Sleep as a Marker in the Effective Management of Chronic Osteoarthritis Pain with Opioid Analgesics

OSTEOARTHRITIS

Sleep as a Marker in the Effective Management of Chronic Osteoarthritis Pain with Opioid Analgesics Dennis C. Turk, PhD,* and Mitchell J.M. Cohen, MD†

Objectives: Sleep disturbances frequently accompany chronic pain from osteoarthritis (OA), and their effective management may reflect successful treatment of chronic pain. The objective of this article is to provide a rationale for using improvement in sleep as a marker for effective management of chronic OA pain with opioid analgesics. For this purpose, available evidence evaluating the relationship between successful management of chronic pain with opioids and improvements in sleep in patients with OA is reviewed. Methods: We conducted a comprehensive PubMed search to identify studies that systematically measured the impact of opioid treatment on pain and sleep parameters in the context of chronic pain from OA. Our search criteria included publication in a recognized peer-reviewed journal, randomized placebo-controlled design, and assessment of both pain intensity and sleep as outcomes. Results: In each of the 10 placebo-controlled studies identified, concurrent improvements in pain intensity and measured sleep disturbances were observed in patients receiving the long-acting opioid analgesics under study. Improved overall sleep quality, reduced awakenings from pain, and increased duration of sleep were among the favorable changes observed in patients with OA treated with long-acting opioids. Conclusions: Current evidence suggests that various long-acting opioid analgesics simultaneously achieve pain control and improve sleep. However, the complex interaction between reduced pain and improved sleep requires further study. © 2010 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:477-490 Keywords: chronic osteoarthritis pain, opioid analgesics, sleep, pain management

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hronic pain has been defined in various ways. It can be defined by absolute duration (for example, pain lasting more than 3 or 6 months) or its persistence beyond what is clinically typical or adaptive for

*John and Emma Bonica Professor of Anesthesiology and Pain Research, Department of Anesthesiology, University of Washington, Seattle, Washington. †Associate Professor of Psychiatry and Human Behavior, Vice Chair for Education, Director, Pain Medicine Program, Department of Psychiatry and Human Behavior, Jefferson Medical College, Philadelphia, Pennsylvania. Disclaimers: Dr. Turk serves as a consultant to Cephalon, Ortho-McNeil Janssen Scientific Affairs, Paramount Biosciences, Schwarz Biosciences, and Wyeth and is a member of advisory boards for Abbott Laboratories, AstraZeneca, Eli Lilly, Pfizer, and Schwarz Biosciences and a Special Government Employee of the United States Food and Drug Administration. Dr. Cohen serves as a consultant to Endo and Cephalon and serves on the speakers bureau for Pfizer. Support for this article was provided by Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, NJ. Address reprint requests to Dennis C. Turk, PhD, John and Emma Bonica Professor of Anesthesiology and Pain Research, Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195. E-mail: [email protected].

0049-0172/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2008.10.006

the person (1,2). Chronic pain has been estimated to afflict approximately 20 to 35% of people worldwide (1,3). More than 60% of people reporting chronic pain rate its intensity as moderate to severe and have experienced chronic pain for more than 5 years (2). Osteoarthritis (OA) is among the most common chronic pain disorders experienced by adults in the United States. There are currently more than 20 million Americans who have been diagnosed with OA, and it has been estimated that approximately 70 million will be at risk for OA by the year 2030, given the aging of the population over coming decades (4). OA is the second leading cause of disability in adults (after heart disease) who are receiving Social Security Disability Income (5) and costs an estimated $7.11 billion/yr in lost work time, the majority (66%) of which has been attributed to costs stemming from chronic pain (6). In addition to their societal impact, chronic pain conditions such as OA exact a high burden on patients and 477

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Sleep OA Abbreviations

APAP bid BPI COX-2 CPSI CR ER IR NSAID OA q12h qam qid qpm VAS WOMAC

Acetaminophen Twice daily Brief Pain Inventory Cyclooxygenase-2 Chronic Pain Sleep Inventory Controlled-release Extended-release Immediate-release Nonsteroidal anti-inflammatory drugs Osteoarthritis Every 12 hours Once daily in the morning 4 times daily Once daily in the evening Visual Analog Scale Western Ontario and McMaster Universities

their significant others. Overall, patient quality of life is reduced (7). Diminished sleep, interference with social relationships and daily activities, impaired cognitive function, and increased anxiety and depression all contribute to the reduction in quality of life (8,9). Consistent with these findings, elderly patients with OA report significantly reduced health-related quality of life compared with matched individuals who are pain free (10). A number of recent papers have emphasized that although pain reduction is a primary outcome for any treatment for chronic pain, other relevant domains should be considered as important outcomes along with pain reduction (11-13). Sleep, in particular, has been shown to be a separate, relevant treatment outcome in chronic pain sufferers (14). In addition, given the reported prevalence of sleep disruptions and nonrestorative sleep among patients with chronic pain (50-70%), sleep is a critical outcome among patients with chronic pain (15). This article provides a rationale for using improvement in sleep as a marker for effective chronic pain management in patients with OA receiving opioid analgesics. Sleep and Chronic Pain in Patients with OA Sleep disturbances are common among people with OA (16,17). In a study involving men and women older than 65 years with chronic knee pain due to OA (N ⫽ 429), 81% of patients reported problems maintaining sleep, 51% reported problems with early morning awakenings, and 31% reported having difficulty falling asleep (17). In another study, significant increases in the lightest stage of sleep and significant decreases in intermediate stage of sleep were observed in patients with OA compared with healthy controls (16). Of note, the investigators concluded that the degree of sleep disturbance was limited by continued treatment with current anti-inflammatory and analgesic medications, suggesting that sleep reflected efficacy of control of inflammation and pain in these patients.

In summary, chronic pain can disrupt sleep. Poor sleep may lower the pain threshold, which may in turn contribute to increased pain, creating a vicious cycle (18-20). Because the relative risk of pain-associated insomnia and nonrestorative sleep increases with severity of pain (21), it is reasonable to predict that effective management of chronic pain may improve these sleep parameters. Sleep improvement has been used as an outcome measure in a number of studies of OA treatments, including studies of opioid analgesics, which we review below. Instruments to Quantify Sleep Disturbances Although objective instruments to evaluate sleep quantity and quality such as polysomonography exist, lower cost, more convenient subjective tools are typically used in clinical studies assessing the effects of chronic pain treatments on sleep parameters. These subjective tools include self-report sleep diaries, where individuals record their sleeping habits on a daily basis, and questionnaires (such as the Pittsburgh Sleep Quality Index, the Sleep Disorders Questionnaire, or the Chronic Pain Sleep Inventory [CPSI]), where patients retrospectively report their sleep quality (15,22-26). In clinical studies, the CPSI has been shown to be a useful questionnaire to measure the effect of opioid treatment on various sleep disturbances and overall sleep quality in patients with chronic pain (25,26). The CPSI is a validated 5-item questionnaire in which the following factors are assessed: trouble falling asleep due to pain (CPSI1), the need for sleep medication (CPSI2), awakenings by pain during the night (CPSI3) and in the morning (CPSI4), and overall sleep quality (CPSI5) (27). All items are scored using a 100-mm visual analog scale (VAS; 0 ⫽ never and 100 ⫽ always for CPSI1 through CPSI4, and 0 ⫽ very poor and 100 ⫽ excellent for CPSI5) (27). Although other sleep-related questionnaires may provide a more conceptually comprehensive measure of sleep, the CPSI provides a brief and valid assessment of the impact of chronic pain on pain-related sleep problems. In fact, psychometric testing has supported the reliability of an abbreviated derivative of this questionnaire, the Sleep Problems Index, which consists of the CPSI items that specifically attribute sleep problems to pain (CPSI1, CPSI3, and CPSI4) (27). Opioids and the Treatment of Chronic OA Pain The prescription of opioids for long-term use to manage chronic noncancer pain continues to be controversial; however, a number of studies have reported on the efficacy and safety of this drug class for various chronic pain conditions in general and for OA in particular (26,2830). Although the American College of Rheumatology recommends reserving opioids primarily for moderate to severe OA pain that is unresponsive to acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or cy-

D.C. Turk and M.J.M. Cohen

clooxygenase-2 (COX-2) inhibitors (31), a 2004 study of 3061 patients with OA diagnoses found that 41% of those patients received at least 1 opioid prescription over a 1-year period (32). Factors other than unrelieved pain may contribute to the decision to prescribe an opioid for treatment of chronic OA pain. Patients at increased risk of specific potential adverse effects of nonopioid medications (eg, cardiovascular, gastrointestinal, or renal toxicities from COX-2 inhibitors or NSAIDs) may be candidates for earlier introduction of opioids for management of their chronic OA pain: for example, the American College of Rheumatology suggests that the relatively weak opioid agonist tramadol could be used for moderate to severe OA pain in patients with contraindications to the use of NSAIDs or COX-2 inhibitors (31). For treatment of chronic pain, long-acting (ie, extended-release [ER] or controlled-release [CR]) opioid formulations are recommended given the provision of sustained analgesia without the need for frequent dosing, including middle-ofthe-night dosing (33-35).

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pain sites, design, and sample size, we felt a metaanalysis of these studies would not produce data that were more meaningful than those conveyed by presentation of the best individual studies. CR Codeine

To evaluate the opioid treatment literature on pain and sleep, we conducted a comprehensive PubMed search to identify studies that systematically measured pain and sleep parameters in the context of OA. The following terms were used for this search: osteoarthritis, opioids, opioid analgesics, sleep, sleep disturbances, sleep disruption, and sleep problems; no date limits were specified at the time of our search, so that all indexed studies meeting criteria up to the time of our search in March 2008 were candidates. Of the references produced by this search, those meeting the following criteria were identified: publication in a recognized peer-reviewed journal, randomized placebo-controlled design, assessment of both pain intensity and sleep as primary or secondary outcomes, clear description of pain conditions experienced by study subjects, and reasonable sample size as assessed by statistical analyses conducted for each study.

The efficacy and safety of a 12-hourly CR codeine formulation (Codeine Contin®; Purdue Frederick, Pickering, Ontario, Canada) were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study of patients with radiographic evidence of OA of the hip or knee (36). Patients were randomized to receive either CR codeine (n ⫽ 31) or placebo (n ⫽ 35) every 12 hours. Study medication doses were escalated on a weekly basis provided that there was ongoing pain and no prohibitive adverse medication effects: in the case of CR codeine, patients were started on 100 mg daily and increased to a maximum of 400 mg daily as needed and/or tolerated. At week 4, patients in the CR codeine group demonstrated significant improvements from baseline compared with placebo in measures of pain intensity, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain VAS score, daily pain intensity VAS scores, and pain intensity VAS scores over the previous week (P ⬍ 0.001 for all comparisons) (36). While the study used a 7-item questionnaire to evaluate sleep (36), the results reported were equivalent to 4 of the 5 items on the CPSI. CR codeine-treated subjects showed greater sleep improvement than placebo-treated subjects on various outcome measures, including need for medication to fall asleep (73% versus 10% improvement, respectively; P ⫽ 0.004), pain on awakening (76% versus 23% improvement, respectively; P ⫽ 0.023), and trouble falling asleep (72% versus 38% improvement, respectively; P ⫽ 0.022). A significantly larger proportion of patients who received CR codeine (39%) reported somnolence as an adverse event compared with patients who received placebo (10%, P ⬍ 0.01).

RESULTS

ER Morphine

Using the aforementioned search terms and limits, a total of 80 separate citations were generated. Of these, only 45 specifically assessed 1 or more opioid analgesics in the setting of OA. A total of 19 of those references were excluded from review because they were not placebo-controlled studies. An additional 16 studies were excluded because they did not assess the impact of treatment on sleep (14 studies) or were post-hoc analyses (2 studies). A total of 10 randomized, placebo-controlled studies assessing the impact of treatment with a long-acting opioid on pain and sleep in patients with OA were identified (Table 1). The following systematic review of studies is a summary of the available literature, and not a formal metaanalysis. Because the 10 identified studies varied substantially in duration, outcome instruments used, OA

An ER capsule formulation of morphine sulfate (AVINZA™; Elan Pharmaceuticals Research Corp., Gainesville, GA) was evaluated in a 4-week, multicenter, randomized, double-blind, double-dummy placebo-controlled and active-controlled, parallel study in patients with chronic moderate to severe OA pain (n ⫽ 295) whose pain was not relieved by NSAIDs or acetaminophen (28). Patients were randomly assigned to treatment with 1 of the following: ER morphine 30 mg once-daily in the morning (qam), ER morphine 30 mg once-daily in the evening (qpm), CR morphine (MS Contin®; Purdue Pharma L.P., Stamford, CT) 15 mg twice daily (bid), or placebo (bid). Using the WOMAC pain subscale, patients who received ER morphine qam, ER morphine qpm, or CR morphine bid experi-

METHODS

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Sleep OA

Table 1 Randomized, Placebo-Controlled Trials Evaluating the Impact of Opioids on Pain and Sleep Disturbances in Osteoarthritis Authors

Study Treatments

Pain Assessments

Sleep Assessments

Sleep-Related Findings ● Significant improvements from baseline to week 4 in the CR codeine versus placebo groups in the following sleep assessments - Trouble falling asleep (72% vs 38% improvement; P ⫽ 0.022) - Need medication to fall asleep (73% vs 10% improvement; P ⫽ 0.004) - Pain on awakening (76% vs 23% improvement; P ⫽ 0.023) ● Overall, patients in the ER morphine groups demonstrated significant improvements in sleep assessments from baseline compared with placebo

Peloso et al (36)

CR codeine to 200 mg q12h (n ⫽ 31) or placebo q12h (n ⫽ 35) for 4 weeks

● WOMAC OA Index pain score ● Daily pain intensity score ● Pain intensity score over the previous week

● Trouble falling asleep ● Need medication to fall asleep ● Awakening by pain at night ● Awakening by pain in the morning

Caldwell et al (28)

ER morphine 30 mg qama (n ⫽ 73); ER morphine 30 mg qpma (n ⫽ 73); CR morphine bid (n ⫽ 76); or placebo bid (n ⫽ 73) for 4 weeks

● WOMAC OA Index pain score

● CPSI itemsb ● Duration of sleep

Matsumoto et al (29)

Oxymorphone ER 20 mg q12h (n ⫽ 121); oxymorphone ER 40 mg q12h (n ⫽ 121); CR oxycodone 20 mg q12h (n ⫽ 125); or placebo q12h (n ⫽ 124) for 4 weeks

● Arthritis pain intensity (VAS)

● CPSI overall sleep quality item

- Patients in the ER morphine qam cohort reported significant improvements in overall quality of sleep at weeks 1, 2, and 4; less need for sleep medication at weeks 1, 3, and 4; increased duration of sleep at week 1; and less trouble falling asleep because of pain at weeks 3 and 4 compared with placebo (all P ⱕ0.05) ● A significant improvement from baseline in overall sleep quality was reported in the oxymorphone ER 40 mg group at week 4 (P ⫽ 0.01 vs placebo) ● A significant improvement from baseline in overall sleep quality was reported in the oxymorphone ER 20 mg group at week 3 (P ⫽ 0.038 vs placebo)

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Table 1 Continued Authors

Study Treatments

Pain Assessments

Sleep Assessments

Sleep-Related Findings

Oxymorphone ER 10 mg q12h weeks 1 and 2 (n ⫽ 95); oxymorphone ER 20 mg q12h week 1 and 40 mg q12h week 2 (n ⫽ 93); oxymorphone ER 20 mg q12h week 1 and 50 mg q12h week 2 (n ⫽ 91); or placebo q12h weeks 1 and 2 (n ⫽ 91) CR oxycodone 10 mg q12h (n ⫽ 56) or placebo q12h (n ⫽ 51) for up to 90 days

● Pain intensity (VAS) ● WOMAC OA Index pain score

● CPSI overall sleep quality item, with emphasis on the quality of sleep since the previous visit

● Mean improvements in overall sleep quality were significantly greater in the groups receiving oxymorphone ER 40 and 50 mg at week 2 compared with placebo (both P ⱕ 0.05, with a 2-fold improvement over placebo)

● BPI average and current pain intensity scores

● BPI Interference score for sleep

Roth et al (37)

CR oxycodone 10 mg q12h (n ⫽ 44); CR oxycodone 20 mg q12h (n ⫽ 44); or placebo q12h (n ⫽ 45) for 14 days

● 20% reduction in baseline pain intensity (measured on a 4-point categorical scale) ● BPI pain intensity scores

● BPI Interference score for sleep ● Overall quality of sleep (5-point scale: 1 ⫽ very poor, 5 ⫽ excellent)

Caldwell et al (38)

CR oxycodone 10 mg q12h (n ⫽ 37); oxycodone/APAP IR 5 to 325 mg q12h (n ⫽ 34); or placebo q12h (n ⫽ 36) for 4 weeks

● Pain intensity (categorical scale ranging from 0 ⫽ none to 3 ⫽ severe)

● Global quality of sleep (categorical scale ranging from 1 ⫽ very poor to 5 ⫽ excellent) ● 3-day sleep diary (last 3 days of the double-blind period)

● The change in the leastsquares mean of the BPI Interference score for sleep at 90 days was greater in the CR oxycodone group (⫺2.8) than the placebo group (⫺0.9; P ⬍ 0.001), indicating greater improvement in this outcome in the CR oxycodone group ● The mean reduction in BPI Interference scores for sleep from baseline to week 2 was significantly greater in the CR oxycodone 20-mg group compared with the placebo group (P ⬍0.05) ● Patients in the CR oxycodone 20-mg group also rated their overall sleep quality significantly higher at week 2 compared with patients in the placebo group (P ⬍ 0.05) ● Patients in the CR oxycodone and oxycodone/APAP IR groups demonstrated significantly improved global quality of sleep and higher mean day 3 diary scores for quality of sleep at the end of the double-blind period compared with placebo (all P ⱕ 0.05)

Kivitz et al (24)

Markenson et al (30)

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Sleep OA

Table 1 Continued Authors

Study Treatments

Pain Assessments

Sleep Assessments

Sleep-Related Findings

Langford et al (39)

Transdermal fentanyl (maximum 100 ␮g/h; n ⫽ 202) q72h or placebo q72h (n ⫽ 197) for 6 weeks

● Pain disturbing night rest (100-mm VAS; difference between the average AUC of the VAS scores over time from baseline to week 6)

● A greater improvement from baseline to week 6 was observed in pain disturbing night rest in the transdermal fentanyl group compared with the placebo group (P ⫽ 0.002)

Babul et al (25)

Tramadol ER 200 to 400 mg qd (n ⫽ 124) or placebo qd (n ⫽ 122) for 12 weeks

● Pain intensity (VAS) ● WOMAC OA Index pain score ● Current target joint pain, worst pain on the day of each visit, pain impairing function, and pain while walking (difference between the average AUC of the VAS scores over time from baseline to week 6) ● Arthritis Pain Intensity VAS score ● WOMAC OA Index pain score

● CPSI

Gana et al (26)

Tramadol ER 100 mg qd (n ⫽ 203); tramadol ER 200 mg qd (n ⫽ 203); tramadol ER 300 mg qd (n ⫽ 204); tramadol ER 400 mg qd (n ⫽ 205); or placebo (n ⫽ 205) qd for 12 weeks

● Arthritis Pain Intensity in the index joint score ● Daily pain intensity scores

● CPSI

● Significant improvements in the following CPSI items from baseline over week 12 were observed in the tramadol ER group compared with the placebo group (all P ⬍ 0.05): trouble falling asleep due to pain, awakenings from pain during the night, awakenings from pain in the morning, and overall sleep quality ● Significant improvements in the following CPSI items from baseline to week 12 were observed in the tramadol ER groups compared with the placebo group (all P ⬍0.05): trouble falling asleep due to pain, awakenings from pain during the night, awakenings from pain in the morning, and overall sleep quality

CR, controlled release; q12h, every 12 hours; qam, once in the morning; qpm, once in the evening; WOMAC, Western Ontario and McMaster Universities; OA, osteoarthritis; ER, extended release; CPSI, Chronic Pain Sleep Inventory; VAS, Visual Analog Scale; BPI, Brief Pain Inventory; APAP, acetaminophen; q72h, every 72 hours; AUC, area under the curve; qd, once daily. aPatients assigned to these treatment groups were given placebo at the opposite time. bThe CPSI consists of 5 items rated on a 100-mm VAS (0 ⫽ never and 100 ⫽ always for first 4 items, and 0 ⫽ very poor and 100 ⫽ excellent for the last item): trouble falling asleep due to pain, the need for sleep medication; awakenings by pain during the night; awakenings by pain in the morning; and overall sleep quality.

enced significant pain reduction from baseline compared with placebo (17% reduction, 20% reduction, and 18% reduction, respectively, versus 4% reduction with placebo; P ⱕ 0.05 for all comparisons) (28). The impact of ER morphine on sleep was measured by a questionnaire that included all 5 items from the CPSI: trouble falling asleep, need for sleep medication, fre-

quency of awakening during the night or morning due to pain, and overall quality of sleep, and a question regarding the duration of sleep each night (28). With the exception of duration of sleep, which was measured on a 12-point scale (1-12 hours), sleep assessments were recorded on a 100-mm VAS, as in the CPSI. Patients in the ER morphine and CR morphine treatment groups showed greater

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Figure 1 (A) Mean changes from baseline in overall sleep quality and duration of sleep each night at weeks 1 and 4 in patients receiving CR morphine, ER morphine, and placebo. Data are presented as mean score ⫾ standard error, measured on a 100-mm VAS with the exception of duration of sleep each night, which was on a 12-point scale (1-12 hours). *P ⱕ 0.05 versus placebo. †P ⱕ 0.05 versus CR morphine (28). (B) Mean changes from baseline in need for sleep medication and trouble falling asleep at weeks 1 and 4 in patients receiving CR morphine, ER morphine, and placebo. Data are presented as mean score ⫾ standard error, measured on a 100-mm VAS. *P ⱕ 0.05 versus placebo (28).

improvements in sleep measures than did the placebo group (Fig. 1). In addition, patients who were treated with ER morphine qam reported a significant improvement in overall quality of sleep at weeks 1, 2, and 4; significantly less need for sleep medication at weeks 1, 3, and 4; significantly increased hours of sleep at week 1; and significantly less trouble falling asleep because of pain at weeks 3 and 4 compared with placebo (P ⱕ 0.05 for all comparisons; Fig. 1). Similarly, patients who were treated with ER morphine qpm reported significant improvements in overall quality of sleep at weeks 1, 2, and 4, as well as in the duration of sleep each night at week 1 compared with placebo (P ⱕ 0.05 for all comparisons).

Patients who were treated with CR morphine bid reported significant improvement in overall quality of sleep at week 2 and less trouble falling asleep due to pain at weeks 3 and 4 compared with those receiving placebo (both P ⱕ 0.05). Finally, when patients who were treated with ER morphine were compared with patients who received CR morphine bid, the patients treated with ER morphine reported significantly greater improvement in overall quality of sleep at weeks 1 and 4 (P ⱕ 0.05 for both comparisons). Overall, treatment was generally well tolerated, and as expected, somnolence was among the most commonly reported adverse events, occurring in 13% of patients treated with ER morphine (28).

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ER Oxymorphone The efficacy and safety of an ER tablet formulation of oxymorphone (OPANA® ER; Endo Pharmaceuticals, Chadds Ford, PA) have been evaluated in a multicenter, doubleblind, placebo- and active-controlled, parallel-group study in patients with chronic pain from OA who did not achieve pain relief with NSAIDs or acetaminophen (29). Patients were randomly assigned to 4 weeks of treatment with oxymorphone ER 20 mg (n ⫽ 121), oxymorphone ER 40 mg (n ⫽ 121), CR oxycodone 20 mg (n ⫽ 125), or placebo (n ⫽ 124) q12h (29). Compared with the placebo group, patients in both oxymorphone treatment groups demonstrated significantly greater improvements from baseline in arthritis pain intensity (VAS), which was the primary efficacy endpoint. Assessments of OA pain from the daily patient diaries provided similar results: those treated with oxymorphone ER 20 mg or 40 mg demonstrated 39% (P ⫽ 0.009) and 44% (P ⫽ 0.004) reductions from baseline in mean pain intensity VAS scores, respectively (29). Along with the improvements seen in pain intensity, patients who received oxymorphone ER experienced improvements of varying significance in VAS scores for overall sleep quality at 3 and 4 weeks. Patients who received oxymorphone ER 40 mg reported a 16.4-point numerical improvement from baseline compared with placebo at 3 weeks, with a significant 18.2-point improvement seen at 4 weeks (P ⫽ 0.01). A significant improvement in overall sleep quality compared with the placebo group was also seen in patients receiving oxymorphone ER 20 mg at 3 weeks, with an 18.1point improvement from baseline VAS score compared with placebo (P ⫽ 0.038); however, the improvement was reduced to 13.8 points and no longer of statistical significance at 4 weeks. Somnolence was one of the most frequently reported adverse events in the oxymorphone ER 20 mg and 40 mg treatment groups (30 and 31%, respectively) (29). Another 2-week, multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the analgesic efficacy, dose-response, and tolerability of oxymor-

Sleep OA

phone ER in patients with moderate to severe pain due to OA of the hip or knee who were receiving opioid analgesics or did not achieve optimal pain relief with NSAIDs or acetaminophen (24). Patients were randomly assigned to receive oxymorphone ER 10 mg q12h during weeks 1 and 2 (n ⫽ 95), oxymorphone ER 20 mg q12h during week 1 and 40 mg q12h during week 2 (n ⫽ 93), oxymorphone ER 20 mg every q12h during week 1 and 50 mg q12h during week 2 (n ⫽ 91), or placebo q12h during weeks 1 and 2 (n ⫽ 91). Patients who received oxymorphone ER experienced significant improvement in mean pain intensity (VAS) from baseline compared with placebo, with least-squares mean changes from baseline pain intensity scores of ⫺21, ⫺28, ⫺29, and ⫺17 mm in the oxymorphone ER 10 mg q12h, 40 mg q12h, 50 mg q12h, and placebo groups, respectively (24). A 63% (P ⫽ 0.012) reduction in pain intensity over placebo was demonstrated in those patients receiving the 40-mg dose, and a 71% (P ⫽ 0.006) reduction in pain intensity over placebo was demonstrated in those receiving the 50-mg dose; percentage changes were not reported for the oxymorphone ER 10-mg group. Furthermore, a dose-response relationship was observed, with higher doses of oxymorphone ER further decreasing arthritis pain intensity (P ⫽ 0.002). There was also a dose-response reduction in WOMAC OA Index pain subscale scores with oxymorphone ER treatment (P ⫽ 0.002) (24). Pain-related sleep disturbances were evaluated at baseline and at each subsequent visit using the CPSI item for overall sleep quality, with emphasis on the quality of sleep since the last visit. Improvements in the CPSI scores for overall sleep quality are depicted in Figure 2. A 2-fold improvement was demonstrated in overall sleep quality for patients who received oxymorphone ER 40 mg and 50 mg compared with placebo (P ⱕ 0.05) (24). Somnolence was 1 of the most commonly reported adverse events, occurring in 18% of patients. Together, these 2 studies provide preliminary evidence demonstrating that oxymorphone ER can provide effective pain relief and im-

Figure 2 Mean improvement in sleep scores at week 2 in patients receiving oxymorphone ER or placebo. Least-squares (LS) mean changes from baseline in CPSI VAS (0-100 mm) scores. *P ⱕ 0.05 versus placebo (24).

D.C. Turk and M.J.M. Cohen

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Figure 3 Mean improvement from baseline in quality of sleep (measured by BPI ranging from 0 to 10) in patients receiving CR oxycodone or placebo. *P ⱕ 0.05 versus placebo (37).

proved overall sleep quality compared with placebo in patients with chronic OA-related pain who experienced suboptimal pain relief with acetaminophen or NSAIDs. CR Oxycodone Three studies evaluated a CR oral formulation of oxycodone hydrochloride (OxyContin®; Purdue Pharma L.P.) in patients with OA. In a multicenter, double-blind, parallel-group study conducted to evaluate the long-term efficacy of CR oxycodone, patients with moderate to severe chronic pain due to OA received either CR oxycodone 10 mg (n ⫽ 44), CR oxycodone 20 mg (n ⫽ 44), or placebo (n ⫽ 45) q12h for 14 days (37). Improvements in pain intensity were evaluated in the context of percentage of reduction; a 20% average reduction in baseline pain intensity is widely considered clinically meaningful (37). Patients who received CR oxycodone 20 mg q12h achieved a 20% average reduction in baseline pain intensity based on the Brief Pain Inventory (BPI) scale within 1 day of beginning treatment, whereas patients who received CR oxycodone 10 mg q12h achieved a 20% average reduction in baseline pain intensity by day 2 of treatment. In contrast, patients who received placebo never achieved a 20% average reduction in baseline pain intensity. Significantly fewer patients in the CR oxycodone groups discontinued treatment because of inadequate pain relief compared with placebo (P ⬍ 0.001). The BPI scale (40), a standardized, validated instrument that assesses pain intensity and the interference of pain with daily activities over the previous 24 hours, was used to assess pain-related sleep disturbance in this study (37). The BPI subscales evaluating interference from pain with daily activities, including sleep, range from a score of 0 (does not interfere) to 10 (completely interferes). Patients who received CR oxycodone 20 mg demonstrated significant mean reductions from baseline to week 2 in interference of pain on sleep (P ⬍ 0.05 versus placebo). Patients also rated their overall quality of sleep using a

5-point scale (1 ⫽ very poor; 5 ⫽ excellent); those who received CR oxycodone 20 mg reported significantly improved quality of sleep at week 2 and overall compared with those who received placebo (P ⬍ 0.05; Fig. 3). Somnolence was reported in 25% of the CR oxycodone 10-mg treatment group and 27% of the CR oxycodone 20-mg treatment group (37). Another multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and safety of CR oxycodone 10 mg given q12h around the clock with that of oxycodone-acetaminophen (APAP) immediate-release (IR; 5-325 mg) given 4 times daily (qid) in patients with moderate to severe chronic OA pain despite regular NSAID use (n ⫽ 167) (38). The first 30 days of the study represented an open-label titration phase, where all patients were titrated to stable pain control with up to 60 mg/d oxycodone IR qid. During the titration period, the intensity of pain (rated using a categorical scale, which ranged from 0 ⫽ none to 3 ⫽ severe) decreased significantly (P ⫽ 0.0001). In addition, the global quality of sleep (assessed using a categorical scale that ranged from 1 ⫽ very poor to 5 ⫽ excellent) scores increased from 2.58 ⫾ 0.08 at baseline to 3.57 ⫾ 0.07 at the end of titration (P ⫽ 0.0001) (38). Following titration, 107 of the 167 patients initially enrolled were randomly assigned to treatment in the double-blind portion of the study; the majority of the remaining 60 patients discontinued because of adverse events (n ⫽ 36) or lack of efficacy (n ⫽ 17) (38). In addition to the assessments of pain and sleep previously mentioned, patients were asked to keep a pain and sleep diary for the 3 days preceding the end of the double-blind treatment phase. Consistent with the results seen during the titration period, patients who received either CR oxycodone or oxycodone-APAP IR during the double-blind phase reported significant reductions in pain intensity and significant improvements in overall sleep quality compared with those who were receiving placebo (P ⱕ 0.05). Nota-

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bly, patients receiving CR oxycodone reported global sleep quality superior to that of those receiving oxycodone-APAP IR throughout the double-blind treatment phase (P ⫽ 0.038). In contrast, global sleep quality decreased significantly in patients receiving placebo (P ⱕ 0.0001). In addition, mean day 3 diary scores for quality of sleep at the end of the double-blind treatment were significantly higher in the CR oxycodone and oxycodoneAPAP IR treatment groups than in the placebo group (P ⫽ 0.0001). There were no significant sleep diary differences between CR oxycodone and oxycodone-APAP IR; as noted for the global score, significant changes from the end of titration occurred only in the placebo group (P ⫽ 0.0001). Somnolence was a frequently reported adverse event during both treatment phases. The incidence of somnolence was 50% in the oxycodone-APAP IR group during the open-label titration phase and 70% during the double-blind phase; 53% of patients receiving CR oxycodone during the double-blind period reported somnolence (38). A relatively high incidence (36%) of somnolence was observed in the placebo group as well. The most recently published study of CR oxycodone was a 90-day, randomized, placebo-controlled, parallel-group study analyzing the efficacy and safety of CR oxycodone in patients with uncontrolled persistent pain due to OA (n ⫽ 109) (30). Patients were randomly assigned to treatment with either CR oxycodone 10 mg or placebo q12h for up to 90 days. The BPI was used in this study to assess average and current pain intensity and the interference of pain with sleep. Average and current pain intensity were measured on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). Patients who received CR oxycodone reported significantly lower mean BPI average pain intensity subscale scores at steady-state compared with patients who received placebo (5.1 ⫾ 0.3 versus 6.0 ⫾ 0.3; P ⫽ 0.042). Approximately 38% of patients receiving CR oxycodone achieved 30% or greater pain relief at the end of the 90-day study period compared with only 18% of those receiving placebo (P ⫽ 0.031). Further, 50% or greater pain relief was achieved at 90 days by 20% of patients receiving CR oxycodone, compared with only 6% of those receiving placebo (P ⫽ 0.045). At all treatment visits, patients who received CR oxycodone had significantly reduced BPI subscale scores for interference caused by pain for sleep compared with placebo (–2.8 versus – 0.9; P ⬍ 0.001). Somnolence was reported in 32% of patients in the CR oxycodone group and was 1 of the most commonly reported adverse events leading to study discontinuation in this group. Taken together, the results of these studies demonstrate that oxycodone-APAP IR and CR oxycodone can improve sleep and reduce pain in OA. CR oxycodone may have a better overall effect on sleep quality over time than oxycodone-APAP IR based on these data.

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Transdermal Fentanyl Transdermal fentanyl is indicated for the management of persistent moderate to severe chronic pain only in opioid-tolerant patients (41). The efficacy of transdermal fentanyl was evaluated in a 6-week, multicenter, randomized, placebo-controlled study of patients with radiographically confirmed OA of the hip or knee who met criteria for joint replacement and had moderate to severe pain that was inadequately controlled by weak opioids (39). All enrolled patients were either awaiting joint replacement, had refused the procedure, or were unable to undergo the surgery for medical reasons. Patients were randomized to receive either transdermal fentanyl (Durogesic; Janssen-Cilag, Beerse, Belgium; n ⫽ 202) starting at a dose of 25 ␮g/h, or a placebo patch (n ⫽ 197). The patches were replaced every 72 hours; at that time, 1 additional patch could be applied (to a maximum of 4 patches, or 100 ␮g fentanyl/h in patients randomized to this treatment) as needed to achieve adequate pain relief. Compared with placebo, transdermal fentanyl was associated with significant improvements in VAS pain scores from baseline to week 6 (P ⫽ 0.025) (39). In this study, current target joint pain, worst pain on the day of each visit, pain impairing function, and pain while walking were compared between baseline and the end of the study using the difference between the average area under the curve of the VAS scores over time between baseline and week 6. Transdermal fentanyl yielded significantly greater improvements in each of these parameters when compared with placebo (all P ⱕ 0.01). Scores on the WOMAC subscale for pain also improved significantly from baseline to week 6 in the transdermal fentanyl group compared with the placebo group (P ⫽ 0.001). A significantly higher percentage of patients in the placebo group (33%) discontinued the study because of insufficient analgesia compared with the transdermal fentanyl group (7%; P ⬍ 0.001). Patients also rated pain disturbing night rest on a 100-mm VAS. As was the case with other parameters measuring pain intensity and its functional impact, there was a greater improvement in pain disturbing night rest from baseline to week 6 in the transdermal fentanyl group compared with the placebo group (⫺19.1 versus ⫺12.0, respectively; P ⫽ 0.002) (39). The incidence of somnolence was significantly higher in the transdermal fentanyl group (22%) compared with the placebo group (4%; P ⬍ 0.001). ER Tramadol Tramadol is a centrally acting synthetic opioid analgesic that exhibits both weak opioid and nonopioid properties, the latter similar to actions of tricyclic antidepressants in the central nervous system (42). Two studies evaluated an ER formulation of tramadol (ULTRAM® ER; Ortho-

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McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ) in patients with chronic pain due to OA. In a 12-week, randomized, double-blind, placebo-controlled parallel-group study, 246 patients with moderate to severe chronic pain from OA received either tramadol ER (n ⫽ 124) at doses of 200 to 400 mg/daily (mean daily dose, 276 mg) or placebo (n ⫽ 122) (25). In this study, the mean changes from baseline in Arthritis Pain Intensity VAS and WOMAC OA Index pain subscale scores (averaged over the 12-week study period) were significantly greater for patients who received tramadol ER compared with those who received placebo (P ⬍ 0.001); the change from baseline in the WOMAC pain subscale score was 120.1 mm for tramadol ER versus 69.0 mm for placebo (0-500 mm possible score). The group receiving tramadol ER had a significantly lower rate of study discontinuations because of lack of analgesic efficacy than the group receiving placebo (19 versus 38%, respectively; P ⬍ 0.001) (25). In addition to improved pain scores, tramadol ER treatment was associated with statistically significant improvements from baseline over the 12 weeks of the study in painrelated sleep parameters (measured using the CPSI) when compared with placebo treatment (Fig. 4) (25). Mean changes averaged over the 12-week study period all demonstrated significant improvements in pain-related sleep parameters in patients receiving tramadol ER, compared with those receiving placebo. Specifically, improvements were seen in trouble falling asleep due to pain (P ⫽ 0.016), awakenings from pain during the night (P ⫽ 0.005), awakenings from pain in the morning (P ⫽ 0.004), and overall sleep quality (P ⫽ 0.031). Somnolence occurred in 8% of patients treated with tramadol ER compared with 2% of patients in the placebo group (25). Tramadol ER was also evaluated in a multicenter, randomized, double-blind, placebo-controlled study involving 1020 patients with OA of the knee or hip (26). Pa-

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tients received either placebo or were titrated to tramadol ER doses of 100, 200, 300, or 400 mg once daily for 12 weeks (26). In this study, tramadol ER was more effective than placebo, producing significantly greater improvements in the scores for pain intensity in the index joint and daily pain intensity at the final visit (P ⱕ 0.05 for all comparisons) (26). Patients receiving tramadol ER showed significant improvements in pain-related sleep parameters as assessed by the CPSI, namely, trouble falling asleep due to pain, being awakened by pain during the night and in the morning, and in overall sleep quality compared with placebo at the final visit (P ⱕ 0.05 for all parameters). The incidence of somnolence was highest in the tramadol ER 400-mg dose group (20%); however, this dose exceeded the maximum recommended daily dose of 300 mg per day. Somnolence occurred in 8 to 10% of patients in all other tramadol ER dose groups compared with 2% of patients in the placebo group. DISCUSSION Chronic pain associated with OA can have a significant impact on normal sleep, which can in turn affect multiple aspects of daily life. Because greater pain intensity has been associated with a host of sleep disturbances (such as decreased sleep time, reduced sleep satisfaction, delayed sleep onset, and more frequent awakenings), greater understanding of the relationship between chronic pain and sleep is vital to successful patient management. A preponderance of the studies produced by our literature review that systematically assessed sleep and pain as outcomes in OA patients also examined the effectiveness of long-acting opioids in OA. These studies suggest that long-acting analgesic therapy may represent an important component of treatment for chronic pain in OA and that the pain

Figure 4 Least-squares (LS) mean changes in CPSI scores (0-100 mm) averaged over weeks 1 to 12 in patients treated with tramadol ER or placebo. *P ⬍ 0.031 versus placebo. †P ⬍ 0.005 versus placebo (25).

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relief rendered by long-acting opioids is associated with a positive impact on sleep quality in these patients. There are, however, several limitations of these studies. First, the majority of these studies were of short duration, and whether these results can be accurately generalized to chronic, longer term use in OA patients with chronic pain is unknown. Given the relatively high dropout rates and the magnitude of pain relief seen in these studies, it is clear that additional longterm studies are needed to assess the persistence over time of demonstrated improvements in pain and sleep and the long-term tolerability of opioids in patients with chronic pain. These studies were also limited by fixed dosing, which may have impacted both efficacy (eg, in opioid-experienced patients) and tolerance (eg, in opioid-naïve patients randomized to a higher starting dose); in fact, the inability to adjust opioid dosing in these studies may have contributed to the relatively high incidence of discontinuations due to adverse events (20 to 55%). Data from these studies suggest that dose is, in fact, a key variable, with the greatest analgesic and sleep benefits being achieved after titration of the long-acting opioid dosage to an effective level (24,29,37). In 1 of the studies, analgesia varied linearly with dose (24). At the same time, data from some of the studies suggested that a long-acting opioid dose that is too high may be associated with excessive adverse effects (26,38). As it turns out, 1 of those studies (26) included a dose of tramadol ER (400 mg once daily) that is not commercially available, given that the maximum recommended daily dose of tramadol ER is 300 mg (43). Another potential limitation was the fact that not all of the studies used validated instruments to assess sleep problems. The majority of studies used all or part of the CPSI, which has been validated for the purpose of assessing sleep disturbances in patients with chronic pain. However, individual items on the inventory are not necessarily as reliable; for example, the item for overall quality of sleep (CPSI5) has demonstrated relatively weak correlation with other health-related scales and weak convergence with other CPSI items during psychometric evaluation (27). Additional limitations of these particular studies reflect the broader challenges faced in clinical studies focused on the impact of analgesic treatment on sleep disturbances in patients with chronic pain. For example, somnolence is a common adverse effect of opioid analgesics, occurring in up to 50% of patients receiving long-acting opioids in these studies, with the typical incidence ranging from 20 to 33%. Therefore, it may be difficult to determine whether reductions in sleep disturbances are the result of attenuation of the interference of pain on sleep (via symptomatic control of OA) or are instead a consequence of the sedating properties of the drugs themselves. Data from these studies

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suggest that the positive impact on sleep is different from sedative effects, since placebo-treated patients experienced deterioration in sleep compared with opioidtreated patients. Additionally, the simultaneous reporting of sleep improvements and somnolence as an adverse event in some of the studies suggests that patients could distinguish chronic sedation from better sleep. Likewise, while improvements in sleep paralleled increases in long-acting opioid dose and decreased pain in these studies, somnolence was not as closely associated with dose and analgesia: the level of somnolence was not significantly different based on varying longacting opioid doses in a number of the studies (24,26,29,37). Somnolence appeared to become significantly more problematic at very high analgesic doses (26,38). Finally, the functional improvements demonstrated in many of these studies also support the differentiation between restorative sleep and sedation. Better measures to parse the sedating effects of analgesics from their sleep-normalizing effects are needed to optimally dose long-acting opioids and control sedation in patients with chronic pain who are suitable candidates for opioid therapy. Other factors that may contribute to sleep disruption in patients with chronic pain were not specifically addressed in these studies. Chronic pain is known to increase the risk of depression and other affective disturbances, which are independently associated with sleep problems such as insomnia (44). In fact, among patients with chronic pain, sleep complaints have been shown to correlate more strongly with severity of depression than severity of pain (45). Some medications, including analgesics, may also contribute to sleep disruption. Although a number of studies, including these, have demonstrated parallel improvements in pain intensity and sleep disturbances in patients with chronic pain receiving analgesics, the precise interaction between these outcomes remains elusive, given the numerous potential confounding factors. The use of opioid analgesics is associated with a number of limitations that include gastrointestinal tolerability problems and central nervous system sedation (46,47). As an example, recent meta-analysis of over 6000 patients who received opioids, NSAIDs, or tricyclic antidepressants for chronic pain (47) showed that gastrointestinal disturbances and central nervous system effects occurred more commonly with opioids than with NSAIDs or placebo. The specific incidences of these events in opioidtreated patients were as follows: constipation, 16%; nausea, 15%; dizziness, 8%; and somnolence, 9%. However, it should also be noted that the other agents most frequently used for OA—NSAIDs and COX-2 inhibitors— are not without potentially serious adverse effects, including gastrointestinal ulcers, hyperkalemia, acute renal failure, and cardiovascular risks (48-50). The morbidity associated with NSAID is substantial, as approximately

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107,000 arthritis patients are hospitalized for NSAIDrelated gastrointestinal events, and 16,500 patients will die from NSAID-associated conditions each year (51). The most common adverse events that led to discontinuation in these studies were constipation, nausea, dizziness, and somnolence, which were among the most common adverse events in general and are typical of treatment with opioid analgesics. As alluded to earlier, the inability to adjust opioid dosing in these studies may have contributed to the high incidence of discontinuations due to adverse events. Respiratory depression, 1 of the most serious adverse events associated with opioids, was not reported in any of the studies. Only the study evaluating CR codeine (36) addressed another potential serious consequence of opioid treatment—addiction. In that study, patients receiving codeine reported a higher mean score (6.4) on the Drug Liking Index compared with those receiving placebo (5.0; P ⫽ 0.001); however, while the Drug Liking Index specifically asks that patients rate the central nervous system effects other than analgesia of their assigned medication on a scale from 1 (“I dislike the drug effect very much”) to 9 (“I like the drug effect very much”), the study investigators could not rule out the influence of improved pain control on the responses (36). Available data suggest that the management of chronic OA pain may include around-the-clock pain control with long-acting opioids. Pain reductions achieved are associated with improved sleep, as well as functional status and other health-related quality of life indicators. We strongly advocate that treatment effects be measured along multiple behavioral and functional dimensions that affect quality of life. This is a more meaningful assessment of treatment outcome than relying primarily on changes in pain ratings. Sleep quality is an important behavioral measure of treatment efficacy. Other investigators and clinical experts have made similar recommendations (11-13). As we continue to assess the efficacy of treatments for chronic OA pain and other disorders, it will be essential that investigators examine effects in multiple relevant domains of patient experience and behavior. The effect on painrelated sleep disturbances is one such important dimension. Future studies are needed to determine the most valid sleep measures for detection of treatment-related sleep changes in chronic pain. It is inadequate to assess efficacy of pain treatments using self-reported reductions in pain as the major outcome measure. Ultimately, the best markers of successful pain treatment will be positive changes in behavioral, functional, and affective domains that represent realworld anchors of patients’ quality of life. REFERENCES 1. Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical management. Anesth Analg 2004;99:510-20, table. 2. Glickman-Simon R. Persistent pain and palliative care. Medscape

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