (except monoamine oxidase inhibitors) and analgesics were allowed, provided the patient was taking a stable dose for a minimum of 3 months before study enrollment.

The screening period for eligibility occurred between visits 1 and 2 and lasted as long as 60 days (approximately 8 weeks) to accommodate the washout period for excluded medications. When no washout was required, patients were enrolled within 3 days after they completed all screening procedures. Eligible patients were randomized in a 1:1:1 ratio to open-label oral treatment with duloxetine monotherapy, pregabalin monotherapy, or a combination of duloxetine and gabapentin. Patients began taking the study drug on the next day after visit 2. Patients in the monotherapy treatment arms were cross-tapered from their current oral dose of gabapentin to 300 mg/d during a 1- to 2-week period; gabapentin therapy was then discontinued. Duloxetine therapy was initiated at 30 mg once daily for 1 week, after which patients received 60 mg once daily. In Germany, Puerto Rico, and the United States, pregabalin was dosed according to the US prescribing information¹³ and initiated at 150 mg/d for the first week with 50-mg doses taken 3 times daily. The following week, the dosage was increased to 300 mg/d and administered at 100 mg 3 times daily. In Canada, pregabalin was dosed according to Canadian prescribing information,¹⁴ and therapy was initiated at 150 mg/d but administered at 75 mg twice daily. The following week, the dosage was increased to 300 mg/d and administered at 150 mg twice daily. Patients randomized to combination treatment continued to take their current dose of gabapentin (≥900 mg once daily), initiated duloxetine therapy at 30 mg once daily for the first week, and then received duloxetine, 60 mg once daily, for the remainder of the study.

Patients were allowed to use concomitant medications for the management of pain or mood during the trial, provided they were taking a stable dose of the medication at study entry. Patients were not allowed to increase the dose of these medications but were allowed to decrease the dose.

The primary efficacy measure was the reduction from baseline in the weekly mean of the daily 24-hour pain (referred to hereafter as daily pain) diary ratings at week 12. Pain was assessed using a numerical rating scale ranging from 0 for no pain to 10 for worst possible pain. Two secondary measures derived from the pain diaries that were also analyzed weekly were worst pain and night pain ratings. Other secondary measures included the Clinical Global Impression of Severity, the Brief Pain Inventory (BPI) severity and interference items,¹⁵ the Beck Depression Inventory II,¹⁶ the Patient Global Impression of Improvement, and the Sheehan Disability Scale.¹⁷

Three response criteria were analyzed on the basis of daily pain ratings: reductions of 30% or higher from baseline, reductions of 50% or higher from baseline, and a reduction of 2 or more points from baseline. Sustained response was defined as at least a 30% reduction from baseline to end point, at least a 30% reduction from baseline 2 weeks before the last week in the study period, and at least a 20% continued reduction from baseline every week in between.

Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs), discontinuation due to adverse events, mean changes and categorical changes in vital signs, and mean changes and rates of abnormal laboratory analytes, including HbA_1c levels.

Noninferiority in this study focuses on differences in improvement in pain reduction between duloxetine and pregabalin (primary objective) and between duloxetine and duloxetine plus gabapentin (secondary objective) at week 12. The 97.5% 1-sided confidence limit, which is equivalent to the lower limit of a 2-sided 95% confidence interval (CI), for the difference between duloxetine and pregabalin was compared with the protocol-defined MoNI. The MoNI represents the maximum disadvantage of duloxetine relative to its comparator that is not considered clinically meaningful. If the lower limit of the CI exceeds the MoNI, noninferiority is established.

The MoNI was based on results from an analysis of 3 DPNP placebo-controlled duloxetine studies^18-20 using only patients previously treated with gabapentin. In these patients, the estimated mean improvement (decrease) in pain severity at week 12 was –2.74 for duloxetine, 60 mg once daily, and –1.09 for placebo, representing a mean –1.65 advantage of duloxetine over placebo. Thus, the prespecified MoNI of –0.8 represents slightly less than 50% of the previously observed advantage for duloxetine over placebo in a similar population of patients.

This study was designed to randomize 400 patients to duloxetine, pregabalin, or duloxetine plus gabapentin in a 1:1:1 ratio. With the assumption that 6% of patients would discontinue the study before providing postbaseline data, approximately 125 patients per arm were included in the primary efficacy analysis. This sample size has 92% power for the noninferiority assessment of duloxetine compared with pregabalin in pain reduction. Assumptions supporting the sample size estimate include the use of a 1-tailed 97.5% CI, a mean improvement of 2.5 for pregabalin and 2.7 for duloxetine, a common SD of 2.3 for change from baseline to end point, and a MoNI of –0.8.

In accordance with International Committee for Harmonization recommendations,²¹ noninferiority analyses were conducted on the intent-to-treat (ITT) population and the per-protocol population. Because results from the ITT population can produce wider CIs owing to attrition than those from the per-protocol population, there may be some bias toward finding no difference between treatments in the ITT analysis. Thus, results of the per-protocol sensitivity analysis can support the results from the ITT population if the outcomes from both analyses are consistent.²² The ITT population included all randomized patients who had weekly mean assessments of baseline and postbaseline diary-based daily pain ratings. The per-protocol population included only those patients in the ITT population who adhered to a predetermined set of key protocol criteria: adherence to study drug therapy, Michigan Neuropathy Screening Instrument score less than 3 at study entry, gabapentin taper length of not more than 14 days, no use of prohibited medications, and no HbA_1c level greater than 12% after randomization.

The primary analysis used a restricted, likelihood-based mixed-models repeated-measures (MMRM) model that included explanatory terms for the fixed, categorical effects of treatment, investigator, week, and treatment by week interaction, as well as the continuous, fixed covariates of baseline average pain severity ratings and the baseline by week interaction. An unstructured correlation matrix was used to model the within-patient errors. The noninferiority assessments were made using pairwise CIs comparing treatments at week 12.

Sensitivity analyses of noninferiority at end point were also characterized using baseline observation carried forward (BOCF) and last observation carried forward (LOCF) imputation techniques for the weekly means, with analysis based on an analysis of covariance (ANCOVA) model with terms for treatment, baseline, and investigator for both the ITT and per-protocol populations. Estimates from MMRM/ANCOVA models reported here are least-squares means.

Baseline characteristics were compared using the Fisher exact test (nominal outcomes) or analysis of variance (numeric outcomes) with terms for treatment and investigator. Analyses of secondary efficacy measures were conducted using the MMRM model as described for the primary analysis (if collected at multiple time points after baseline) and the ANCOVA model as already described (if collected at baseline or end point only) but without noninferiority assessment.

Demographic and baseline clinical characteristics of the ITT patient population, as well as preexisting conditions, were generally similar across treatment groups (Table 1 and Table 2). Most patients were white men with type 2 diabetes who were in their early 60s. The mean duration of diabetes was more than 12 years, which was significantly longer for each of the monotherapy groups compared with the combination treatment group, and the average duration of DPNP was almost 4.5 years. On average, mean HbA_1c values were less than 8%. Daily pain severity as reported in patient diaries and as assessed by the BPI was moderate (rating of 4-6),²³ and severity of functional disability was rated as mild (rating of 3-9) to moderate (rating of 12-18).¹⁷ Less than 5% of the patients had a comorbid major depressive disorder or generalized anxiety disorder. Preexisting conditions included arthritis, osteoarthritis, and back pain. The average gabapentin dose at baseline was more than 1200 mg/d; more than 50% of the patients reported using concomitant pain medications, and less than 20% used antidepressants (Table 3).

During the study, amitriptyline was the most common TCA used across treatment groups; its use was significantly greater for patients in the pregabalin group (Table S1, Supporting Online Material). Opioids were used by 57 patients, with the combination of hydrocodone bitartrate and acetaminophen being the most common. No significant between-treatment differences were found with the use of any of the opioids.

The per-protocol patient population was composed of 281 patients from the ITT population (Table S2, Supporting Online Material). More than 70% of the patients in the pregabalin and the duloxetine plus gabapentin groups were included in the per-protocol population, whereas less than 60% of the patients in the duloxetine monotherapy group were included. The most common reason for excluding patients from the per-protocol population was nonadherence to study drug therapy, which was significantly greater in the duloxetine monotherapy group (P=.02) vs the pregabalin and duloxetine plus gabapentin groups (P=.01).

The interpretation of the noninferiority outcomes is supported by several features of the trial design. The primary outcome measure in this study is comparable to that used in previous duloxetine^18-20 and pregabalin^24,25 randomized, double-blind, placebo-controlled efficacy trials of 12 weeks' duration. In addition, both monotherapy groups were cross-tapered from gabapentin and titrated to fixed doses of duloxetine or pregabalin over 2 weeks, so timing of escalation to the therapeutic dose did not vary. Furthermore, the therapeutic dose for each medication was consistent with current dosing guidelines for patients with DPNP, which reduces potential bias against either treatment. However, patient selection was based on not having an adequate response to gabapentin, which has a proposed mechanism of action similar to pregabalin, so this could be considered a potential bias against pregabalin. Although pregabalin and gabapentin share the characteristic of binding to the α₂-δ subunit of calcium channels, subtle differences were seen between these agents in other mechanisms of action that differentiate them as analgesics. For example, in an open-label study, pregabalin effectively reduced pain in patients with DPNP or postherpetic neuropathic pain who were refractory to or had experienced intolerable adverse events from treatment with gabapentin, a TCA, or a third medication.²⁶

To our knowledge, this is the first study to investigate adding duloxetine to gabapentin. This combination was efficacious with patients experiencing baseline to end point reductions in pain, similar to treatment with duloxetine monotherapy and pregabalin monotherapy. Although adding duloxetine to gabapentin may provide increased efficacy, further studies of combination therapies in inadequate responders or naive patients are warranted. Duloxetine plus gabapentin was generally well tolerated, with an adverse event profile and rate similar to those of duloxetine monotherapy treatment, with the exception of significantly less insomnia occurring in the combination treatment group. Also, the adverse event profile for duloxetine plus gabapentin was not different from that reported for gabapentin monotherapy.²⁷

The analysis of concomitant pain medication use (including opioids and TCAs) found no differential treatment effect with these agents. However, the analysis of concomitant antidepressant use yielded intriguing results, suggesting that switching to duloxetine instead of pregabalin could provide better pain reduction, particularly in those patients who were not taking antidepressants. Conversely, adding duloxetine to gabapentin in nonresponders who are already using an antidepressant may not provide better pain reduction than switching to pregabalin. Although concomitant antidepressant medications were allowed in this study, the use of multiple serotonergic agents should be avoided or approached with caution because of the risk of serotonin syndrome.

Duloxetine, pregabalin, and duloxetine plus gabapentin were safely administered and well tolerated. No significant differences were found between treatments in the frequency of these events. Although the TEAE profile for each treatment varied, each profile was consistent with previous reports for duloxetine,^18-20 pregabalin,^24-26,28-30 and gabapentin.²⁷