A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans® Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic®) in Patients With Osteoarthritis Pain

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Vol. 40 No. 2 August 2010

Original Article

A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTransÒ Seven-Day Patches) With Buprenorphine Sublingual Tablets (TemgesicÒ) in Patients With Osteoarthritis Pain Ian G.V. James, MBChB, DCH, DRCOG, Catherine M. O’Brien, MSc, and Chris J. McDonald, MBBS, MRCOphth, FFPM Spring House Surgery (I.G.V.J.), Bolton, Lancashire; Fincham Statistics (C.M.O.), King’s Lynn, Norfolk; and Medical Services and Pharmacovigilance (C.J.M.), Napp Pharmaceuticals Limited, Cambridge, United Kingdom

Abstract Context. Osteoarthritis (OA) is a common cause of chronic pain, particularly in the older population. Modern approaches to the management of OA pain recommend tailoring treatment to the individual. This study examines treatment options for OA pain in the form of low-dose transdermal and sublingual opioid analgesia. Objectives. The aims of this trial were to compare the efficacy and tolerability of seven-day, low-dose transdermal buprenorphine patches (BuTransÒ, Napp Pharmaceuticals Limited UK) with sublingual buprenorphine (TemgesicÒ, Schering-Plough Limited UK) in patients with moderate to severe pain caused by OA of the hip(s) and/or knee(s), and to establish analgesic equivalence of the two products. Methods. Two hundred forty-six patients with OA pain in the hip(s) and/or knee(s) were enrolled in this randomized, double-blind, parallel-group study; 110 completed the study. Patients were randomized to receive transdermal buprenorphine patches (5, 10, and 20 mg/hour) or sublingual buprenorphine (200 and 400 mg tablets). Their medication was titrated to pain control and they were treated for up to seven weeks. The main outcome measures were pain intensity (primary outcome), sleep disturbance, quality of life, and safety assessments.

This trial was sponsored by Napp Pharmaceuticals Limited, United Kingdom. Address correspondence to: Chris J McDonald, MB, BS, Napp Pharmaceuticals Limited, Cambridge Science Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.

Park, Milton Road, Cambridge CB4 0GW, United Kingdom. E-mail: [email protected] Accepted for publication: January 12, 2010.

0885-3924/$esee front matter doi:10.1016/j.jpainsymman.2010.01.013

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Results. Patients’ Box Scale-11 pain scores decreased between entry and assessment in both treatment groups. During the 28-day assessment period, the estimated mean treatment differences (95% confidence intervals) were 0.00 (0.68,0.69), 0.11 (0.85,0.63), and 0.13 (0.95,0.68), for the morning, midday, and evening scores, respectively. All the confidence intervals were within the prespecified limits for equivalence (1.5, 1.5). Use of escape medication was low. In both treatment groups, sleep disturbance caused by pain decreased between entry and assessment. Patients’ quality of life improved during the study. Significantly fewer patients receiving the transdermal buprenorphine patches reported nausea (P ¼ 0.035), dizziness (P ¼ 0.026), and vomiting (P ¼ 0.039). Conclusion. In conclusion, seven-day, low-dose transdermal buprenorphine patches are as effective as sublingual buprenorphine, with a better tolerability profile. J Pain Symptom Manage 2010;40:266e278. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words 7-day, low dose, transdermal, buprenorphine, patches, osteoarthritis, pain, sublingual

Introduction Buprenorphine is a synthetic opioid analgesic derived from the opium alkaloid, thebaine. It is a partial mu opioid receptor agonist that provides sustained analgesia and has been shown to be well tolerated and effective for treating moderate to severe pain in a wide range of acute and chronic pain states.1e8 Buprenorphine has high affinity for mu, delta, and kappa opioid receptors, with lower but significant affinity at opioid receptors like 1 (ORL1) receptors in vitro.9 It is generally accepted as a partial mu opioid receptor agonist, an antagonist at delta receptors, a low-efficacy agonist or antagonist at kappa receptors, and an agonist at ORL1 receptors.10 Studies in mice have shown that the mu opioid receptor is the primary mediator of nociceptive pain.11 The main hepatic metabolite of buprenorphine is norbuprenorphine, which is an agonist at the delta opioid receptor. Recent rodent studies suggest that delta opioid agonism may provide analgesia in bone pain.12 Osteoarthritis (OA) is mainly a disease of the elderly population, and buprenorphine has several potential therapeutic advantages in this age group over other opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) selective inhibitors. As a partial mu opioid receptor agonist, there is a ceiling to its respiratory depressive effects,13e15 meaning that respiratory depression is rare in patients receiving

buprenorphine for pain relief. Binding to and dissociation from the receptor is slow, giving sustained analgesia and a low level of physical dependence.16,17 Buprenorphine’s actions as a kappa opioid receptor antagonist 18 also mean that it is less likely to cause adverse psychomimetic effects (e.g., dysphoria and hallucinations). Buprenorphine does not require dose adjustment in the elderly or in patients with renal impairment and avoids the emerging cardiovascular risks as well as the established gastrointestinal risks (mucosal ulceration with potentially life-threatening bleeds) that are associated with COX-2 inhibitors and NSAIDs, respectively.19e21 In the United Kingdom, parenteral buprenorphine was first approved for the treatment of moderate to severe pain in 1978. Since then, buprenorphine has become available as sublingual tablets and transdermal patches. Sublingual buprenorphine has high systemic availability and reaches maximal plasma concentrations within a few hours,22 but this can lead to characteristic peaks and troughs in plasma buprenorphine concentrations, with the potential to result in side effects. In contrast, transdermal delivery ensures a constant level of analgesia for extended periods of time,23 making transdermal buprenorphine patches particularly suitable for the treatment of chronic conditions, such as OA. The United Kingdom’s first low-dose buprenorphine transdermal patch was launched in

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September 2005, providing prolonged analgesia over a seven-day period. To assess the efficacy and tolerability of the seven-day, lowdose transdermal buprenorphine patch, it was compared with sublingual buprenorphine tablets, which have been shown to be effective in the treatment of postoperative and chronic pain.5,7,8 We chose OA as a model for this study, because it is a common condition, and OA pain is chronic and stable, allowing a large number of patients to be followed over a long period of time. Patients who took part in this research were suffering moderate to severe pain immediately before entering the study, despite receiving oral and topical analgesia.

Methods We designed this study to assess the efficacy and tolerability of seven-day, low-dose transdermal buprenorphine patches compared with sublingual buprenorphine in patients with pain caused by OA of the hip(s) and/or knee(s), and to establish analgesic equivalence of the two products.

Protocol The study was approved by local research ethics committees, and patients were recruited from 24 general practices in the United Kingdom and a single hospital in Australia. All patients gave written informed consent before enrolling in the study. Patients were of either sex, aged 18e80 years, with moderate to severe pain caused by OA of the hip(s) and/or knee(s). Moderate to severe pain was defined as a score of at least 4 boxes on the Box Scale-11 (BS-11), where 0 ¼ no pain and 10 ¼ pain as bad as you can imagine. Patients had to stop taking their current analgesic medication for the duration of the study. Patients entering the study had not taken strong (i.e., WHO ladder Step 3) opioids in the last six weeks, long-acting NSAIDs (e.g., meloxicam, naproxen) in the last seven days, or modified-release NSAIDs in the last 24 hours. Patients who had received an intraarticular injection in the last six weeks or who were scheduled to receive one within the study period also were excluded. Other reasons for exclusion included patients with chronic painful conditions or joint disorders other than OA.

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Table 1 Dose Levels of Study Medication

Dose Level

7-Day, Low-Dose Transdermal Buprenorphine Patches (mg)

Buprenorphine Sublingual Tablets

1 2 3

5 (5 mg/houra) 10 (10 mg/houra) 20 (20 mg/houra)

200 mg, 8 hourly 200 mg, 6 hourly 400 mg, 8 hourly

a

Buprenorphine release rate.

This was a randomized, double-blind, doubledummy study, consisting of a titration period (up to 21 days) and an assessment period (up to 28 days). Patients received their allocated study medication (a seven-day, low-dose transdermal buprenorphine patch or sublingual buprenorphine tablets) and a placebo version of the alternative medication. Table 1 shows the dose levels of study medication that were available to patients. All patients started treatment on Dose Level 1. During the titration period, the investigator titrated the dose of study medication every seven days until the patient achieved optimal pain control. The investigator decided whether or not the patient had achieved optimal pain control by assessing pain intensity, use of escape medication, sleep disturbance because of pain, and adverse events. If the patient had not achieved optimal pain control after three weeks, they were discontinued from the study. Patients who achieved optimal pain control entered the assessment period, during which they received their optimum dose of study medication, as identified during the titration period. During the assessment period, the investigator could increase or decrease the patient’s dose after two weeks if he/she considered it was necessary.

Pain Intensity. The primary efficacy variable was the patient’s current level of pain intensity recorded during the assessment period (i.e., when the patient was in stable pain control). Patients changed their patch every seven days during the 28-day assessment period. Pain intensity was recorded each day in a patient diary card using the BS-11 scale. Patients recorded scores before taking their study medication in the morning, at midday, and in the evening on a daily basis throughout the study. They

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also recorded their pain intensity each time they took escape medication. Escape Medication. Patients were allowed to take oral paracetamol (acetaminophen) tablets (500 mg) as escape medication for breakthrough pain (they could take 1,000 mg every four to six hours up to a maximum daily dose of 4,000 mg per day). Each day, patients recorded the number of tablets they had taken and the times at which they took them. Sleep Disturbance. Each day during the study, patients recorded whether they had been woken during the previous night because of pain and, if so, the number of times they were woken, that is, once, twice, or more than twice. At each study visit, patients rated their quality of sleep over the last seven nights as very poor, poor, fair, good, and very good. Patients also rated their average pain over the last seven nights using the BS-11 scale. Quality of Life Assessment. At study entry and on completion of, or discontinuation from, the study, patients completed the Brief Pain Inventory24 and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index.25,26 Acceptability of Treatment. At study entry, patients and investigators were asked to rate the efficacy of the patient’s pre-study painkiller as very poor, poor, fair, good, or very good. On completion of the study, patients and investigators rated the efficacy of the study medication in the same way and rated the patient’s pain relief with the study medication compared with the pre-study painkiller as much worse, worse, same, better, and much better. Safety Assessments. At each study visit, the investigator recorded any adverse events that the patients volunteered. Adverse events that the investigator considered to be possibly or probably related to drug treatment were classified as adverse drug reactions. Patients assessed the application site of the transdermal patches for redness, itchiness, and swelling, at 0, 12, and 24 hours after removal of each transdermal patch.

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Patch Durability. By questioning the patient, the investigator assessed the durability of the transdermal patch (i.e., whether it had fallen off, needed taping, moved from the original application site, buckled, curled, changed color or shape, or produced a bad odor) at each visit.

Assignment Investigators enrolled patients and assigned them sequentially to treatment according to a computer-generated randomization schedule produced by the sponsor. Treatments were randomized in balanced, complete blocks of equal size. The packs of study medication were labeled with the patient number.

Masking This was a double-blind, double-dummy study. Neither the investigators nor the patients were aware of the treatment allocation. Initial data analysis was carried out blinded, using the treatment group codes (i.e., Group A and Group B). After this initial analysis, the blind was broken, and the full data analysis was carried out. Placebo versions of the seven-day, low-dose transdermal buprenorphine patches and sublingual tablets were manufactured to appear identical to the active medication.

Statistical Analyses It was estimated that, with 55 completing patients in each treatment group, the study would have 90% power at the 5% significance level to confirm that transdermal buprenorphine patches were equivalent to sublingual buprenorphine if the 95% confidence interval for the estimated mean treatment difference fell within the range (1.5, 1.5) boxes on the BS-11 scale, assuming that the standard deviation (SD) was 2.4. We defined these limits on the basis of discussions with pain specialists. To analyze the data, we used analysis of covariance for the primary outcome (mean BS-11 scores on Days 3 and 7 for each patch worn during the assessment period). We chose to look at Days 3 and 7 to counteract the misconception that the low-dose transdermal buprenorphine patch was only effective for three days. We also used the Chi-squared test for the adverse drug reactions and withdrawals and Friedman’s two-way analysis of variance

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Assessed for eligibility (n = 246) Excluded (n = 8) Failed to meet inclusion criteria (n = 8)

Randomized (n = 238)

Allocated to seven-day, low- dose transdermal buprenorphine (n = 118)

Allocated to buprenorphine sublingual tablets (n = 120)

Completed study (n = 56)

Completed study (n = 54)

Withdrawn (n = 62)

Withdrawn (n = 66)

Adverse event (n = 43)

Adverse event (n = 53)

Lack of efficacy (n = 11)

Lack of efficacy (n = 7)

Adverse event and lack of efficacy (n = 5)

Adverse event and lack of efficacy (n = 4)

Other (n = 2)

Other (n = 2)

Adverse event and other (n = 1)

Adverse event and other (n = 0)

Included in primary analysis (n = 51)

Included in primarya nalysis (n = 51)

Excluded from primary analysis (n = 67)

Excluded from primary analysis (n = 69)

Did not complete all three pain scores on at least 21 occasions during the assessment period (n = 63)

Did not complete all three pain scores on at least 21 occasions during the assessment period (n = 66)

Wore patch for eight or more days on more than one occasion (n = 2)

Did not take study medication during the first week of the assessment period because of adverse event(s) (n = 1)

Had been diagnosed with OA less than one month before study entry (n = 2)

Recorded a Brief Pain Inventory score of less than 4 boxes for “pain right now” at screening (n = 2)

Fig. 1. Participant flow through the study.

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for the transdermal patch application site assessments.

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Table 3 BS-11 Pain Scores at Study Entry and During the Assessment Period (Per-Protocol Population) Mean (SD) BS-11 Scores (Boxes)

Results Participant Flow Figure 1 shows the flow of patients through the study. The first patient was enrolled on July 22, 1999, and the last patient completed on July 24, 2000. The intention-to-treat population included all patients who were randomized to treatment: 118 who received sevenday, low-dose transdermal buprenorphine patches and 120 who received sublingual buprenorphine. The per-protocol population included 102 patients (51 in each treatment group). As this was an equivalence study based on pain intensity, we considered the perprotocol population to be the primary analysis. Unless otherwise stated, the data quoted in this article are for the per-protocol population.

Analysis Baseline Characteristics. Patients’ baseline characteristics were similar between treatment groups. Table 2 shows patient baseline characteristics at study entry (intention-to-treat population). The mean (range) age was 64.9 (44e81) years in the seven-day, low-dose transdermal buprenorphine patch group and 63.7 (42e80) years in the sublingual buprenorphine group. More than 80% of patients in each treatment group had been suffering

Table 2 Baseline Characteristics at Study Entry

Characteristic

7-Day, Low-Dose Transdermal Buprenorphine Patches (n ¼ 118)

Buprenorphine Sublingual Tablets (n ¼ 120)

Number (%) of patients Male 41 (35) Female 77 (65)

46 (38) 74 (62)

Age (years) Mean Range

64.9 44e81

63.7 42e80

Weight (kg) Mean Range

84.0 49e155

85.4 44e171

Number (%) of patients Caucasian 117 (>99) Black 1 (<1) Asian 0

119 (>99) 0 1 (<1)

Study Time Point Study entry Morning (Day 1) Midday (Day 0)c Evening (Day 0)

7-Day, Low-Dose Buprenorphine Transdermal Sublingual Buprenorphine Patches (n ¼ 51)a Tablets (n ¼ 51)b 5.7 (2.3) 6.3 (1.5) 6.4 (1.9)

5.9 (2.3) 6.2 (1.6) 6.8 (1.7)

Assessment period (Weeks 1e4) Day 3 Morning 3.1 (1.9) Midday 3.3 (2.0) Evening 3.3 (2.1)

3.1 (2.1) 3.3 (1.9) 3.2 (2.0)

Day 7 Morning Midday Evening

3.0 (2.0) 3.3 (1.9) 3.4 (2.0)

3.1 (2.0) 3.2 (2.0) 3.2 (2.0)

a

Except for study-entry morning (n ¼ 50) and evening (n ¼ 41). Except for study-entry morning and midday (n ¼ 50) and studyentry evening (n ¼ 41). c Patients did not record a midday score at study entry; hence, the values in this table are those recorded for ‘‘current pain’’ in the Brief Pain Inventory. b

with OA for at least one year before they entered the study. The most common site of pain was the knee(s).

Box Scale-11 Pain Scores. BS-11 pain scores decreased between study entry and assessment in both treatment groups (Table 3). There was no evidence for a difference in the pain scores recorded on Day 3 and Day 7 of the assessment period. The estimated mean treatment difference between patients receiving seven-day, low-dose transdermal buprenorphine patches compared with sublingual buprenorphine was, therefore, calculated from the overall mean pain scores from Days 3 and 7 combined. During the assessment period, the estimated mean treatment differences (95% confidence intervals) were 0.00 (0.68, 0.69), 0.11 (0.85, 0.63), and 0.13 (0.95, 0.68), for the morning, midday, and evening scores, respectively. All of these confidence intervals were within the prespecified limits for equivalence (1.5, 1.5). Use of escape medication was low throughout the study in both treatment groups: median use during the assessment period was 0.3 doses per day on Day 3 and Day 7 in both

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Table 4 Number of Nights Woken Because of Pain During the Past Seven Nights (Per-Protocol Population) Mean (SD) Number of Nights Woken

Study Time Point

7-Day, Low-Dose Transdermal Buprenorphine Patches (n ¼ 51)a

Buprenorphine Sublingual Tablets (n ¼ 51)

Study entry End of titration End of assessment

4.06 (2.93) 2.90 (2.78) 2.73 (2.82)

3.94 (2.74) 3.06 (2.83) 2.57 (2.79)

a

Except for study entry (n ¼ 50).

groups (one dose ¼ two 500 mg paracetamol (acetaminophen) tablets). Sleep Disturbance. The number of nights woken because of pain decreased during the study in both treatment groups (Table 4). Both treatment groups also showed an improvement in the number of occasions per night that patients were woken because of pain and in patients’ quality of sleep. At study entry, nine patients (18%) treated with the seven-day, low-dose transdermal buprenorphine patch and 11 patients (22%) treated with sublingual buprenorphine rated their sleep over the last seven nights as good or very good. At the end of the assessment period, this had increased to 37 (73%) and 32 patients (63%), respectively. Average nocturnal pain decreased during the study for patients in both groups. Quality of Life. Data from the Brief Pain Inventory showed that pain intensity and

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interference with parameters, such as general activity, mood, normal work, and enjoyment of life, decreased during the study in both treatment groups. For example, the mean (SD) BS-11 score for pain interference with general activity at study entry was 6.7 (2.2) boxes in the seven-day, low-dose transdermal buprenorphine patch group and 6.4 (2.2) boxes in the sublingual buprenorphine group. At study completion, the corresponding scores were 3.0 (2.4) and 3.4 (2.4) boxes, respectively. For the WOMAC OA Index, the total score from the three subscales (pain, stiffness, and physical function) decreased between study entry and completion in both treatment groups. At study entry, the mean (SD) total score was 54.9 (12.8) in the seven-day, lowdose transdermal buprenorphine patch group and 53.2 (12.5) in the sublingual buprenorphine group. At completion, the corresponding scores were 37.4 (16.2) and 37.6 (19.3), respectively. Acceptability of Treatment. At study completion, at least 70% of the patients in each treatment group rated their pain relief with the study medication as ‘‘good’’ or ‘‘very good.’’ In addition, 33 patients (60%) receiving the seven-day, lowdose transdermal buprenorphine patch and 42 patients (79%) receiving sublingual buprenorphine rated their study medication as ‘‘better’’ or ‘‘much better’’ than their pre-study medication. The investigators’ assessments of acceptability of treatment were similar. Safety Assessments. Safety parameters were analyzed for the intention-to-treat population.

Table 5 Most Common ADRs Reported During the Study (Intention-to-Treat Population) Number (%) of Patients 7-Day, Low-Dose Transdermal Buprenorphine Patches ADR Nausea Dizziness Vomiting Somnolence Headache Constipation Asthenia

Titration (n ¼ 118) 37 29 20 13 23 13 11

(31) (25) (17) (11) (19) (11) (9)

Assessment (n ¼ 70) 18 10 4 10 9 14 3

(26) (14) (6) (14) (13) (20) (4)

a

Overall (n ¼ 118) 44 32 21 19 26 19 12

(37) (27) (18) (16) (22) (16) (10)

Sublingual Buprenorphine Tablets Titration (n ¼ 120) 59 45 35 20 13 16 10

(49) (38) (29) (17) (11) (13) (8)

Assessment (n ¼ 66) 14 (21) 13 (20) 0 12 (18) 3 (5) 11 (17) 5 (8)

Overalla (n ¼ 120) 61 49 35 23 15 17 13

(51) (41) (29) (19) (13) (14) (11)

a Subjects may have reported the same ADR during both the titration and assessment periods, which would only be counted once in the overall ADR total.

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Table 6 Skin Reactions at the Transdermal Patch Application Site (Intention-to-Treat Population) Number (%) of Patients Reporting a Reaction Active Transdermal Patches Time After Patch Removal

End of Titration

a

Placebo Transdermal Patches b

End of Assessment

End of Titrationc

End of Assessmentd

Irritation (hours) 0 12 24

22 (25) 18 (20) 10 (11)

14 (22) 11 (18) 6 (10)

12 (17) 14 (19) 7 (10)

14 (23) 12 (19) 8 (13)

Redness (hours) 0 12 24

47 (51) 42 (45) 29 (32)

36 (55) 30 (46) 15 (23)

30 (39) 26 (35) 16 (21)

25 (40) 25 (40) 19 (31)

Swelling (hours) 0 12 24

3 (4) 5 (6) 2 (2)

6 (10) 5 (9) 1 (2)

3 (4) 6 (9) 3 (4)

2 (3) 3 (5) 3 (5)

a

The number of patients with data available ranged from 80 to 93. The number of patients with data available ranged from 57 to 65. The number of patients with data available ranged from 70 to 76. d The number of patients with data available ranged from 61 to 62. b c

Significantly fewer patients receiving the sevenday, low-dose transdermal buprenorphine patches reported adverse drug reactions (ADRs) during treatment: 96 patients (81%) compared with 110 patients (92%) receiving sublingual buprenorphine (P ¼ 0.0197). The most commonly reported ADRs are shown in Table 5. Most of the reported ADRs were of mild to moderate intensity. Nausea was the most common ADR in both groups; however, only nine patients (six in the seven-day, low-dose transdermal buprenorphine patch group and three in the sublingual buprenorphine group) were prescribed concomitant antiemetics during the study. Nausea, dizziness, and vomiting occurred in fewer patients treated with seven-day, low-dose transdermal buprenorphine patches; the differences were statistically significant (P ¼ 0.035, 0.026, and 0.039, respectively). The percentage of patients reporting nausea, dizziness, and vomiting decreased between the assessment and titration periods in both treatment groups. One patient receiving seven-day, low-dose transdermal buprenorphine patches had a myocardial infarction and died during the study. The patient had no predisposing factors for myocardial infarction, and the investigator did not consider the myocardial infarction and subsequent death to be related to buprenorphine. Five other patients had serious adverse events. In three patients, they were not related

to treatment. The other two patients had serious adverse events that the investigator considered were related to treatment: one patient receiving seven-day, low-dose transdermal buprenorphine patches was hospitalized with suspected biliary colic/spasm of the sphincter of Oddi, and one patient receiving sublingual buprenorphine was hospitalized with dizziness, nausea, and asthenia. All of these events are known side effects of opioids in general and buprenorphine specifically. The patients recovered once therapy was stopped. The discontinuation rates for the intention-totreat population were as expected for both groups treated with an opioid analgesic: 62 patients (53%) receiving seven-day, low-dose transdermal buprenorphine patches and 66 patients (55%) receiving sublingual buprenorphine discontinued from the study (P ¼ 0.704). Fortynine patients (42%) receiving seven-day, lowdose transdermal buprenorphine patches and 57 (48%) patients receiving sublingual buprenorphine discontinued because of adverse event(s) with/without other reasons. Most patients who discontinued did so during the titration period. Some patients had skin reactions (redness, swelling, or irritation) at the patch application site. Irritation was reported by no more than 25% of patients in either group immediately after patch removal at the end of the titration and assessment periods; redness was reported

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by no more than 55% of patients and swelling by no more than 10%. The percentages of patients reporting these reactions decreased with time after patch removal (Table 6). There were no statistically significant differences between the active and placebo transdermal patches, except for redness during the titration period, which was more common with the active transdermal patch (P ¼ 0.016). Most patients graded their reaction as mild or moderate in intensity. Durability of the Patch. The most common problem with the patch was buckling or curling. This was reported by 18 patients (17%) treated with the active patch and 16 patients (15%) treated with the placebo patch at the end of the titration period. The corresponding numbers at the end of the assessment period were seven patients (10%) treated with the active patch and 10 patients (16%) treated with the placebo patch. No patients discontinued because of mechanical problems with the transdermal patches.

Discussion Overall, seven-day, low-dose transdermal buprenorphine patches have been shown to deliver effective analgesia in OA pain comparable to sublingual buprenorphine tablets, with a better tolerability profile. Both treatments gave effective pain control, as shown by the results for BS-11 pain scores and sleep disturbance and by the low use of escape medication. There was no statistical evidence for a difference in the BS-11 pain scores recorded on Day 3 and Day 7 for either of the treatment groups, showing that the analgesic efficacy of the low-dose transdermal buprenorphine patches lasted for the full seven days of treatment. Equivalence was shown for the two treatments with respect to BS-11 pain scores. The results were similar for the perprotocol and intention-to-treat populations, which increases the robustness of the findings. Patients’ quality of life improved during the study, as shown by the results for quality of sleep, the pain interference scores from the Brief Pain Inventory, and results from the WOMAC OA Index.

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Patients found the seven-day, low-dose transdermal buprenorphine patches and sublingual buprenorphine as acceptable treatment for their OA pain. As this study was double-dummy, it was not possible for us to assess whether patients found the transdermal buprenorphine patches more convenient than the sublingual tablets. However, published literature, including a review of data spanning 25 years,27 suggests that transdermal administration of medications has the potential to improve compliance. For example, one study in the elderly demonstrated 96% compliance with transdermal delivery of an antihypertensive agent, compared with 80% compliance with an oral agent,28 and patient compliance was significantly improved with hormone replacement therapy patches when compared with repetitive oral dosing.29 Further evidence suggests that transdermal opioids are preferred by patients over oral administration, and they improve the quality of life.30 The seven-day, low-dose transdermal buprenorphine patch was better tolerated than sublingual buprenorphine. The percentage of patients reporting ADRs with the seven-day low-dose transdermal buprenorphine patches was significantly lower than that for the sublingual tablets. Overall, significantly fewer patients treated with seven-day, low-dose transdermal buprenorphine patches reported typical opioid-related side effects, such as nausea, dizziness, and vomiting. The improved tolerability of seven-day, low-dose transdermal buprenorphine patches compared with sublingual buprenorphine may be because of the mode of drug administration. Pharmacokinetic studies have shown that repetitive sublingual or oral dosing of immediate-release analgesics is associated with characteristic peaks and troughs.31 In contrast, after administration of the transdermal patches, plasma concentrations of buprenorphine increase steadily and are maintained at a consistent level for up to seven days.32 Therefore, the potential adverse effects associated with plasma concentration peaks and the inadequate analgesia associated with the troughs that occur with other routes of opioid administration will be avoided with transdermal buprenorphine patches.33 However, in both treatment groups, we found that the percentage of patients reporting these ADRs was lower during the assessment period than during the titration period.

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This suggests that the incidence of these ADRs diminished once a stable dose was reached, possibly because patients who were more likely to suffer adverse events withdrew during the titration period. More than half the patients in each group discontinued, and most of these discontinued during the titration period. In addition, most patients who discontinued had adverse events as at least one of their reasons for discontinuation. A high discontinuation rate might be expected in patients whose ADRs were not being effectively managed. Nausea was the most common ADR in both groups; however, only nine patients (six in the seven-day, low-dose transdermal buprenorphine patches group and three in the sublingual buprenorphine group) were prescribed concomitant antiemetics. As expected for a transdermal patch, some patients had skin reactions at the application site. The percentages of patients who reported a reaction decreased with time after patch removal. The high rate of patient withdrawals is a common feature of clinical trials in chronic pain patients. For example, in two placebocontrolled trials of tramadol in OA, the withdrawal rates for patients receiving tramadol were 41%34 and 51%.35 In another placebocontrolled trial in OA, 39% of patients treated with controlled-release codeine withdrew from the study.36 Most patients who discontinued from the study did so during the titration stage, and patients receiving sublingual buprenorphine withdrew from the study earlier than those receiving transdermal buprenorphine patches. Patients were not allowed to take opioid medications for at least six weeks before entering the study and were not allowed to use NSAID medication throughout the study. The study medication may, therefore, have represented a significant change to the products that patients may be used to and could have resulted in a higher number of negative experiences in this elderly population than expected. It is not uncommon to see higher numbers or variability regarding side effects and responsiveness to opioid medications in studies of this kind.37 Patients included in this study had a mean age (range) of 64.3 (42e81) years, and more than 80% had been suffering with OA for at least one year, with the most common site of pain being the knee(s). This is consistent

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with a review by Peat et al., which states that during a one-year period, 25% of people older than 55 years have a persistent episode of knee pain, of whom about one in six in the United Kingdom consult their general practitioner.38 The review also states that the prevalence of painful disabling knee OA in people older than 55 years is 10%, of whom one-quarter are severely disabled. Controversy and concern with respect to some pharmacological treatments for painful OA make appropriate prescribing in the elderly increasingly difficult, especially because poor compliance, polypharmacy, and comorbid conditions occur more frequently in this group. In addition, NSAIDs, including COX-2 selective inhibitors, are associated with serious adverse events, such as gastrointestinal bleeding, cardiovascular complications, and renal impairment, and are not considered suitable for long-term use in the elderly.39,40 Tramadol is commonly used for chronic pain in the elderly; however, psychiatric reactions have been reported.41 This leaves limited options for this age group with painful OA. Buprenorphine is metabolized in the liver into N-dealkylbuprenorphine (norbuprenorphine) and to glucuronide-conjugated metabolites.10,42 Norbuprenorphine is a potent opioid agonist with high affinity for mu, delta, and kappa opioid receptors, and low affinity for the ORL1 receptor9 and has been detected in human plasma after a single sublingual dose of buprenorphine.43 At the mu and kappa opioid receptors, norbuprenorphine acts as a partial agonist, whereas at the delta and ORL1 receptors, norbuprenorphine is a full agonist with low potency at the ORL1 receptors.9 Recent evidence in a validated animal model that mimics human cancer-induced bone pain has shown that systemically delivered delta opioid receptor agonists can have pronounced analgesic effects, with greater potency than morphine.12 Evidence in humans has shown that spinally delivered delta opioid receptor agonists produce analgesia.44,45 The systemic effect of delta opioid receptor agonists was thought to be limited because of their inability to penetrate the blood-brain barrier and their rapid degeneration. However, in a recent in vivo study conducted in sheep, both buprenorphine and norbuprenorphine have been shown to pass through the blood-brain barrier and enter

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the brain.46 Although the cerebral kinetics showed slow entry into the brain, results indicated a significant uptake of norbuprenorphine, suggesting that norbuprenorphine may be able to contribute to the central pharmacological effects of buprenorphine in this species. In addition to this, studies in mice have shown that permeability of the blood-brain barrier may be increased by the stimulation of the mu opioid receptors by buprenorphine.47 In combination, these findings indicate that, as a potent delta opioid receptor agonist, norbuprenorphine may be one of the factors that plays a role in mediating the analgesic effects of buprenorphine in relieving somatic pain, such as bone pain and OA. In conclusion, the low-dose transdermal buprenorphine patch (BuTransÒ) is designed to be worn for seven days. This study has shown that it provides effective analgesia for this period with an improved tolerability profile in terms of nausea, dizziness, and vomiting, than sublingual buprenorphine tablets. Because of its seven-day treatment cycle, it is likely that patients will find it simple to use, especially elderly patients, who may have poor compliance with their oral medications, polypharmacy, and other significant comorbid conditions. There is a lack of high-quality clinical trials in the use of low-dose strong opioids to treat OA in general and in the elderly age group in particular. Although data are accumulating,48e50 further high-quality clinical studies are warranted to extend our knowledge of the effectiveness of this therapy in the increasing elderly population. This is even more important in the light of recent concerns over the relative safety profiles of alternative pharmacological therapies, such as the NSAIDs and COX-2 inhibitors. There is also a clinical need for greater clarity about the different pharmacological properties among the opioids as a therapeutic class, as it becomes increasingly apparent that not all opioids are the same.

Acknowledgments The authors thank all the investigators who participated in the trial: Dr. K. Ball, Dr. B. Bodalia, Dr. I. D. Caldwell, Dr. M. Duckworth, Dr. H. Duncalf, Dr. K. Gruffydd-Jones, Dr. N. Gough, Dr. J. Ham, Dr. Hamling, Dr. J. Hole,

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Dr. P. J. Horn, Dr. T. K. Khong, Dr. A. Kothari, Dr. K. Korlipara, Dr. J. Oldring, Dr. A. Prasad, Dr. S. Rowlands, Dr. P. A. Saul, Dr. N. G. Shaffu, Dr. B. D. Silvert, Dr. A. S. Thomson, Dr. W. Turner, Dr. P. Williams, Dr. N. Willmott (UK), and Prof. T. Crammond (Australia). The authors also thank Dr. J. L. Todd, Dr. S. J. Johnson and Dr. R. J. Down for preparation of the manuscript.

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