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A Double-Blind, Randomized Multicenter Trial Comparing Duloxetine with Placebo in the Management of Diabetic Peripheral Neuropathic Pain

Joel Raskin MD, FRCPC, Yili L. Pritchett PhD, Fujun Wang PhD, Deborah N. D'Souza PhD, MBA, Amy L. Waninger BS, Smriti Iyengar PhD, Joachim F. Wernicke MD, PhD
DOI: http://dx.doi.org/10.1111/j.1526-4637.2005.00061.x 346-356 First published online: 1 September 2005

ABSTRACT

Objective. Assess efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, on the reduction of pain severity, in patients with diabetic peripheral neuropathic pain (DPNP).

Methods. This was a multicenter, parallel, double-blind, randomized, placebo-controlled trial that enrolled 348 patients with pain due to peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. Patients (N = 116 per group) were randomly assigned to receive duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo, for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity evaluated on an 11-point Likert scale. Secondary outcome measures and safety were evaluated.

Results. Compared with placebo-treated patients, both duloxetine-treated groups improved significantly more (P < 0.001) on the 24-hour average pain score. Duloxetine demonstrated superiority to placebo in all secondary analyses of the primary efficacy measure. A significant treatment effect for duloxetine was observed in most secondary measures for pain. Discontinuations due to adverse events were more frequent in the duloxetine 60 mg BID- (12.1%) versus the placebo- (2.6%) treated group. Duloxetine showed no adverse effects on diabetic control, and both doses were safely administered and well tolerated.

Conclusions. In this clinical trial, duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the management of DPNP.

  • Duloxetine
  • Diabetic Neuropathy
  • Pain
  • Antidepressant
  • Serotonin
  • Norepinephrine

Introduction

Diabetes mellitus is predicted to afflict 220 million people worldwide by the year 2010 [1]. The prevalence of diabetes in the adult U.S. population is estimated to be 7.8%, and may be as high as 12–14% in people over 40 years [2]. Approximately 30–60% of patients with diabetes develop long-term complications of peripheral neuropathy, and up to 10–20% of these patients experience pain [3–5] often described as a steady aching or burning pain and characterized by hyperalgesia, allodynia, and paresthesia [6–8].

Serotonergic and noradrenergic neurons have been implicated in the mediation of endogenous pain inhibitory mechanisms via descending inhibitory pain pathways in the brain and spinal cord [9,10]. In pathological pain states, these endogenous pain inhibitory mechanisms may be dysfunctional, contributing to the central sensitization and hyperexcitability of the spinal and supraspinal pain transmitting pathways and manifesting as persistent pain [11]. In rodents, duloxetine has demonstrated efficacy in the formalin and capsaicin models of persistent pain, the partial sciatic nerve ligation [12], and L5/L6 spinal nerve ligation models of neuropathic pain [8]. Preclinical models of central sensitization suggest that duloxetine is effective in the treatment of persistent pain [13]. This is likely due to the effect of duloxetine on central sensitization rather than on nociception, suggested by its minimal efficacy in the tail-flick model of acute nociceptive pain. These results are indicative of pain inhibitory effects of duloxetine in the treatment of neuropathic, persistent, and inflammatory pain, but not in acute nociceptive pain. Because central sensitization and disinhibition mechanisms are believed to be involved in the development and maintenance of chronic neuropathic pain, including diabetic peripheral neuropathic pain (DPNP), duloxetine was considered to be a good clinical candidate for evaluating treatment of DPNP.

Duloxetine hydrochloride (Cymbalta®) is a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor that is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition [14] and it is the first U.S. Food and Drug Administration (FDA)-approved drug for the management of DPNP. In a randomized, controlled, 12-week trial comparing duloxetine 60 mg once daily (QD) and duloxetine 60 mg twice daily (BID) or 20 mg QD with placebo in the management of 477 patients [15] with DPNP and without depression, duloxetine was found to be effective and safe for DPNP management. Based on this evidence [15], two more independent studies were conducted to assess the safety and efficacy of duloxetine 60 mg QD and 60 mg BID in the management of patients with DPNP. The first of these two studies [16] confirmed findings reported earlier [15], and the second study is reported here.

Methods

Overview

Enrollment for this study extended from November 2003 to March 2004 and was conducted in 26 centers worldwide. This was a Phase III, multicenter, parallel, double-blind, randomized, placebo-controlled trial. The study protocol was approved in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent.

Entry Criteria

Patients were eligible for the study if they were ≥18 years, and presented with pain due to bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. The pain had to begin in the feet and with relatively symmetrical onset. The daily pain must have been present for at least 6 months, and the diagnosis was to be confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument (MNSI). Patients had to have a mean score of ≥4 when assessed for 24-hour average pain severity on the 11-point Likert scale (from the patient diary prior to randomization), and stable glycemic control. Patients were excluded if they were pregnant or breastfeeding, had prior renal transplant or current renal dialysis, or had a serious or unstable illness, symptomatic peripheral vascular disease, or other medical condition or psychological conditions that might compromise participation in the study. Patients were also excluded if they had a current (≤1 year) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [17] Axis I diagnosis of major depressive disorder (MDD), dysthymia, generalized anxiety disorder, alcohol, or eating disorders as determined by the Mini International Neuropsychiatric Interview (MINI) [18], or if they had a DSM-IV diagnosis or a previous diagnosis of mania, bipolar disorder, or psychosis. Other exclusion criteria included historical exposure to drugs known to cause neuropathy, history of substance abuse or dependence within the previous year (excluding nicotine and caffeine), a positive urine drug screen for any substances of abuse or excluded medication, or a history of a medical condition including pernicious anemia and hypothyroidism that could have been responsible for neuropathy, and treatment with a monoamine oxidase inhibitor (MAOI) or fluoxetine within 30 days of randomization. Patients were excluded if they had severe allergic reactions to multiple medications, and prior participation in a study of duloxetine.

Concomitant medication exclusions included chronic use of antidepressants, antiemetics, analgesics with the exception of acetaminophen up to 4 g/day and aspirin up to 325 mg/day. Antimanics, antimigraine medications, antipsychotics, benzodiazepines, capsaicin, chloral hydrate, guanethidine, topical lidocaine, MAOIs, narcotics, psychostimulants, oral and injectable steroids, and anticonvulsants were excluded. Concomitant medication inclusions (chronic and episodic) were antacids, antiasthma agents, aminophylline, birth control medication, cough/cold preparations (that did not contain dextromethorphan), diuretics, inhaled and topical steroids, hypoglycemics, insulin, laxatives, theophylline, anticoagulants, antibiotics, antidiarrheals, and antihistamines. Medications including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor agonists, antiarrythmics, anticoagulants, calcium channel blockers, and others were allowed provided the patient had been on a stable dose for 3 months prior to enrollment.

Study Design

This study was designed to enroll 330 patients to three treatment groups. With 110 patients per arm, the study had at least 90% power to detect a treatment-group difference of −1.20 points in the baseline-to-endpoint mean change on the weekly mean of 24-hour average pain severity between duloxetine 60 mg BID and placebo treatment groups. The sample size was determined using a two-sided test with α = 0.05, and assuming a common standard deviation of 2.2 and a discontinuation rate of 35%.

Patients who met entry criteria following an up to 3-week screening phase (study period I) were randomized to treatment with duloxetine 60 mg QD, duloxetine 60 mg BID, or placebo, with randomization performed at visit 3 in a 1:1:1 ratio. Assignment to treatment groups was determined by a computer-generated random sequence using an Interactive Voice Response System. Patients received either of (or a combination of, depending on their randomly assigned treatment) the following: 30 mg capsules of duloxetine hydrochloride or placebo capsules identical to duloxetine capsules. Patients randomly assigned to all treatment groups were instructed to take two capsules (by mouth) every morning and every evening. Study period II consisted of a 12-week, double-blind acute therapy period and 1-week study drug tapering period. Visits to the site occurred weekly for the first 2 weeks, biweekly for the next 10 weeks, and then weekly for the next week. All patients randomized to duloxetine treatment were treated initially with 60 mg QD. After 3 days, those patients randomized to the 60 mg BID treatment group received 60 mg BID. Patients in the 60 mg QD treatment group continued at 60 mg QD. At Visit 2 (week prior to randomization) through Visit 10 (week 12), patients received a diary and at Visit 3 through Visit 10 (week 12), patients received study drug. At Visit 10, the patient's study drug dose was halved to 30 mg QD and 60 mg QD for the duloxetine 60 mg QD- and 60 mg BID-treated group, respectively. The efficacy and safety evaluation of duloxetine versus placebo was conducted using data from the 12-week acute therapy period where duloxetine 60 mg was administered at a full dosage.

Efficacy Measures

The primary efficacy measure was the change in the weekly mean of the 24-hour average pain scores (referred to as the 24-hour average pain score) as measured by an 11-point Likert scale that was completed daily by the patients in a diary. At Visit 2, site personnel dispensed daily diaries and educated patients on proper completion of the diary. The mean score in a week was determined by averaging the daily scores (among the days in the week) on the 24-hour average pain collected from the diary. Overall study diary compliance was defined as being compliant at each visit in the study period from Visit 4 through Visit 10. A patient was considered to be compliant with the diary at a certain visit if the patient completed at least 80% of the diary over the total days since the last visit. Scores for 24-hour average pain, worst pain, and night pain were derived from the patient diary collected at each visit. Protocol-specified response at endpoint was defined as a 30% reduction from baseline to endpoint in the 24-hour average pain score. Responses based on 50%, 75%, and 100% reductions from baseline were also reported. Sustained response at endpoint was defined as a 30% reduction from baseline to endpoint in the 24-hour average pain severity with a 30% reduction from baseline at a week at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.

Secondary efficacy measures for pain were the weekly mean of daily worst pain and night pain on the 11-point Likert scale (collected from patient's diary), Brief Pain Inventory (BPI) [19], the Short-Form McGill Pain Questionnaire (sensory portion) (SF-MPQ) [20] (sum of 11 pain descriptor terms—throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, and splitting; the pain intensity for each pain descriptor was rated on a scale of 0 = none, 1 = mild, 2 = moderate, and 3 = severe), and dynamic allodynia. Dynamic allodynia was assessed by the clinician using a brush stroke (to the same body location at baseline and endpoint) to elicit pain severity from the patient. The patient was asked to answer whether a brush swept over the skin caused pain. The score range was from a scale of 0 (no pain) to 3 (severe pain). The interference portion of the BPI was completed by the patient to measure how much pain had interfered with patient outcomes. Other secondary measures included the 17-item Hamilton Depression Rating Scale (HAMD17) [21,22], the Clinical Global Impression of Severity (CGI-Severity) scale [23], and Patient Global Impression of Improvement (PGI-Improvement) scale. The average daily intake of acetaminophen taken for DPNP was recorded.

Schedule of Assessments

The screening portion of the protocol (Visits 1–3) included the medical history and the MINI [18] to determine whether patients met criteria for excluded primary DSM-IV Axis I diagnoses. Patients also underwent a physical exam, electrocardiogram (ECG), and laboratory tests. At randomization (Visit 3), and at each subsequent visit the diary was collected, vital signs were checked, and adverse events and concomitant medication were reviewed. BPI and CGI-Severity were completed at Visits 3, 6, 8, and 10. The PGI-Improvement was measured at Visits 6, 8, and 10. The HAMD17, SF-MPQ, and dynamic allodynia were measured at Visits 3 and 10.

Safety Assessments

Safety was evaluated by measuring discontinuation rates, treatment-emergent adverse events (TEAEs), serious adverse events, vital signs, weight, laboratory analyses, ECGs, frequency of significant hypoglycemic events, and electrophysiology assessments.

Statistical Analysis

All analyses were conducted on an intent-to-treat basis. Treatment effects were evaluated based on a two-sided significance level of 0.05, and interaction effects at 0.10. The change from baseline to endpoint (the last nonmissing observation after randomization) on the continuous efficacy measures was analyzed using an analysis of covariance (ancova) model with the terms of treatment, investigator, treatment-by-investigator interaction, and baseline scores. When the interaction was not statistically significant, the treatment-group contrasts were made from the model without interaction. Type II sum-of-squares for the least-squares means were used. Repeated measure analysis [24] was used as the secondary methodology to demonstrate the invariance of the results and the time course of the treatment effect. The model included terms of the treatment, investigator, visit, and treatment-by-visit interaction, as well as the covariate of baseline score and baseline-by-visit interaction. The unstructured covariance was used in the model, and the analysis was implemented using SAS PROC MIXED. An analysis of variance (anova) model with the terms of treatment and investigator was used to analyze the continuous safety measures or the corresponding rank-transformed data (labs and daily average of concomitant acetaminophen use). Proportions were analyzed using Fisher's exact test. Time to first response (30% reduction from baseline) and time to the first visit where sustained response was observed were analyzed by a log-rank test.

Path analysis [25,26] was used to assess the direct treatment effect on pain reduction after accounting for the possible treatment effect on mood. This analysis tested the null hypothesis that change in the 24-hour average pain score depended on change of mood, as measured by HAMD17 total score, versus the alternative that the reduction in 24-hour average pain score was due to a direct analgesic effect of the treatment and was independent of the treatment effect on mood.

Throughout the article, the term “significant” indicates statistical significance, and “mean change” refers to “least-squares mean change.”

Results

Patient Disposition

A total of 475 patients were screened to enroll 348 patients who met entry criteria and were randomly assigned to duloxetine 60 mg QD, duloxetine 60 mg BID, or placebo (116 patients in each group). Fifty-two (15%) patients withdrew for all reasons during the acute therapy phase, 15 (13%) from the duloxetine 60 mg QD group, 21 (18%) from the duloxetine 60 mg BID group, and 16 (14%) from the placebo group. Twenty-two (6.3%) patients discontinued due to adverse events, 5 (4.3%) from the duloxetine 60 mg QD group (P = 0.72 vs placebo), 14 (12.1%) from the duloxetine 60 mg BID group (P = 0.01 vs placebo), and 3 (2.6%) from the placebo group.

Baseline Clinical and Demographic Characteristics

The majority of the patients in the study were Caucasian (99.7%) with a mean age of 58.8 years (Table 1). The mean duration of diabetes was 13.8 years. Type 2 diabetes was the most prevalent (84.5%), and the mean MNSI score at the time of screening was 5.0. At baseline, there was a significant difference between treatment groups for the MNSI score, with placebo-treated patients having a slightly higher score (P = 0.036). At baseline, the mean dynamic allodynia score was 0.38 and HAMD17 total score was 3.89.

View this table:
Table 1

Demographics and baseline assessments

VariablePlacebo (N = 116)Duloxetine 60 mg QD (N = 116)Duloxetine 60 mg BID (N = 116)Total (N = 348)P Value
Age, years,* mean (SD)  59.2 (9.8)  58.3 (10.9)  59.0 (9.6)  58.8 (10.1)  0.711
Gender, N (%)  0.237
  Female  63 (54.3)  68 (58.6)  55 (47.4)186 (53.4)
Race (origin), N (%)>0.999
  Caucasian116 (100)115 (99.1)116 (100)347 (99.7)
  East/Southeast Asian   0   1 (0.9)   0   1 (0.3)
Weight, kg,* mean (SD)  87.2 (16.5)  83.3 (19.6)  87.1 (19.2)  85.9 (18.5)  0.128
Type of diabetes mellitus, N (%)  0.269
  Type 1  14 (12.1)  23 (19.8)  17 (14.7)  54 (15.5)
  Type 2102 (87.9)  93 (80.2)  99 (85.3)294 (84.5)
Duration of diabetes, years,* mean (SD)  12.8 (8.6)  14.6 (8.9)  13.9 (9.7)  13.8 (9.1)  0.372
Duration of DN, years,* mean (SD)   4.0 (3.5)   4.5 (4.4)   4.5 (4.6)   4.3 (4.2)  0.570
MNSI,* mean (SD)   5.2 (1.6)   4.9 (1.4)   4.8 (1.4)   5.0 (1.5)  0.036
Pain severity at baseline,* mean (SD)
  24-hour average pain severity   5.5 (1.3)   5.5 (1.1)   5.7 (1.3)   5.6 (1.2)  0.542
  24-hour worst pain severity   6.5 (1.4)   6.7 (1.3)   6.9 (1.3)   6.7 (1.4)  0.213
  Night pain severity   6.2 (1.7)   5.9 (1.7)   6.1 (1.6)   6.1 (1.7)  0.523
Mood and general illness at baseline,* mean (SD)
  HAMD17 total score   3.8 (3.2)   3.8 (3.7)   4.2 (3.1)   3.9 (3.3)  0.608
  CGI-Severity   4.5 (0.9)   4.6 (0.9)   4.5 (1.0)   4.5 (0.9)  0.563
  • * Means were analyzed using a Type III Sum of squares analysis of variance.

  • Frequencies were analyzed using a Fisher's exact test.

  • QD = once a day; BID = twice daily; SD = standard deviation; BPI = Brief Pain Inventory; CGI-Severity = Clinical Global Impressions of Severity; DN = diabetic neuropathy; MNSI = Michigan Neuropathy Screening Instrument; HAMD17 = 17-item Hamilton Depression Rating Scale.

Efficacy

In the mean change analyses, duloxetine 60 mg QD and 60 mg BID were statistically superior to placebo on the primary and all secondary measures (Table 2) except for HAMD17 total score and dynamic allodynia. After adjusting for the baseline MNSI score, the P value for the primary analysis did not change. There was no significant difference in efficacy measures between duloxetine 60 mg QD and 60 mg BID. The repeated measure analysis showed that duloxetine was significantly superior to placebo beginning 1 week after randomization and continuing through the study in the analyses of the 24-hour average pain (Figure 1), worst pain severity, and night pain scores. Duloxetine was significantly better than placebo in reducing BPI Severity scores for worst pain, least pain, average pain, and pain right now using both mean change analysis and repeated measure analysis (Figure 2). There were no statistically significant differences among treatment groups for study diary compliance.

View this table:
Table 2

Mean change in efficacy measures

Measure (Score Range)PlaceboDuloxetine 60 mg QDDuloxetine 60 mg BID
NMean Change (SE)NMean Change (SE)Between-Group Difference (95% CI) Versus PlaceboNMean Change (SE)Between-Group Difference (95% CI) Versus Placebo
Weekly mean score from patients diary
  24-hour average pain score113−1.60 (0.18)113−2.50 (0.18)***−0.90 (−1.39, −0.42)114−2.47 (0.18)***−0.87 (−1.36, −0.39)
  24-hour worst pain score113−2.03 (0.20)113−2.97 (0.20)***−0.95 (−1.51, −0.39)114−2.84 (0.20)**−0.81 (−1.37, −0.25)
  Night pain score113−1.87 (0.19)113−2.81 (0.19)***−0.94 (−1.46, −0.41)114−2.78 (0.19)***−0.92 (−1.45, −0.38)
BPI Severity
  Average pain109−1.82 (0.19)108−2.65 (0.19)**−0.84 (−1.36, −0.32)108−2.62 (0.19)**−0.81 (−1.33, −0.28)
  Worst pain109−2.20 (0.22)108−3.00 (0.22)*−0.80 (−1.41, −0.19)108−3.09 (0.22)**−0.89 (−1.50, −0.28)
  Least pain109−1.17 (0.18)108−1.98 (0.18)**−0.80 (−1.30, −0.31)108−1.86 (0.18)**−0.69 (−1.19, −0.19)
  Pain right now109−1.48 (0.21)108−2.25 (0.21)**−0.77 (−1.34, −0.19)108−2.56 (0.21)***−1.08 (−1.66, −0.50)
CGI Severity113−0.93 (0.09)110−1.42 (0.09)***−0.49 (−0.75, −0.23)109−1.40 (0.10)***−0.47 (−0.74, −0.20)
SF-MPQ total score101−4.96 (0.60)102−7.47 (0.61)**−2.51 (−4.20, −0.82)104−7.82 (0.61)***−2.86 (−4.54, −1.17)
PGI Improvement112  3.04 (0.10)109  2.50 (0.10)***−0.53 (−0.81, −0.26)111  2.54 (0.10)***−0.49 (−0.77, −0.21)
Hamilton depression rating scale101−0.55 (0.25)103−1.17 (0.25)−0.62 (−1.32, 0.07)100−0.65 (0.25)−0.10 (−0.80, 0.60)
Dynamic allodynia108−0.14 (0.04)108−0.22 (0.04)−0.08 (−0.19, 0.02)108−0.14 (0.04)−0.00 (−0.10, 0.10)
BPI Interference
  General activity109−1.38 (0.22)108−2.22 (0.22)**−0.84 (−1.46, −0.23)108−2.39 (0.22)**−1.01 (−1.63, −0.39)
  Mood109−1.76 (0.20)108−2.32 (0.20)−0.56 (−1.12, 0.01)108−2.60 (0.20)**−0.84 (−1.40, −0.28)
  Walking ability108−1.51 (0.22)108−2.50 (0.21)**−0.99 (−1.59, −0.40)108−2.68 (0.22)***−1.17 (−1.77, −0.56)
  Normal work109−1.45 (0.20)108−2.24 (0.20)**−0.78 (−1.35, −0.21)108−2.46 (0.21)***−1.01 (−1.58, −0.43)
  Relationships108−1.19 (0.18)108−1.56 (0.18)−0.37 (−0.86, 0.13)108−1.78 (0.18)*−0.59 (−1.09, −0.10)
  Sleep108−2.25 (0.24)108−3.30 (0.23)**−1.04 (−1.70, −0.39)107−3.00 (0.24)*−0.75 (−1.41, −0.08)
  Enjoyment of life109−1.79 (0.22)108−2.63 (0.22)**−0.83 (−1.44, −0.23)108−2.64 (0.22)**−0.84 (−1.44, −0.25)
  Average of seven questions109−1.56 (0.18)108−2.43 (0.18)***−0.88 (−1.38, −0.38)108−2.54 (0.18)***−0.98 (−1.49, −0.47)
  • * P < 0.05 versus placebo;

  • ** P < 0.01 versus placebo;

  • *** P < 0.001 versus placebo.

  • Least square means at endpoint.

  • BPI = Brief Pain Inventory; CGI = Clinical Global Impressions; PGI = Patient's Global Impression; SE = standard error; SF-MPQ = Short-Form McGill Pain Questionnaire; CI = confidence interval; QD = once daily; BID = twice daily.

Figure 1

Mean change in 24-hour average pain severity score. **P ≤ 0.01 versus placebo; ***P ≤ 0.001 versus placebo.

Figure 2

Brief Pain Inventory individual severity score. *P ≤ 0.05 versus placebo; **P ≤ 0.01 versus placebo; ***P ≤ 0.001 versus placebo.

Both duloxetine groups were superior to placebo on CGI-Severity and PGI-Improvement scores, and demonstrated an improvement in the total score of the sensory component of the SF-MPQ. The 24-hour average pain severity response rate at endpoint showed significant superiority for both duloxetine 60 mg QD (68.14%, P < 0.001) and duloxetine 60 mg BID (64.04%, P = 0.002) compared with placebo (43.36%). A 50%, 75%, and 100% reduction in the 24-hour average pain response rate at endpoint was achieved by 30%, 11%, and 4% of patients, respectively, in the placebo group, 50%, 20%, and 5% of patients, respectively, in the duloxetine 60 mg QD group, and 39%, 22%, and 8% of patients, respectively, in the duloxetine 60 mg BID group. Duloxetine 60 mg QD (60.18%, P = 0.002) and duloxetine 60 mg BID (57.02%, P = 0.008) also demonstrated significant superiority to placebo (38.94%) at achieving sustained response at endpoint. Compared with placebo, patients in both of the duloxetine treatment groups achieved first response and sustained response in a significantly shorter amount of time (P < 0.001).

The path analysis for the 24-hour average pain score showed that the direct treatment effect of duloxetine on pain accounted for the major portion of the total effect (98.0% and 92.7% for duloxetine 60 mg BID and 60 mg QD vs placebo, respectively).

The mean average daily dose for concomitant use of acetaminophen for DPNP (placebo-treated group: 202.52 mg, duloxetine 60 mg QD-treated group: 151.88 mg, duloxetine 60 mg BID-treated group: 121.65 mg) indicated significant treatment-group differences between duloxetine 60 mg BID and placebo (P = 0.040). The mean change analysis of 24-hour average pain adjusted for the concomitant acetaminophen use still showed significant superiority of both duloxetine groups to the placebo group.

In the BPI Interference scale, both duloxetine doses were significantly superior to placebo at reducing scores in all measures (P < 0.05), except relationship with other people item (P = 0.146) and mood item (P = 0.053) for 60 mg QD-treated patients (Table 2).

Safety

Of the 348 randomly assigned patients, 57 (49.1%) placebo-, 71 (61.2%) duloxetine 60 mg QD- (P = 0.086 vs placebo), and 73 (62.9%) duloxetine 60 mg BID- (P = 0.047 vs placebo) treated patients reported at least one TEAE. Patients in both duloxetine groups reported treatment-emergent nausea, somnolence, hyperhidrosis, and anorexia significantly more frequently than placebo-treated patients. Additionally, vomiting and constipation were reported by duloxetine 60 mg BID-treated patients significantly more frequently than placebo-treated patients. Twenty-two patients discontinued during the therapy phase due to adverse events (duloxetine 60 mg QD, 5 [4.3%]; duloxetine 60 mg BID, 14 [12.1%]; placebo 3 [2.6%]), with significant differences between duloxetine 60 mg BID- and placebo-treated groups (P = 0.010). Eighty-six percent of patients who discontinued due to adverse events did so during the first 4 weeks of the study. Vomiting (3.4%) and nausea (1.7%) were reported as reasons for discontinuation in >1% of duloxetine 60 mg BID-treated patients. Ten (2.9%) patients experienced 13 serious adverse events with no significant treatment-group differences. These included 4 (3.4%) placebo-treated patients (events: anemia, cerebrovascular accident, chest pain, chronic obstructive airways, dyspnea, melaena, pneumonia), 4 (3.4%) duloxetine 60 mg QD-treated patients (events: atrial fibrillation, cholecystitis, diabetes mellitus, nephrolithiasis), and 2 (1.7%) duloxetine 60 mg BID-treated patients (events: urinary calculus, ventricular extrasystoles). The weekly average of significant hypoglycemic events showed no significant differences between treatment groups.

Duloxetine 60 mg QD-treated patients experienced a mean increase in alkaline phosphatase, aspartate transaminase/serum glutamic oxaloacetic transaminase, inorganic phosphorous, fasting glucose, and uric acid compared with placebo-treated patients. Duloxetine 60 mg BID-treated patients experienced a mean increase in cholesterol, alkaline phosphatase, low-density lipoprotein cholesterol, and bicarbonate HCO3, and a mean decrease in urea nitrogen compared with placebo treated patients. These mean differences were transient, and generally of low magnitude and not considered to be clinically relevant. There were no significant treatment-group differences observed in any of the mean change analyses of electrophysiology measures.

There was a slight but significant mean decrease in weight from baseline to endpoint for duloxetine 60 mg BID- (mean change [SD]: −0.90 kg [2.39]; P = 0.006) treated patients compared with placebo-treated patients. There was a significant mean increase in heart rate from baseline to endpoint for duloxetine 60 mg BID- (mean change [SD] beats/minute: 4.22 [10.72]; P = 0.005 vs duloxetine 60 mg QD; P < 0.001 vs placebo) treated patients compared with duloxetine 60 mg QD- (mean change [SD]: 0.47 [9.02]), and placebo- (mean change [SD]: −0.82 [10.97]) treated patients. These changes were not of clinically relevant magnitude. There were no significant treatment-group differences in mean change of systolic and diastolic blood pressure. Seventeen patients (7 [6.1%] placebo-, 4 [3.5%] duloxetine 60 mg QD-, and 6 [5.2%] duloxetine 60 mg BID-treated) experienced sustained elevation of blood pressure (defined as a sitting diastolic blood pressure ≥85 mm Hg and an increase from baseline of at least 10 mm Hg, or sitting systolic blood pressure ≥130 mm Hg and an increase from baseline of at least 10 mm Hg, for three consecutive visits), but the treatment-group differences were not significant.

Placebo-treated patients experienced mean increases in QT interval and PR interval compared with duloxetine 60 mg BID-treated patients who experienced mean decreases in QT interval (mean change [SD]: −10.44 [25.76]; P < 0.001) and PR interval (mean change [SD]: −4.14 [14.81]; P = 0.006).

Twenty-three of the 348 patients reported at least one adverse event that emerged during the 1-week drug taper phase (7 [6.0%] duloxetine 60 mg BID-treated group, 8 [6.9%] duloxetine 60 mg QD-treated group, and 8 [6.9%] placebo-treated group, all events reported in <1% of patients except hypertension [1.7%] in duloxetine 60 mg BID-treated patients), with no significant treatment-group differences in the overall incidence of taper-emergent adverse events or in any single taper-emergent adverse event.

Discussion

In this randomized, double-blind, 12-week trial, duloxetine at doses of 60 mg QD and 60 mg BID had significantly greater efficacy than placebo on most outcome measures in the management of patients with DPNP. Compared with placebo, both doses of duloxetine significantly reduced pain, beginning in the first week of management and continuing throughout the 12 weeks of therapy. Response rates demonstrated greater pain reduction for both duloxetine groups compared with placebo, and patients in the duloxetine groups were more likely to achieve a sustained response over time. Farrar et al. 2001 [27] analyzed the pooled results of 10 placebo-controlled studies involving patients with chronic pain syndromes (diabetic neuropathy, postherpetic neuralgia, chronic low back pain, fibromyalgia, and osteoarthritis) in order to corroborate the association between change in pain intensity numeric rating scale and an improvement in quantifiable measures of clinical status. Their results indicate that on average a reduction of approximately two points from baseline on an 11-point pain rating scale (shown to be equivalent to a 30% reduction on pain severity from baseline) corresponds to a clinically meaningful improvement. In this study, the 24-hour average pain severity was reduced about two points and the response rate (defined as 30% reduction from baseline to endpoint) showed significant superiority for both duloxetine 60 mg QD and duloxetine 60 mg BID compared with placebo. Significant pain reduction was observed on the 24-hour worst, and night pain scores, respectively, thus stressing the clinical relevance of duloxetine in the management of DPNP.

A significant treatment effect was observed for both duloxetine treatment groups for most BPI Interference items. Duloxetine was not statistically superior to placebo on the HAMD17 total score and dynamic allodynia. Given the dynamic allodynia rating at baseline of less than 1 on a scale of 0–3, the patients did not have much room for improvement on this measure.

Duloxetine is known to be an effective antidepressant, raising the question as to how much of the pain reduction effect may be attributed to relief of depressive symptoms, and what would be the impact on mood when the drug was used for the management of pain on patients who do not have MDD. The potential confounding relationship between pain and mood was recognized when this study was designed, which is why patients with a clinical diagnosis of depression were excluded. This does not preclude the possibility that patients had subclinical depression. Thus, HAMD17 was used to measure the mood change in the trial and the change in HAMD17 was taken into account for the evaluation of pain reduction by the path analysis. A HAMD17 score of ≤7 is often used as an indicator of remission in the MDD population. In this study, since patients with a clinical diagnosis of depression were excluded, the HAMD17 score at baseline was low (3.89) and well below the standard remission criterion. This might explain the lack of an antidepressant effect observed in this study. The path analysis showed that the reduction of pain was a direct treatment effect on pain modulation, and cannot be attributed to an antidepressant effect. In addition, the analyses on HAMD17 total showed that the mean changes from baseline to endpoint were very similar between duloxetine-treated patients and placebo-treated patients, which suggests that duloxetine has a neutral effect on mood for those patients who do not have clinically diagnosed MDD.

Duloxetine is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition [14]. These results confirm findings from previous studies where duloxetine 60 mg QD and 60 mg BID demonstrated superiority over placebo in improving DPNP [15,16], and are consistent with data that suggest that drugs with inhibition of 5-HT and NE reuptake are effective in the management of DPNP [28]. These results are also consistent with findings that duloxetine is effective in treating pain in animal models [13] and in reducing severity of painful physical symptoms in depressed patients [29–31]. Since noradrenergic and serotonergic neurons modulate the endogenous pain inhibitory pathways [9,10], the ability of duloxetine to exert its effects on both these neurotransmitter systems may explain its effectiveness in this clinical trial.

In the present study, there were no significant differences between the duloxetine 60 mg QD and duloxetine 60 mg BID treatment groups in efficacy outcomes. However, the study was not adequately powered to detect a difference between duloxetine 60 mg QD and duloxetine 60 mg BID treatment groups. Patients treated with duloxetine 60 mg BID took significantly less concomitant acetaminophen during the study than placebo-treated patients, and this finding provided some evidence of additional efficacy of duloxetine 60 mg BID.

Both doses of duloxetine were well tolerated by most patients and safely administered. Significantly more duloxetine 60 mg BID-treated patients than placebo-treated patients reported TEAEs, but these events were generally mild to moderate in severity. Although 17 patients had sustained elevation in blood pressure, several factors may explain this rate. The majority of patients (73.6%) were known to have hypertension as a secondary condition, and 7.2% of patients were known to have diabetic nephropathy, which predisposed them to elevated blood pressure. Although observed, sustained elevations in blood pressure were not likely to result from duloxetine use, as four placebo- versus one duloxetine 60 mg QD- and two duloxetine 60 mg BID-treated patients experienced sustained elevation in blood pressure. Duloxetine treatment did not result in QTc prolongation. The lack of significant cardiovascular changes due to duloxetine therapy in these patients and other studies [29,30,32,33] suggests that patients with diabetes mellitus do not require more intensive assessment of their cardiovascular status when treated with duloxetine than they require for their underlying diabetes. There were no treatment-group differences in any of the electrophysiology measures of nerve function, indicating that the reduction in pain was not related to deterioration of nerve function. Clinical laboratory assessments, vital signs, and physical findings were stable relative to baseline and no clinically relevant differences were detected between treatment groups.

Significantly more patients in the duloxetine 60 mg BID group than the placebo group discontinued treatment due to adverse events. Most patients who discontinued due to adverse events did so within the first 4 weeks of the study. This could be due to the titration of duloxetine in which patients were started on 60 mg QD and underwent titration to 60 mg BID over just 3 days, suggesting that some patients would have better tolerability with a lower duloxetine starting dose and slower titration.

Several limitations of this study should be considered. The results are based on an acute treatment trial of 12 weeks, and may not generalize to a longer duration of treatment, and DPNP, a chronic condition, likely requires management for more than 12 weeks. Further evaluation of the long-term efficacy of duloxetine on DPNP would be required to assess the effects on progression of neuropathy. Since patients were selected from among those with very limited or stable medical conditions, and stable doses of concomitant medications, the generalizability of the results to typical outpatients is limited.

In summary, this randomized, placebo-controlled study provides substantial evidence and confirms previously reported findings that treatment with duloxetine 60 mg QD and 60 BID for up to 12 weeks is safe and effective in the management of DPNP.

Acknowledgments

The authors thank David J. Goldstein, MD, PhD, Mark Demitrack, MD, and the Duloxetine Product Team for their contributions to the design and implementation of this clinical trial, the clinical investigators, staff, and patients for their participation in this clinical trial. The authors also thank Barry Brolley and Bruce Spotts for their statistical programming support.

References

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