Journal of Pain and Symptom Management
Volume 40, Issue 2 , Pages 266-278, August 2010

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

  • Ian G.V. James, MBChB, DCH, DRCOG

      Affiliations

    • Spring House Surgery, Bolton, Lancashire, United Kingdom
    • ,
  • Catherine M. O'Brien, MSc

      Affiliations

    • Fincham Statistics, King's Lynn, Norfolk, United Kingdom
    • ,
  • Chris J. McDonald, MBBS, MRCOphth, FFPM

      Affiliations

    • Medical Services and Pharmacovigilance, Napp Pharmaceuticals Limited, Cambridge, United Kingdom
    • Corresponding Author InformationAddress correspondence to: Chris J McDonald, MB, BS, Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0GW, United Kingdom.

Accepted 12 January 2010. published online 14 June 2010.

Article Outline

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 (BuTrans®, Napp Pharmaceuticals Limited UK) with sublingual buprenorphine (Temgesic®, 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 20μg/hour) or sublingual buprenorphine (200 and 400 μg 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.

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=0.035), dizziness (P=0.026), and vomiting (P=0.039).

Conclusion

In conclusion, seven-day, low-dose transdermal buprenorphine patches are as effective as sublingual buprenorphine, with a better tolerability profile.

Key Words: 7-day, low dose, transdermal, buprenorphine, patches, osteoarthritis, pain, sublingual

 

Back to Article Outline

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.1, 2, 3, 4, 5, 6, 7, 8

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,13, 14, 15 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.19, 20, 21

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 September 2005, providing prolonged analgesia over a seven-day period. To assess the efficacy and tolerability of the seven-day, low-dose 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.

Back to Article Outline

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 18–80 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=no pain and 10=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.

This was a randomized, double-blind, double-dummy 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.

Table 1. Dose Levels of Study Medication
Dose Level7-Day, Low-Dose Transdermal Buprenorphine Patches (mg)Buprenorphine Sublingual Tablets
15 (5μg/houra)200μg, 8 hourly
210 (10μg/houra)200μg, 6 hourly
320 (20μg/houra)400μg, 8 hourly

aBuprenorphine release rate.

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 also recorded their pain intensity each time they took escape medication.

Escape Medication 

Patients were allowed to take oral paracetamol (acetaminophen) tablets (500mg) as escape medication for breakthrough pain (they could take 1,000mg every four to six hours up to a maximum daily dose of 4,000mg 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.

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 for the transdermal patch application site assessments.

Back to Article Outline

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 seven-day, 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 per-protocol 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 (44–81) years in the seven-day, low-dose transdermal buprenorphine patch group and 63.7 (42–80) years in the sublingual buprenorphine group. More than 80% of patients in each treatment group had been suffering with OA for at least one year before they entered the study. The most common site of pain was the knee(s).

Table 2. Baseline Characteristics at Study Entry
Characteristic7-Day, Low-Dose Transdermal Buprenorphine Patches (n=118)Buprenorphine Sublingual Tablets (n=120)
Number (%) of patients
Male41 (35)46 (38)
Female77 (65)74 (62)

Age (years)
Mean64.963.7
Range44–8142–80

Weight (kg)
Mean84.085.4
Range49–15544–171

Number (%) of patients
Caucasian117 (>99)119 (>99)
Black1 (<1)0
Asian01 (<1)
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).

Table 3. BS-11 Pain Scores at Study Entry and During the Assessment Period (Per-Protocol Population)
Study Time PointMean (SD) BS-11 Scores (Boxes)
7-Day, Low-Dose Transdermal Buprenorphine Patches (n=51)aBuprenorphine Sublingual Tablets (n=51)b
Study entry
Morning (Day 1)5.7 (2.3)5.9 (2.3)
Midday (Day 0)c6.3 (1.5)6.2 (1.6)
Evening (Day 0)6.4 (1.9)6.8 (1.7)

Assessment period (Weeks 1–4)
Day 3
Morning3.1 (1.9)3.1 (2.1)
Midday3.3 (2.0)3.3 (1.9)
Evening3.3 (2.1)3.2 (2.0)

Day 7
Morning3.0 (2.0)3.1 (2.0)
Midday3.3 (1.9)3.2 (2.0)
Evening3.4 (2.0)3.2 (2.0)

aExcept for study-entry morning (n=50) and evening (n=41).

bExcept for study-entry morning and midday (n=50) and study-entry evening (n=41).

cPatients 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.

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 groups (one dose=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.

Table 4. Number of Nights Woken Because of Pain During the Past Seven Nights (Per-Protocol Population)
Study Time PointMean (SD) Number of Nights Woken
7-Day, Low-Dose Transdermal Buprenorphine Patches (n=51)aBuprenorphine Sublingual Tablets (n=51)
Study entry4.06 (2.93)3.94 (2.74)
End of titration2.90 (2.78)3.06 (2.83)
End of assessment2.73 (2.82)2.57 (2.79)

aExcept for study entry (n=50).

Quality of Life 

Data from the Brief Pain Inventory showed that pain intensity and 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, low-dose 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, low-dose 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. Significantly fewer patients receiving the seven-day, low-dose transdermal buprenorphine patches reported adverse drug reactions (ADRs) during treatment: 96 patients (81%) compared with 110 patients (92%) receiving sublingual buprenorphine (P=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.

Table 5. Most Common ADRs Reported During the Study (Intention-to-Treat Population)
ADRNumber (%) of Patients
7-Day, Low-Dose Transdermal Buprenorphine PatchesSublingual Buprenorphine Tablets
Titration (n=118)Assessment (n=70)Overalla (n=118)Titration (n=120)Assessment (n=66)Overalla (n=120)
Nausea37 (31)18 (26)44 (37)59 (49)14 (21)61 (51)
Dizziness29 (25)10 (14)32 (27)45 (38)13 (20)49 (41)
Vomiting20 (17)4 (6)21 (18)35 (29)035 (29)
Somnolence13 (11)10 (14)19 (16)20 (17)12 (18)23 (19)
Headache23 (19)9 (13)26 (22)13 (11)3 (5)15 (13)
Constipation13 (11)14 (20)19 (16)16 (13)11 (17)17 (14)
Asthenia11 (9)3 (4)12 (10)10 (8)5 (8)13 (11)

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

Nausea, dizziness, and vomiting occurred in fewer patients treated with seven-day, low-dose transdermal buprenorphine patches; the differences were statistically significant (P=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-to-treat 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=0.704). Forty-nine patients (42%) receiving seven-day, low-dose 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 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=0.016). Most patients graded their reaction as mild or moderate in intensity.

Table 6. Skin Reactions at the Transdermal Patch Application Site (Intention-to-Treat Population)
Time After Patch RemovalNumber (%) of Patients Reporting a Reaction
Active Transdermal PatchesPlacebo Transdermal Patches
End of TitrationaEnd of AssessmentbEnd of TitrationcEnd of Assessmentd
Irritation (hours)
022 (25)14 (22)12 (17)14 (23)
1218 (20)11 (18)14 (19)12 (19)
2410 (11)6 (10)7 (10)8 (13)

Redness (hours)
047 (51)36 (55)30 (39)25 (40)
1242 (45)30 (46)26 (35)25 (40)
2429 (32)15 (23)16 (21)19 (31)

Swelling (hours)
03 (4)6 (10)3 (4)2 (3)
125 (6)5 (9)6 (9)3 (5)
242 (2)1 (2)3 (4)3 (5)

aThe number of patients with data available ranged from 80 to 93.

bThe number of patients with data available ranged from 57 to 65.

cThe number of patients with data available ranged from 70 to 76.

dThe number of patients with data available ranged from 61 to 62.

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.

Back to Article Outline

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 per-protocol 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.

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. 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 placebo-controlled trials of tramadol in OA, the withdrawal rates for patients receiving tramadol were 41%34 and 51%.35 In another placebo-controlled 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 (42–81) 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 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 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 (BuTrans®) 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,48, 49, 50 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.

Back to Article Outline

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, 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.

Back to Article Outline

References 

  1. Likar R, Kayser H, Sittl R. Long-term management of chronic pain with transdermal buprenorphine: a multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther. 2006;28:943–952
  2. Bach V, Kamp-Jensen M, Jensen N-H, Eriksen J. Buprenorphine and sustained release morphine—effect and side-effects in chronic use. Pain Clin. 1991;4:87–93
  3. De , Conno F, Ripamonti C, Sbanotto A, et al. A clinical study on the use of codeine, oxycodone, dextropropoxyphene, buprenorphine, and pentazocine in cancer pain. J Pain Symptom Manage. 1991;6:423–427
  4. Nasar MA, McLeavy MA, Knox J. An open study of sub-lingual buprenorphine in the treatment of chronic pain in the elderly. Curr Med Res Opin. 1986;10:251–255
  5. Adriaensen H, Mattelaer B, Vanmeeden H. A long-term open, clinical and pharmacokinetic assessment of sublingual buprenorphine in patients suffering from chronic pain. Acta Anaesthiol Belg. 1985;36:33–40
  6. Blamey SL, Finlay IG, Carter DC, Imrie CW. Analgesia in acute pancreatitis: comparison of buprenorphine and pethidine. BMJ. 1984;288:1494–1495
  7. Ventafridda V, De Conno F, Guarise G, Tamburini M, Savio G. Chronic analgesic study on buprenorphine action in cancer pain. Arzneimittelforschung. 1983;33:587–590
  8. Masson AHB. Sublingual buprenorphine versus oral dihydrocodeine in post-operative pain. J Int Med Res. 1981;9:506–510
  9. Huang P, Kehner GB, Cowan A, et al. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001;297:688–695
  10. Cowan A, Friderichs E, Staßburger , et al. Basic pharmacology of buprenorphine. In:  Budd K,  Raffa RB editor. Buprenorphine—the unique opioid analgesic. New York: Thieme; 2005;p. 3–21
  11. Ide S, Minami M, Satoh M, et al. Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in μ-opioid receptor knockout mice. Neuropsychopharmacology. 2004;29:1656–1663
  12. Brainin-Mattos J, Smith ND, Malkmus S, et al. Cancer-related bone pain is attenuated by a systemically available δ-opioid receptor agonist. Pain. 2006;122:174–181
  13. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth. 2005;94:825–834
  14. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006;96:627–632
  15. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569–580
  16. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth. 1985;57:192–196
  17. Villiger JW, Taylor KM. Buprenorphine: characteristics of binding sites in the rat central nervous system. Life Sci. 1981;29:2699–2708
  18. Romero DV, Partilla JS, Zheng QX, et al. Opioid peptide receptor studies. 12. Buprenorphine is a potent and selective mu/kappa antagonist in the [35S]-GTP-gamma-S functional binding assay. Synapse. 1999;34:83–94
  19. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332:1302–1308
  20. Goldstein JL. Challenges in managing NSAID-associated gastrointestinal tract injury. Digestion. 2004;69:25–33
  21. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520–1528
  22. Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA. Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol. 1981;12:117–122
  23. Langford R, McKenna F, Ratcliffe S, Vojtassák J, Richarz U. Transdermal fentanyl for improvement of pain and functioning in osteoarthritis: a randomized, placebo-controlled trial. Arthritis Rheum. 2006;54:1829–1837
  24. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23:129–138
  25. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833–1840
  26. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes following total knee or hip arthroplasty in osteoarthritis. J Orthopaed Rheumatol. 1988;1:95–108
  27. Potts RO, Lobo RA. Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist. Obstet Gynecol. 2005;105:953–961
  28. Burris JF, Papademetriou V, Wallin JD, Cook ME, Weidler DJ. Therapeutic adherence in the elderly: transdermal clonidine compared to oral verapamil for hypertension. Am J Med. 1991;91:22S–28S
  29. Cano A. Compliance to hormone replacement therapy in menopausal women controlled in a third level academic centre. Maturitas. 1994;20:91–99
  30. Allan L, Hays H, Jensen NH, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001;322:1154–1158
  31. Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs. 1979;17:81–110
  32. Reidenberg B, Eltahtawy A, Munera C, et al. Daily pharmacokinetic performance of a buprenorphine transdermal system (BTDS) for up to 7 days [abstract]. Proceedings of the 30th Annual American College of Clinical Pharmacy Meeting, October 18–21, 2009, Anaheim, California, p. 1027.
  33. Simpson RK, Edmondson EA, Constant CF, Collier C. Transdermal fentanyl as treatment for chronic low back pain. J Pain Symptom Manage. 1997;14:218–224
  34. Gana TJ, Pascual MLG, Fleming RRB, et al. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin. 2006;22:1391–1401
  35. Babul N, Noveck R, Chipman H, et al. Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee. J Pain Symptom Manage. 2004;28:59–71
  36. Peloso PM, Bellamy N, Bensen W, et al. Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee. J Rheumatol. 2000;27:764–771
  37. Katz N. Methodological issues in clinical trials of opioids for chronic pain. Neurology. 2005;65:S32–S49
  38. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary care. Ann Rheum Dis. 2001;60:91–97
  39. Medicines and Healthcare products Regulatory Agency . Cardiovascular safety of non-steroidal anti-inflammatory drugs: Overview of key data. London, UK: MHRA; 2005;
  40. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:1075–1078
  41. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;3:CD005522
  42. Cone EJ, Gorodetzky CW, Yousefnejad D, Darwin WD. 63Ni electron-capture gas chromatographic assay for buprenorphine and metabolites in human urine and feces. J Chromatogr. 1985;337:291–300
  43. Polettini A, Huestis MA. Simultaneous determination of buprenorphine, norbuprenorphine, and buprenorphine-glucuronide in plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001;754:447–459
  44. Moulin DE, Max MB, Kaiko RF, et al. The analgesic efficacy of intrathecal D-Ala2-D-Leu5-enkephalin in cancer patients with chronic pain. Pain. 1985;23:213–221
  45. Onofrio BM, Yaksh TL. Intrathecal delta-receptor ligand produces analgesia in man. [letter] Lancet. 1983;1:1386–1387
  46. Jensen ML, Foster D, Upton R, et al. Comparison of cerebral pharmacokinetics if buprenorphine and norbuprenorphine in an in vivo sheep model. Xenobiotica. 2007;37:441–457
  47. Baba M, Oishi R, Saeki K. Enhancement of blood-brain barrier permeability to sodium fluoroscein by stimulation of μ opioid receptors in mice. Naunyn-Schmiedeberg's Arch Pharmacol. 1988;337:423–428
  48. Landau CJ, Carr WD, Razzetti AJ, et al. Buprenorphine transdermal delivery system in adults with persistent noncancer-related pain syndromes who require opioid therapy: a multicenter, 5-week run-in and randomized, double-blind maintenance-of-analgesia study. Clin Ther. 2007;31:2179–2193
  49. Spyker DA, Hale ME, Lederman M, et al. Long-term use of buprenorphine transdermal system (BTDS) in patients with chronic pain. [abstract] J Am Geriatr Soc. 2002;50(Suppl 4):S66
  50. Conaghan P, Schofield JP, O'Brien C. A head-to-head comparison of BuTrans® (buprenorphine transdermal patches) versus co-codamol in elderly patients with severe hip and knee osteoarthritis [abstract]. Annual European Congress of Rheumatology, June 11–14, 2008, Paris, France.

 This trial was sponsored by Napp Pharmaceuticals Limited, United Kingdom.

PII: S0885-3924(10)00324-6

doi:10.1016/j.jpainsymman.2010.01.013

Journal of Pain and Symptom Management
Volume 40, Issue 2 , Pages 266-278, August 2010

Article Tools

* Image Usage & Resolution