Vol. 36 No. 6 December 2008 Journal of Pain and Symptom Management 639

Vol. 36 No. 6 December 2008 Journal of Pain and Symptom Management 639 Original Article Does Pain Mediate the Pain Interference with Sleep Problem in Chronic Pain? Findings from Studies for Management of Diabetic Peripheral Neuropathic Pain with Duloxetine David A. Fishbain, MD, Jerry Hall, MD, Adam L. Meyers, MS, Jill Gonzales, BS, and Craig Mallinckrodt, PhD Departments of Psychiatry, Neurological Surgery and Anesthesiology (D.A.F.), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry (D.A.F.), Veterans Administration Hospital, Miami; and Rosomoff Pain Center (D.A.F.), Miami, Florida; and Lilly Research Laboratories (J.H., A.L.M., J.G., C.M.), Eli Lilly and Company, Indianapolis, Indiana, USA Abstract Although sleep problems are common in patients with chronic pain, it is unclear whether pain mediates (causes) impaired sleep. The relationship between pain and sleep has been difficult to investigate because of the potential confounds of depression and somnolence. This report used clinical trials data for duloxetine in the management of diabetic peripheral neuropathic pain (DPNP) to investigate the direction of this association. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP without mood disorder (n ¼ 1,139). DPNP patients reporting somnolence and those who were receiving sedating concomitant medications were removed from the analyses (n ¼ 93). Efficacy measures included weekly mean scores for average daily pain severity, night pain severity, and pain interference with sleep. Duloxetine at 60 and 120 mg per day separated from placebo for average pain and night pain improvement as early as one week after treatment began, whereas sleep interference improvement separated from placebo at the three visits it was assessed (Weeks 4, 8, and 12). Change in sleep interference was moderately to strongly correlated (P < 0.001) with changes in average pain (r ¼ 0.46) and nighttime pain severity (r ¼ 0.53). These results confirm the association between the improvement in daily pain and nighttime pain, and improvement in sleep interference for a large population without depression or somnolence. Although this association cannot establish causality, these results provide some evidence for the possibility that pain may mediate the sleep problem associated with DPNP and perhaps chronic pain in general. J Pain Symptom Manage Jerry Hall, Adam Meyers, Craig Mallinckrodt, and Jill Gonzales are stock shareholders and full-time employees of Eli Lilly and Company. David Fishbain has served on advisory boards and speaker s bureaus and as a consultant for Eli Lilly and Company. Address correspondence to: David A. Fishbain, MD, Departments of Psychiatry, Neurological Surgery, and Published by Elsevier Inc on behalf of U.S. Cancer Pain Relief Committee. Anesthesiology, Miller School of Medicine, University of Miami, P.O. Box 016960, Miami, FL 33173, USA. E-mail: dfishbain@med.miami.edu Accepted for publication: December 28, 2007. 0885-3924/08/$esee front matter doi:10.1016/j.jpainsymman.2007.12.012

640 Fishbain et al. Vol. 36 No. 6 December 2008 2008;36:639e647. Committee. Published by Elsevier Inc on behalf of U.S. Cancer Pain Relief Key Words Duloxetine, sleep, diabetic peripheral neuropathic pain, diabetes, chronic pain, insomnia Introduction Although 30% of the general population suffers from sleep problems, the prevalence of this problem within the chronic pain (CP) population treated at pain centers may be much higher. 1 Researchers have suggested figures of 50%e70% in this population. 1 Recent evidence indicates that pain is associated with insomnia within the general population, as 23.3% of subjects with painful physical conditions reported insomnia, and 40% of subjects with insomnia report at least one painful physical condition. 2 Although these data suggest an association between pain and sleep problems, it is unknown whether CP is the cause or the effect of poor sleep. 3 Because chronic insufficient sleep itself may contribute to the onset and amplification of pain, 4 the concept that CP is the cause of sleep problems in patients with chronic pain (PWCPs) is still in doubt. Psychopharmacological studies of pain and sleep can address this question. For example, hypnotics without analgesic properties, such as zopiclone 5 and zolpidem, 6 improve sleep in PWCPs without improving pain. On the other hand, opioids have been documented to simultaneously improve pain and sleep 7e9 in PWCPs; yet, it is not clear whether the observed sleep improvement is due to the sedative effects of these drugs. Anticonvulsants such as gabapentin 10 and pregabalin 11 have also been shown to decrease pain and sleep interference in PWCPs. However, both of these drugs also have sedating properties, and consequently, it is not clear whether the sleep improvement in these studies is secondary to the analgesic properties of the drug or its sedative properties. Similarly, some antidepressants (nortriptyline, desipramine 12 ) have also been shown to decrease pain and reduce sleep disturbance in PWCPs. Again, both of these drugs can be sedating in some patients, and this issue was not addressed in the study. Although each of these studies shed some light on the pain/sleep association problem, the confounding influence of the sedating properties of the drugs prohibits definitive conclusions regarding causal associations between pain and sleep. Another potential confounder to the results of these studies is the association in PWCPs between pain and depression. Many PWCPs are depressed, 13 possibly as a result of their pain. 14 Nonsedating antidepressants have been shown to improve both sleep and depression in patients who are depressed. 15 Thus, antidepressant treatment studies of CP cannot clarify the nature of the sleepepain association without some type of control for the confounding effects of depression. Recent randomized controlled trials of duloxetine in diabetic peripheral neuropathic pain (DPNP) evaluated both analgesia and sleep interference. These trials are notable for three reasons. First, nighttime pain was measured. This is unusual, as previous studies in this area have usually recorded average daily pain. 16e20 Given that PWCPs often are troubled by prolonged sleep latency or are awakened by pain, 21 and that pain usually fluctuates during 24 hours, nighttime pain may be a better measure of pain interference with sleep. Second, these studies involved a large group (over 1,000) of PWCPs with DPNP. This large group size enabled statistical control for any sedating properties of duloxetine and for any patients on sedating concomitant medications. Third, PWCPs with DPNP were selected for these trials only if they were not depressed. 22,23 As such, it was possible to examine the improvement in sleep without the confounding effect of improvement in depression. The pooled data from these duloxetine DPNP trials in PWCPs were analyzed to provide further insight into the association between pain and sleep, and to clarify whether pain mediates (causes) impaired sleep.

Vol. 36 No. 6 December 2008 Sleep-Pain Relationships: DPNP and Duloxetine 641 Methods Study Design The protocols for these studies (F1J-MC- HMAW, F1J-MC-HMAVa, and F1J-MC-HMAVb) were filed with the United States Food and Drug Administration prior to study initiation. They included all of the methodology presented here in addition to complete statistical analysis plans. The study protocols were approved in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent after the procedure(s) and possible side effects were fully explained. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week, multicenter, acute therapy trials of patients with DPNP (Studies 1e3). 22e24 Entry criteria and study designs were nearly identical for these large, Phase 3 clinical trials, and primary efficacy and safety results of these studies have previously been published. 22e24 For Study 1, patients (n ¼ 457) were randomly assigned to duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), or placebo in a 1:1:1:1 ratio for the 12-week therapy phase, as determined by a computer-generated random sequence using an interactive voice response system. Patients were seen weekly for the first five weeks of treatment and biweekly thereafter. Studies 2 and 3 were designed identically and assessed the efficacy and safety of duloxetine 60 mg QD and 60 mg BID. In Studies 2 and 3, patients were randomly assigned to duloxetine 60 mg QD, 60 mg BID, or placebo in a 1:1:1 ratio. The duration of treatment for Studies 2 and 3 was 12 weeks of active treatment plus a one-week taper phase. Only acetaminophen was allowed as adjuvant pain therapy in all patients. Several sedating medications, such as zolpidem, zolpiclone, zaleplon, and melatonin, were allowed to be used episodically during the acute phase of the study. Chronic use of sedating antihistamines and melatonin was allowed if the patient was on a stable dose for a minimum of three months prior to study enrollment and remained on the medication for the duration of the study. No specific directions were included in the study protocols with regard to sleep hygiene techniques or physical exercise instructions. Patient Selection Patients were adults with type 1 or type 2 diabetes, entry HbA1c #12% (to exclude patients with poorly controlled diabetes), and bilateral peripheral neuropathic pain of at least moderate severity ($4 on an 11-point Likert scale). The patients pain had to begin in the feet and with relatively symmetrical onset. The daily pain must have been present for at least six months, and the diagnosis of diabetic peripheral neuropathy was to be confirmed by a score of $3 on the Michigan Neuropathy Screening Instrument. 25 Patients were excluded if they had a current (#one year) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 26 (DSM-IV) Axis I diagnosis of major depressive disorder, dysthymia, generalized anxiety disorder, or alcohol or eating disorders, as determined by the Mini-International Neuropsychiatric Interview, or a previous diagnosis of these conditions. 26,27 Patients with a DSM-IV diagnosis of mania, bipolar disorder, or psychosis determined either by patient history or by diagnosis using specific Mini-International Neuropsychiatric Interview modules also were excluded. Efficacy Measures The primary efficacy measure was the reduction in the weekly mean of the 24-hour average pain score, calculated from daily patient diary entries and measured by an 11-point (0 ¼ no pain, 10 ¼ worst possible pain) numeric rating scale. Secondary efficacy measures included: (1) average daily night pain severity (recorded daily by patients in a diary and calculated weekly), as measured by an 11-point numeric rating scale, and (2) pain interference with sleep assessed using the Brief Pain Inventory (BPI). 28 The BPI has seven pain interference questions, assessing pain interference with general activity, mood, walking ability, normal work, relationships with other people, sleep, and enjoyment of life. Pain-sleep interference was rated with scores ranging from 0 (does not interfere) to 10 (completely interferes). Somnolence Recording Data on treatment-emergent somnolence were elicited by spontaneous patient report or nonspecific questioning at each visit, and

642 Fishbain et al. Vol. 36 No. 6 December 2008 were reported by the patient as mild, moderate, or severe. The Medical Dictionary for Regulatory Activities-preferred terms mapped the following clinician-provided adverse event descriptions for the term somnolence: daytime sleepiness, drowsiness, drowsy on awakening, excessive daytime sleepiness, feeling of residual sleepiness, groggy, groggy and sluggish, groggy on awakening, hard to awaken, less alert on arising, sleepiness, sleepy, and somnolence. Statistical Analysis Data were pooled from all placebocontrolled studies of duloxetine for DPNP to obtain the most precise estimates of the treatment effects and the relationships between pain and sleep. Studies were amenable to pooling because they all were 12 weeks in duration, had similar inclusion criteria and allowable concomitant medications, and used a common battery of instrumentation. Patients reporting treatment-emergent somnolence and those taking sedating concomitant medications were removed from the correlation and longitudinal mean change in efficacy measure analyses. The sedating concomitant medications causing exclusion of patients were as follows: alprazolam, chlordiazepoxide, amitriptyline, chlorphenamine, cyproheptadine, diazepam, diphenhydramine, flurazepam, lorazepam, melatonin, midazolam, oxazepam, promethazine, codeine, temazepam, triprolidine, zaleplon, zolpidem, and zopiclone. A patient was considered to have had treatment-emergent somnolence (as defined previously in the section Somnolence Recording) if at any time after randomization the patient either first reported somnolence or reported it at a level of severity greater than was reported during the baseline and screening visits. Baseline was defined as the last nonmissing observation at or before randomization, and endpoint was defined as the last nonmissing observation in the acute therapy phase. The similarity of treatment groups at baseline was evaluated for continuous outcomes, such as age and baseline severity, using analysis of variance with a model that included treatment group and investigator. Baseline comparisons for categorical outcomes such as ethnicity were compared using Fisher s exact test. The association between pain and sleep interference outcomes was evaluated using Pearson s (simple) correlation. Longitudinal mean changes in efficacy measures were assessed using a likelihood-based repeated measures approach, and comparisons were made between duloxetine treatment arms (60 mg QD or 60 mg BID) and placebo. Duloxetine 20 mg QD was found to be a nonefficacious dose in patients with DPNP and was not included in the longitudinal analysis of mean changes. 22 Models for mean changes included the fixed categorical effects of investigator, visit, therapy, and the therapy-by-visit interaction, along with the fixed covariates of baseline severity and baseline severity-by-visit interaction. Within-patient errors were modeled using an unstructured approach. Results Patient Demographics and Characteristics Baseline demographics and characteristics of all patients (n ¼ 1,139) in the three studies are summarized in Table 1. A majority of the patients in these studies were Caucasian (84.4%); the mean age was 59.9 years. No Table 1 Baseline Characteristics of All Patients in Pooled DPNP Studies Characteristic Placebo (n ¼ 339) Duloxetine (n ¼ 800) Gender, male, n (%) 181 (53.4) 466 (58.3) Age, years, mean (SD) 60.1 (10.3) 59.8 (10.7) Weight, kg, mean (SD) 94.9 (22.4) 93.8 (22.1) Origin, n (%) Caucasian 291 (85.8) 670 (83.8) Hispanic 29 (8.6) 76 (9.5) African descent 16 (4.7) 32 (4.0) Other 3 (0.9) 22 (2.8) Type of diabetes, n (%) Type 1 36 (10.6) 101 (12.6) Type 2 303 (89.4) 699 (87.4) Duration of diabetes, years, 11.8 (9.7) 11.7 (9.4) mean (SD) Duration of diabetic neuropathy, 3.9 (3.6) 4.0 (4.3) years, mean (SD) 24-hour average pain severity, 5.7 (1.4) 5.9 (1.5) mean (SD) Night pain severity, mean (SD) 6.0 (2.1) 6.1 (2.1) BPI sleep interference score, mean (SD) 5.2 (2.9) 5.4 (2.8) DPNP ¼ diabetic peripheral neuropathic pain; SD ¼ standard deviation; BPI ¼ Brief Pain Inventory.

Vol. 36 No. 6 December 2008 Sleep-Pain Relationships: DPNP and Duloxetine 643 significant differences were observed between the duloxetine and placebo groups for any of the variables in Table 1. On average, patients reported moderately severe daily and night pain prior to treatment (Table 1), as measured using Likert scales. 29 Mean BPI sleep interference scores at baseline were 5.4 out of 10. Time Course of Changes in Pain and Sleep Ninety-three patients reporting treatmentemergent somnolence and taking sedating concomitant medications were removed from the longitudinal mean change in efficacy measure analyses. Of the 93 patients removed, 21 were first removed due to treatment-emergent somnolence; and of those remaining without treatment-emergent somnolence, another 72 were removed for having taken a sedating concomitant medication. For both average daily pain and night pain, both 60 mg and 120 mg doses of duloxetine were significantly superior to placebo at Week 1 and at all subsequent weeks throughout the trial (Figs. 1 and 2). Although all treatment groups showed continued average improvements throughout the trial, most of that improvement was observed in the first four to six weeks. For BPI sleep interference, assessments were taken at Weeks 4, 8, and 12. Hence, early onset could not be evaluated. Both duloxetine doses were significantly superior to placebo at Weeks 4, 8, and 12 (Fig. 3). Average improvement in BPI sleep interference as a percentage of the baseline means for the 60 mg QD and 60 mg BID groups were 47% and 45% at Week 4, and 55% and 57% at Week 12, respectively. Corresponding improvements for duloxetine-treated patients in both average daily pain and night pain were as follows: daily paind38% (60 mg QD) and 40% (60 mg BID) at Week 4, and 47% (60 mg QD) and 50% (60 mg BID) at Week 12; night paind40% (60 mg QD) and 41% (60 mg BID) at Week 4, and 47% (60 mg QD) and 51% (60 mg BID) at Week 12. However, the time course of improvements in changes for placebo-treated patients showed a larger difference between pain and sleep. At Weeks 4 and 12, the percentage change in pain for placebo-treated patients was 19% and 29% for daily pain and 24% and 34% for night pain, whereas the change in sleep was 37% and 45%, respectively. Relationships Between Average Pain, Night Pain, and Sleep Interference At baseline, both 24-hour average pain severity and average daily night pain severity were significantly (P < 0.001) correlated with BPI sleep interference, but the correlation was numerically greater for average daily night pain (r ¼ 0.57) than for average pain (r ¼ 0.37). Changes from baseline to endpoint in BPI sleep interference were positively (P < 0.001) correlated with improvements in both 24- hour average pain severity (r ¼ 0.46) and average daily night pain severity (r ¼ 0.53). Fig. 1. Time course of change in 24-hour average pain severity in pooled patients with DPNP who did not demonstrate somnolence and were not on sedating medications. MMRM ¼ mixed-effects model repeated measures; DPNP ¼ diabetic peripheral neuropathic pain.

644 Fishbain et al. Vol. 36 No. 6 December 2008 Fig. 2. Time course of change in night pain severity in pooled patients with DPNP who did not demonstrate somnolence and were not on sedating medications. MMRM ¼ mixed-effects model repeated measures; DPNP ¼ diabetic peripheral neuropathic pain. Discussion The results of these retrospective analyses suggest the following: (1) duloxetine improved daily average pain and night pain within one week of treatment initiation in patients with DPNP who did not report treatment-emergent somnolence and were not taking sedating drugs; (2) duloxetine decreased sleep interference scores at the three assessment timesdweeks 4, 8, and 12; (3) the relative magnitude of improvement in sleep interference was similar to changes in both daily average pain and night pain for patients on duloxetine; (4) improvements in average pain and night pain were positively and moderately to strongly correlated with improvement in sleep interference; and (5) correlations between improvement in sleep interference and improvement in night pain were similar to correlations between improvement in sleep interference and average daily pain. These observations were made free from the confounding influences of somnolence and sedating medications and were in a population of patients who did not meet criteria for major depressive disorder. Fig. 3. Improvement in interference with sleep as measured by BPI in pooled patients with DPNP who did not demonstrate somnolence and were not on sedating medications. BPI ¼ Brief Pain Inventory; MMRM ¼ mixedeffects model repeated measures; DPNP ¼ diabetic peripheral neuropathic pain.

Vol. 36 No. 6 December 2008 Sleep-Pain Relationships: DPNP and Duloxetine 645 Given the control for these potential confounds, the highly significant correlations between changes in pain and changes in sleep interference clearly establish an association between pain severity and sleep interference in PWCPs; however, this association does not clarify causality. Ideally, one would like to establish that the changes in sleep are caused by the changes in pain rather than merely noting, as in the present studies, an association between these outcomes (sleep improving with less pain). Recently, Fishbain and colleagues (Fishbain DA, Cole B, Lewis J, Rosenblat HR, Steele- Rosomoff R. What is the direction of the relationship in the pain/sleep association? Does pain mediate the sleep disorder or vice versa? A structured, evidence-based review, paper under review). completed an evidence-based review on the sleep-pain association in an effort to determine the direction of that association. They used different lines of evidence for this review: multivariate analyses, prospective studies, path analyses, correlations between sleep disturbance and pain, univariate analyses, analyses using comparison groups, and effects of nonsedating drugs with analgesic properties on sleep improvement. The results of this review indicated that in all the aforementioned lines of evidence except for multivariate analysis, each of the studies supported the hypothesis that pain mediates sleep disorder. Unfortunately, many of the studies used in this evidence-based structured review did not control for the associated somnolence of the drug or the sedative properties of concomitant medications the patients were taking. The present investigation is in agreement with the review by Fishbain and colleagues, and further, adds the control for these potential confounds, making it the strongest evidence supporting the concept that pain mediates sleep interference. Another finding in the present investigation was that improvements in night pain correlated with sleep interference and that this correlation was similar to that for average pain. This speaks to the utility of considering nighttime pain rather than average pain when studies are performed. In future studies of this type, use of night pain numerical rating scales may not provide an advantage over use of daily pain scales in determining potential relationships between sleep and pain. The present investigation has additional strengths and limitations. The data presented herein represent all the data from acute phase placebo-controlled trials of duloxetine (around 1,000 patients) at its efficacious doses in the treatment of DPNP. This large pool of data from similarly designed clinical trials fostered precise estimates of treatment effects and relationships between outcomes. One possible limitation, however, is the issue of the measurement of somnolence. The present investigation was somewhat limited in its ability to assess the role of somnolence because adverse events were evaluated using spontaneous reports. Although spontaneous reporting is the standard practice for confirmatory clinical trials intended to support regulatory approvals, solicited scales specifically designed for particular adverse events would have been preferable for the investigation. Nevertheless, these findings suggest the reasonable expectation that reduction in pain with duloxetine management in DPNP patients will be associated with less interference with sleep. Another limitation is that the results are not generalizable to patients with DPNP who also are diagnosed with major depressive disorder, as this patient group was excluded from the studies included in our analyses. A recently published study 30 appears to lend significant importance to the results of the study presented here. In that study, Zelman and colleagues 30 demonstrated that DPNP patients had significantly higher scores on the sleep problem index and six sleep attribute scales (sleep disturbance, snoring, awakening with shortness of breath or headache, sleep adequacy, daytime somnolence, and sleep quantity) than the general population, a chronic disease patient sample, and patients with postherpetic neuralgia. There was also a positive correlation between pain and sleep problem index scores. The findings in both of these studies speak to the importance of the sleepepain associations in DPNP and underscore the need for agents that have an impact on both pain and sleep in DPNP. Acknowledgments This work used data from clinical trials sponsored by Eli Lilly and Company, Indianapolis,

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