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Psychosomatics 45:17-28, February 2004
© 2004 The Academy of Psychosomatic Medicine

Effects of Duloxetine on Painful Physical Symptoms Associated With Depression

David J. Goldstein, M.D., Ph.D., Yili Lu, Ph.D., Michael J. Detke, M.D., Ph.D., James Hudson, M.D., Sc.D., Smriti Iyengar, Ph.D., and Mark A. Demitrack, M.D.

Presented in part at the 23rd Collegium Internationale Neuro-Psychopharmacologicum Congress, Montreal, June 23–27, 2002. Received July 16, 2002; revision received March 27, 2003; accepted April 15, 2003. From the Department of Psychiatry and the Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis; PRN Consulting, Indianapolis; the Joint Antidepressant Team—Cymbalta, Lilly Research Laboratories, Indianapolis; the Department of Psychiatry, Harvard Medical School; the Psychiatric Epidemiology Laboratory, McLean Hospital, Belmont, Mass.; and the Department of Neuroscience, Wyeth Pharmaceuticals, Radnor, Pa. Address reprint requests to Dr. Goldstein, PRN Consulting, 1212 Kirkham Lane, Indianapolis, IN 46260; DJGoldstein{at}consultPRNC.com (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Painful physical symptoms are common features of major depressive disorder and may be the presenting complaints in primary care settings. The effect of the dual serotonin (5-HT) and norepinephrine reuptake inhibitor duloxetine on emotional and painful physical symptoms in outpatients with major depressive disorder was evaluated in three randomized, double-blind, placebo-controlled trials. The trials' primary objective was to evaluate the effect of duloxetine on mood, and subjects were not enrolled on the basis of presence, type, or severity of pain. However, the pain-relieving effects of duloxetine were evaluated by a priori defined analyses of results from a visual analogue scale and the Somatic Symptom Inventory. Compared with placebo, duloxetine was associated with significant reduction in pain severity. The authors concluded that duloxetine reduces the painful physical symptoms of depression.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
The full spectrum of symptoms of major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)1 includes both emotional and physical symptoms. In clinical populations of depressed patients, physical symptoms, such as pain, are well documented2,3 and common4 and may be of greater importance to patients than the mood disturbance. In a multicenter, international epidemiologic study, 69% of the patients who met the criteria for depression reported physical symptoms as their only reason for consulting a physician.5 In the general population, depression commonly coexists with a wide variety of physical symptoms, such as widespread pain,6 unexplained gastrointestinal pain,7 and headache.8 In patients who present with physical complaints, up to 60% have painful physical complaints, including headache, back pain, stomachache, and poorly localized musculoskeletal pains.9,10 In many of these patients, particularly those seen in nonpsychiatric settings where most depression treatment occurs and as many as 80% of depressed patients present with unexplained physical symptoms, physical symptoms obscure the accurate clinical diagnosis of depression.3,11–19 In many other cases, the treating physician may assume that treatment of the mood disorder will lead to resolution of the physical symptoms and may ignore these symptoms altogether. Failure to address physical complaints, however, may adversely affect the treatment of depression.20,21

The existence of pain in depression is important because painful physical symptoms substantially contribute to direct and indirect health care costs, including disability and reduced productivity.22 Patients with painful physical symptoms as part of their depression take more medications and have worse outcomes, more frequent health care visits, more diagnostic testing, and more referrals to specialists than depressed patients without pain.23

Depression and pain are thought to be mediated by the neurotransmitters serotonin (5-HT) and norepinephrine by means of different but overlapping neuroanatomical pathways. Depression is believed to be mediated by 5-HT and norepinephrine through the raphe nucleus and locus coeruleus projections to the cerebral cortex and forebrain limbic system,24 whereas pain is believed to be mediated in part through descending 5-HT and norepinephrine pain pathways that provide inhibitory input to the dorsal horn neurons in the spinal cord.25–28 Despite differences in the neuroanatomy of these pathways, global deficiencies in 5-HT or norepinephrine neurotransmission would be predicted to affect both mood and pain thresholds, possibly accounting for the high comorbidity of painful symptoms in patients with depression. Accordingly, enhancement of both 5-HT and norepinephrine reuptake by dual reuptake inhibitors, such as duloxetine, would be expected both to improve symptoms of depression and to normalize pain thresholds.

The effects of antidepressants have been studied in various painful conditions,17,19,29–32 and evidence clearly shows that the use of a medication with both 5-HT and norepinephrine reuptake inhibition provides greater effectiveness in treating painful conditions than a medication with only selective 5-HT reuptake inhibition.32,33 Thus, we were interested in evaluating the effects on painful physical symptoms of duloxetine, a potent and selective inhibitor of 5-HT and norepinephrine reuptake in vitro and in vivo.34 Previously, duloxetine had been shown to have analgesic effects in several animal models of chronic pain, including the formalin test, capsaicin test, carrageenan test, and both the Chung and Selzer tests of nerve ligation injury.35,36

Despite the obvious clinical significance of physical symptoms such as pain in depression, clinical trials of antidepressant medications have largely ignored the evaluation of physical symptoms. To investigate the effects of treatment with duloxetine on painful physical symptoms in patients with depression, we incorporated pain measures into three placebo-controlled studies that were done primarily to evaluate the efficacy of duloxetine in treating depressed mood. The results of these three trials37–39 demonstrated that duloxetine improved painful physical symptoms in addition to reducing the severity of depressed mood. Here, we further evaluate the effect of duloxetine on the physical symptoms of pain in patients with depression and consider whether the effects on depressed mood are related to the effects on painful physical symptoms.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
Study 137 was a randomized, multicenter, double-blind, placebo- and active-comparator-controlled study that was designed to assess the effectiveness of 40 mg/day of duloxetine (two 20-mg doses per day) and 80 mg/day of duloxetine (two 40-mg doses per day), compared with placebo and 20 mg/day of paroxetine (one 20-mg dose per day) in patients with major depressive disorder during 8 weeks of treatment. Patients (N=353) were randomly allocated to each treatment.

Study 238 and study 339 were two randomized, multicenter, double-blind, placebo-controlled studies conducted by using the same protocol and designed to assess the effectiveness of a once daily dose of 60 mg of duloxetine, compared with placebo, in patients with major depressive disorder during 9 weeks of treatment. Patients (N=245 for study 2 and N=267 for study 3) were randomly assigned to receive 60 mg/day of duloxetine or placebo.

Patients
The patients in all three studies were at least 18 years old and had a diagnosis of DSM-IV1 major depressive disorder that was confirmed by means of the Mini-International Neuropsychiatric Interview.40 Patients were recruited primarily through advertisement, and most of the investigators were psychiatrists. Patients were required to have a rating of at least 4 (moderate) on the Clinical Global Impression (CGI)41 of severity and a total score of at least 15 on the 17-item Hamilton Depression Rating Scale42 at the screening and randomization visits. Patients were excluded if they had any current primary DSM-IV diagnosis other than major depressive disorder; a prior diagnosis of bipolar disorder, psychosis, or schizoaffective disorder; or any anxiety disorder as a primary diagnosis within the year preceding enrollment. Patients were also excluded if they had a history of substance abuse or dependence within the past year or a positive urine drug screen or if they had failed to respond to two or more adequate courses (at least 4 weeks of treatment) of antidepressant therapy for their current episode of depression. Patients were not selected for the presence or absence of pain; however, patients in study 1 could not use prescription analgesics for pain. The appropriate institutional review boards reviewed the protocols, and all patients or their authorized legal representative gave written informed consent.

Efficacy Measures
At each visit during the studies, the patients' mood was assessed with the Hamilton depression scale. In addition, the severities of overall pain, headache, back pain, and shoulder pain; time in pain while awake; and the amount that pain interfered with daily activities were assessed by means of 100-mm visual analogue scales.43 The pain severity visual analogue scale was anchored by "no pain" on one end and "as severe as I can imagine" on the other. The time in pain visual analogue scale was anchored by "none" and "all the time." The interference visual analogue scale was anchored by "none" and "complete." Somatic symptoms were assessed at baseline and at the end of double-blind therapy by using the Somatic Symptom Inventory. The original Somatic Symptom Inventory consists of 26 somatic symptoms and evaluates how much the patient has been "bothered" from "not at all" to "a great deal."44 Two additional items, "pain in your joints" and "neck pain," were added because these complaints are common among patients with depression,10 and they were not represented in the original instrument. The mean score of the 28-item Somatic Symptom Inventory was used to evaluate the treatment effect on somatic symptoms. In addition, the Somatic Symptom Inventory pain score—the mean score for the seven pain-related items (items 2, 3, 9, 14, 19, 27, and 28) in the 28-item Somatic Symptom Inventory—was used in the efficacy analysis. Data from the CGI, the Patient Global Impression of Improvement Scale,45 and Quality of Life in Depression Scale46 were also used.

Statistical Analysis
Given that the outcome measures analyzed in this report are secondary measures from studies designed primarily to evaluate the effectiveness of duloxetine on the treatment of depressive symptoms, no adjustment for multiple comparisons was made.

All analyses were conducted on an intent-to-treat basis. All patients who were randomly assigned to a study group and who had a baseline value and at least one postbaseline value for an outcome measure were included in the analysis for that particular measure. Main effects were tested at a two-sided significance level of 0.05, and interactions were tested at a significance level of 0.10 per protocol. In this report, the term "significant" indicates "statistically significant."

Longitudinal observations for overall pain severity as measured by the visual analogue scale and for somatic symptoms as measured by the Somatic Symptom Inventory were analyzed by using a mixed-effects model for repeated measures. The model included the fixed, categorical effects of treatment, investigator, visit, and the treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline scores and the baseline-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors. The primary treatment comparisons were the contrasts between the duloxetine treatment group and the placebo group at the last visit of double-blind therapy (week 8 or 9). The least squares mean changes are presented with standard errors.

The baseline-to-endpoint (the last non-missing observation during the postbaseline visits) change scores on the visual analogue scale assessments were transformed by rank and analyzed by using a two-way analysis of variance (ANOVA) model with the terms of treatment and investigator, given that the distribution of those variables was skewed and that, in some cases, heterogeneity of variance was observed. For change in visual analogue scale scores, median and the 25% and 75% quartiles are presented. For the visual analogue scale measure of overall pain severity, the area under the curve (AUC) of the visit-wise improvement scores (postbaseline minus baseline) over the visit intervals was calculated by using the trapezoidal approach. The AUC provides valid assessment of improvement by accounting for the magnitude of change in pain severity together with the duration of the treatment, as recommended by the U.S. Food and Drug Administration's guidelines.47 The greater the AUC value, the greater the patient's improvement in overall pain severity during the treatment. The rank-transformed AUC values were analyzed by using the two-way ANOVA model because of the skewed distribution of the data.

Spearman's correlation coefficients were computed to test the correlations between study measures in baseline-to-endpoint change in scores. The correlation pairs were change in score on the visual analogue scale for overall pain severity and change in Hamilton depression scale total score, change in score on the visual analogue scale for overall pain severity and change in Somatic Symptom Inventory pain score, and change in Hamilton depression scale total score and change in CGI rating.

In addition, patients were assigned to two subgroups on the basis of their baseline scores on the visual analogue scale for overall pain severity and their Somatic Symptom Inventory pain items. Patients with scores in the lower 30th percentile for each scale (scores <30 for the visual analogue scale and <2.2 for the Somatic Symptom Inventory pain score) were considered to be without pain at baseline. Since the patients enrolled in these studies were not screened for any predefined pain symptom, considering those patients who had a pain measure that was greater than or equal to the 30th percentile to be the ones with baseline pain was a reasonable approach. No significant treatment-by-subgroup interaction was observed for subgroups defined by baseline scores on the visual analogue scale for overall pain severity. However, a statistically significant treatment-by-subgroup interaction (p<0.10) was observed for the subgroup defined by baseline Somatic Symptom Inventory pain score. The effect of duloxetine treatment was much greater among patients with a high baseline Somatic Symptom Inventory pain score (>=2.2) than among those with a low Somatic Symptom Inventory pain score (<2.2). Nevertheless, in both of these subgroups, the reduction from baseline in score on the visual analogue scale for overall pain severity was significantly greater (p<=0.05) in the duloxetine group (–17.03 and –5.81, respectively) than in the placebo group (–7.69 and –2.41, respectively).


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
The demographic characteristics and the results of pain assessments at baseline of the patients in these studies were similar across treatment groups and across studies (Table 1). At baseline, the overall pain severity score was at least 30 (0–100 scale) in 122 (34.6%) of the patients in study 1, 98 (40.0%) in study 2, and 95 (35.6%) in study 3.


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TABLE 1. Baseline Demographic and Clinical Characteristics of Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms



Efficacy
Pain scores. Figure 1 shows the changes over time from baseline in the score on the visual analogue scale for overall pain severity by treatment in the three studies. In study 1, treatment with duloxetine led to dose-related decreases from baseline in overall pain severity from week 2 through week 8 of treatment. Patients treated with 80 mg/day of duloxetine had significantly greater reduction in overall pain severity than those in the placebo group at weeks 6 and 8 (p<0.05). In studies 2 and 3, treatment with 60 mg/day of duloxetine also resulted in significantly greater reduction in overall pain severity, compared with placebo, within 2 weeks of the start of treatment. In study 2, the reduction in overall pain severity in the group that received 60 mg/day of duloxetine was significantly greater than that in the placebo group from week 2 through week 7, but not at week 9 (p=0.055). In study 3, reduction in overall pain severity in the group that received 60 mg/day of duloxetine was significantly greater than that in the placebo group from week 2 through week 5.



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FIGURE 1.  Change From Baseline in Overall Pain Severity Scores of Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms

aSignificant difference, compared with placebo, p<=0.05.

bSignificant difference, compared with placebo, p<=0.001.

cSignificant difference, compared with placebo, p<=0.01.


Median baseline-to-endpoint change scores for the six visual analogue scale assessments are shown in Table 2. In study 1, the decreases from baseline were significantly greater in the group that received 80 mg/day of duloxetine than in the placebo group for overall pain severity (p=0.005), severity of shoulder pain (p<0.03), and time in pain while awake (p<0.03). In study 2, the reductions from baseline were significantly greater in the group that received 60 mg/day of duloxetine than in the placebo group for overall pain severity (p=0.01), severity of back pain (p=0.009), and severity of shoulder pain (p=0.003). In study 3, the reduction from baseline was significantly greater in the group that received 60 mg/day of duloxetine than in the placebo group for severity of overall pain (p<0.05).


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TABLE 2. Change From Baseline to Last Observation in Scores on Visual Analogue Scales of Pain Severity, Time in Pain, and Interference of Pain With Daily Activities of Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms



Figure 2 shows the median scores for the AUCs for visual analogue scale overall pain severity in the three studies. The AUCs for overall pain severity for the groups that received 40 mg/day of duloxetine (AUC=132.0) and 80 mg/day of duloxetine (AUC=139.5) in study 1 were significantly greater than that for the placebo group (AUC=0.0) (p=0.016 and p=0.004, respectively). The AUC for the group that received 60 mg/day of duloxetine was significantly greater than those for the placebo group in study 2 (p=0.009) and in study 3 (p<0.02). In addition, in study 1, the AUCs for back pain severity for the groups that received 40 mg/day of duloxetine (AUC=59.0) and 80 mg/day of duloxetine (AUC=24.5) were significantly greater than that for the placebo group (AUC=0.0) (p=0.008 and p=0.03, respectively). Also, the AUC for time in pain while awake for the groups that received 40 mg/day of duloxetine (AUC=263.0) and 80 mg/day of duloxetine (AUC=110.5) were significantly greater than that for the placebo group (AUC=0.0) (p=0.005 and p<0.05, respectively). The AUC for shoulder pain was significantly greater for the group that received 80 mg/day of duloxetine (AUC=36.8) than that for the placebo group (AUC=0.0) (p=0.005). It is noteworthy that, in study 2, the AUC for the group that received 60 mg/day of duloxetine was significantly greater than that for the placebo group for severity of back pain (AUC=115.5 and AUC= 35.0, respectively; p<0.02), severity of shoulder pain (AUC=6.0 and AUC=0.0, respectively; p=0.003), and interference with daily activities (AUC=0.0 and AUC=–46.0, respectively; p<0.03). In general, the findings from the AUC analyses were consistent with those from the analyses of mean change from baseline in visual analogue scale overall pain score (Table 2). It is noteworthy that the median durations of exposure were identical for the placebo group and the duloxetine groups at both doses in study 1 (56 days) and for the placebo groups and the groups that received 60 mg/day of duloxetine in studies 2 and 3 (63 days). Mean durations of exposure were slightly lower for the duloxetine group or groups than for the placebo group in all studies.



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FIGURE 2.  Area Under the Curve (AUC) for Visual Analogue Scale Overall Pain Severity Scores for Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms

aSignificant difference, compared with the placebo group (p<=0.01).

bFor the placebo group, AUC=0.


Table 3 presents the mean changes from baseline to endpoint for the score on Hamilton depression scale item 13 (somatic symptoms general, which measures aches, fatigue, etc.), the Somatic Symptom Inventory total score, and the Somatic Symptom Inventory pain score. Among the four treatment groups in study 1, the reduction was greatest in the group that received 80 mg/day of duloxetine for both Somatic Symptom Inventory scores, although no significant differences were observed among the treatment groups. For studies 2 and 3, the reduction from baseline to endpoint was greater in the group that received 60 mg/day of duloxetine than in the placebo group for both Somatic Symptom Inventory scores, and the difference was significant for the Somatic Symptom Inventory pain score in study 2 (p<0.05).


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TABLE 3. Change From Baseline to Last Observation in Scores on Hamilton Depression Rating Scale Item 13 and the Somatic Symptom Inventory for Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms



It is interesting to note that Hamilton depression scale item 13, which assesses physical symptoms, particularly painful ones, showed significantly greater decreases for the duloxetine groups than for the placebo groups in study 1 (p<0.04 for the group that received 80 mg/day of duloxetine) and study 2 (p<0.02), consistent with the Somatic Symptom Inventory pain scores.

Correlations. To examine the relationship between improvement in pain severity and improvement in depressive symptoms, the correlations between change from baseline to endpoint in the overall pain severity score and the change from baseline to endpoint in the Hamilton depression scale score were calculated (Table 4). For comparison, the correlations between change in the Hamilton depression scale score and change in the CGI score, and between change in the overall pain severity score and change in the Somatic Symptom Inventory pain score were also calculated and are presented in Table 4. In all the studies, the correlations of change in the overall pain severity score with change in the Hamilton depression scale score were low (rs=0.11–0.30), and only the group that received 80 mg/day of duloxetine in study 1 had a statistically significant correlation. In contrast, the correlations between change in the Hamilton depression scale score and change in the CGI score were all high (rs>0.75) and highly significant (p<0.001), and the coefficients for the correlations between change in the overall pain severity score and change in the Somatic Symptom Inventory pain score were moderate to high (rs=0.32–0.72) and highly significant (p<0.001) for all treatments in all three studies.


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TABLE 4. Correlations Between Measures of Change From Baseline to Endpoint in Pain, Depressed Mood, and Clinical Impression for Patients With Major Depressive Disorder in Three Studies Evaluating the Effects of Duloxetine on Painful Physical Symptoms



Subgroup analysis of scores on the visual analogue scale for overall pain severity. No significant treatment-by-subgroup interactions were observed for the demographic subgroups, indicating that the superior improvement in score on the visual analogue scale for overall pain severity in the duloxetine group relative to the placebo group was not affected by the patients' age, gender, or racial origin.

No significant treatment-by-subgroup interaction was observed for subgroups defined by baseline scores on the visual analogue scale for overall pain severity. However, a statistically significant treatment-by-subgroup interaction (p<0.10) was observed for the subgroups defined by baseline Somatic Symptom Inventory pain scores. The effect of duloxetine treatment was much greater among patients with a high baseline Somatic Symptom Inventory pain score (>2.2) than among those with a low Somatic Symptom Inventory pain score (<2.2). Nevertheless, the reduction from baseline in scores on the visual analogue scale for overall pain severity was significantly greater within each of these subgroups for the patients who received duloxetine than for those who received placebo (–17.03, compared with –7.69 and –5.81, compared with –2.41, respectively) (p<0.05).


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
The full spectrum of symptoms of DSM-IV major depressive disorder includes both emotional and physical symptoms. The physical symptoms of depression are common2,3 and well documented. In clinical populations of depressed patients, physical symptoms, such as musculoskeletal pain and abdominal pain, are well documented.3,6–8,12,16–19 In the general population, depression commonly coexists with a wide variety of physical symptoms, including various painful symptoms such as widespread pain, headache, and chest pain. 5-HT and norepinephrine pathways, which ascend to affect traditional emotional symptoms of depression and which descend through the brainstem and spinal cord to inhibit pain, may explain this coexistence of pain and depression.

We included measures such as a visual analogue scale for pain severity and the Somatic Symptom Inventory, which are intended to measure painful physical symptoms, in the design of three clinical studies of the effects of duloxetine in major depressive disorder to evaluate whether duloxetine might relieve the painful symptoms of patients with depression who were not selected on the basis of the presence, type, or severity of pain. Despite the exploratory nature of this evaluation, duloxetine was effective in treating both the mood and painful physical symptoms of depressed patients. Improvement of the a priori declared primary outcome measure, the Hamilton depression scale total score,42 was significantly greater in patients treated with duloxetine than in those who received placebo. Moreover, duloxetine significantly improved additional efficacy measures of mood, anxiety, and patient-reported quality of life.38,39,48

In addition to its effects on the emotional symptoms of depression, duloxetine treatment also led to statistically significant improvement in painful physical symptoms as measured by visual analogue scale assessments and Somatic Symptom Inventory pain score. The effect of duloxetine on overall pain severity as measured by the visual analogue scale was robust and confirmed by several analytic methods: repeated measures analysis, analysis of mean changes in scores, and the analysis of the AUC. Given that the study patients were not screened for the presence of pain or painful conditions and that the number of patients whose data were analyzed was not adjusted to detect treatment group differences in any pain assessment, the overall pain severity measure would be expected to be available for the highest possible number of study patients and, thus, would be the most likely to demonstrate a treatment effect. Nevertheless, this effect was also reflected by the significantly greater reduction in back pain and in shoulder pain in the duloxetine group in some of the studies and by the consistent trend in favor of duloxetine across studies and assessments. In addition, studies 2 and 3 showed significant differences in change from baseline in scores on the visual analogue scale for overall pain severity between the group that received 60 mg/day of duloxetine and the placebo group starting at week 2. These findings suggest that the pain-relieving effect of duloxetine on the painful physical symptoms of depression may be considerable, but this effect will require further evaluation in studies specifically designed to demonstrate an analgesic effect.

The overall effect of the treatment should account for both the magnitude of change in severity and the duration of the treatment effect; the result from the AUC analysis provides the best assessment of this overall effect. Duloxetine demonstrated a substantial effect in reducing pain severity over the duration of the study by AUC analysis. Although this finding could have been biased by the differential durations of exposure between treatment groups, the exposures were virtually identical between treatments within studies. The improvement in pain severity indicated by the AUC equates to pain relief that is of benefit to patients and improves quality of life.49

The results of the subgroup analysis of scores on the visual analogue scale for overall pain severity suggest that the effectiveness of duloxetine in reducing painful physical symptoms was unrelated to patients' demographic characteristics or baseline pain conditions. Nevertheless, patients who had greater baseline severity of physical symptoms, as assessed by the Somatic Symptom Inventory pain score, had greater improvement in overall pain.

As noted earlier, this evaluation is exploratory, since demonstration of pain relief was not the primary objective in these studies, the patient population may have varied across studies despite similar study designs and entry criteria, and many patients lacked pain at baseline. Thus, studies specifically designed to assess pain relief will be required to confirm the effects seen here. These additional studies should also evaluate the effects of duloxetine on painful physical symptoms both in patients with depression and in those without depression.

One might have expected that a significant reduction in pain would have been reflected in a significant improvement in the measure of interference of pain in daily activities; however, this effect was not seen in this study. There are several possible reasons why the interference of pain in daily activities did not change significantly, although the change in scores suggested improvement and approached significance. First, a considerable number of patients were without pain, and, among the patients with pain, the severity of the pain was low. As a consequence, the amount of pain relief may have been too little to be clinically meaningful. The magnitude of pain relief required to be clinically meaningful in this population is unknown. In a population of patients with cancer pain, a 30% reduction in pain from baseline was considered clinically meaningful.50 Second, pain may not be the primary limitation on activity, since the baseline interference scores reported by the patients were low. Third, the emotional component of depression may have been a greater hindrance to activity. These factors will need to be evaluated in studies in which pain relief is the primary objective.

The emotional and painful symptoms of depression reflect different domains in depressed patients. The emotional symptoms of many depressed patients who received duloxetine improved, whether or not they had painful symptoms. Future studies will need to evaluate whether duloxetine improves pain in the absence of depression. The low correlation between change in the measure of mood and change in the pain severity measures implies that there may be a relationship, but it does not imply causality, as both domains may have improved independently, as might be expected, given that different neural pathways (the 5-HT pathway and the norepinephrine pathway) are responsible for the two types of symptoms.

The efficacy of duloxetine in these studies suggests that a balanced reuptake inhibitor of both 5-HT and norepinephrine is effective in relieving both the emotional and painful physical symptoms of depression. If these findings are confirmed, such dual activity would be an important consideration in treating depression, since treatment that addresses only the emotional or only the physical symptoms of depression is less likely to be successful than treatment that addresses the full spectrum of symptoms associated with the disorder.


  ACKNOWLEDGMENTS

 
Supported by Eli Lilly and Company. The authors thank Jackie Strasser and Renee Bacall for editorial assistance, Dr. Jyoti Rayamajhi and Bruce Spotts for statistical programming, and Dr. Craig Mallinckrodt for scientific review.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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