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Benefits of Transdermal Fentanyl in Patients With Rheumatoid Arthritis or With Osteoarthritis of the Knee or Hip: an Open-Label Study to Assess Pain Control

Posted on: Friday, 25 February 2005, 15:00 CST

Key words: Opioids - Osteoarthritis - Pain control - Rheumatoid arthritis - Transdermal fentanyl

SUMMARY

Objectives: To evaluate the effectiveness and safety of transdermal fentanyl (TDF) for the treatment of pain associated with rheumatoid arthritis (RA) or osteoarthritis of the knee or hip (OA), which was not adequately controlled by non-opioid analgesics and/or weak opioids.

Methods: The study design incorporated a 1-week run-in period when current analgesic medications were optimised, a 28-day treatment period and a 1-week taper-off period. Patients with RA (n = 104) and OA (n = 159) started treatment with TDF 25 g/h. Patches were replaced every 72 h, with the option to up-titrate until adequate pain control was achieved. Metoclopramide was taken during the first treatment week and as needed thereafter.

Results: 203 patients completed the treatment phase, 90 entered the taper-off phase. 25 g/h was the most frequently used maximum dose (51%). Pain control was increased from 4% to 29% of patients during run-in. The number of patients reaching adequate pain control in the first treatment week was increased to 75%, and increased further to 88% on day 28 and to 80% at endpoint. From baseline (screening) to endpoint, there were significant reductions in pain (p < 0.001) on the Wisconsin Brief Pain Inventory, and significant improvements in quality of life (Short-Form-36: physical p < 0.001; mental health p < 0.05). Eighty per cent of the patients (n = 134) assessed the treatment favourably; nausea and vomiting were the most common adverse events, mainly occurring at treatment initiation. Efficacy of metoclopramide appeared limited. TDF could be initiated in patients pre-treated with non-opioid analgesics or weak opioids and tapered off without major complications.

Conclusions: TDF significantly improved pain control and quality of life, and was well tolerated in patients with RA or knee/hip OA who continued to experience pain on their current analgesic treatment. Treatment could be discontinued without issues. Nausea and vomiting was usually mild during treatment initiation. Patients' well being could be further accommodated by optimising prophylactic treatment.

Introduction

Pain is a principal symptom of rheumatoid arthritis (RA) and osteoarthritis (OA) that aggravates disability, and works negatively on physical functioning, sleep and mood1,2. With disease progression, there is increasing pain, even at times of joint rest, and dependency on others, which can sometimes not be controlled by causative treatment. With 55% of people with OA reporting pain as the worst aspect of the disease3, 65% with RA ranking pain as the most important symptom to be treated4, and pain being the primary reason why people with arthritis seek medical attention5,6, control of chronic pain is of primary concern.

Pain from arthritis may be caused by a number of mechanisms and is only partly related to inflammation7. Pharmacotherapy in musculo- skeletal diseases mainly centres round the use of non-steroidal anti- inflammatory drugs (traditional NSAIDs and Cox-2 selective inhibitors) and non-opioid analgesics. The anti-inflammatory effects play an important role in treatment, although their analgesic efficacy is limited8 and their regular use is often interrupted by side effects9-13 Many patients, therefore, continue to suffer pain despite taking anti-inflammatory drugs at optimal doses and need additional treatment for relief. Drugs with mechanisms of activity other than anti-inflammatory should, therefore, be considered. The role of opioids in the treatment of pain associated with cancer is well established but, despite providing effective pain relief in cancer pain, there is debate over their appropriateness for long- term use in the treatment of pain of non-cancer origin14. However, with the need to find more successful ways to control chronic non- malignant pain, there is a growing body of experience to support their use in this indication15-19.

Several recent double blind, randomised studies with opioids have specifically addressed the treatment of pain associated with OA. The efficacy of opioids in controlling pain in patients with OA has been demonstrated in three randomised-controlled trials20-22. Although opioids are suggested to be beneficial and an effective treatment option for those with RA, there are no randomised controlled studies in this patient population23,24.

Recent guidelines for the management of chronic non-cancer pain recommended that opioid treatment should be considered if other reasonable therapies fail to provide adequate analgesia within a reasonable time-frame25. More specifically for pain relief in knee OA, guidelines recommend paracetamol, followed by anti-inflammatory agents, and note the use of opioids in this condition26,27. Furthermore, the development of management guidelines to optimise opioid effectiveness and safety in chronic non-malignant pain propose the use of formulations that provide continuous drug delivery28,30. Transdermal fentanyl (TDF), providing systemic delivery of fentanyl at a constant rate for 72 h31, has been shown to be effective for pain control and for improvement of some quality of life parameters for those with chronic non-malignant pain32-35. More specifically, a prospective study to investigate the efficacy and tolerability of TDF in 243 patients with severe OA pain of the knee and/or hip demonstrated significant reductions in pain at rest and on movement, and provided evidence of functional improvement, with very few patients needing doses higher than the 25 g/h starting dose after 30 days36. Similar benefits of TDF on pain intensity and quality of life were seen over 30 days in a prospective study of severe pain caused by RA37.

The present study was undertaken to evaluate the effectiveness and safety of TDF for the treatment of pain associated with RA or OA of the knee or hip, which was not adequately controlled (poor or very poor pain control) by anti-inflammatory agents, paracetamol or weak opioids at optimal doses. The study was not designed to prove efficacy of the treatment but was to investigate practical aspects of opioid therapy, such as the value of a test period, or concomitant use of anti-emetic therapy, or whether pre-treatment with weak opioids reduces side effects. This open-label study was planned as a pilot for a double-blind trial in patients with RA or with OA. A test period for evaluation of a patient's response to opioid treatment is recommended25 and in this study a test period of 1-month duration was chosen to assess the practicality of these recommendations in this patient population. The test period is recommended, patients might be not opioid responsive, not responsive to a specific opioid or may experience cumbersome side-effects with one opioid, which may not be present with another one.

As nausea and vomiting frequently occur with opioid use, particularly in the first week of treatment, all patients received metoclopramide during the first week of TDF treatment, and as needed thereafter, to help patients overcome these self-limiting effects and remain on treatment. In addition, the design enabled TDF to be tapered off if a patient did not show adequate response. Results from the two patient populations - those with RA and those with OA of the knee and hip - will be reported elsewhere. This report presents the results of the total study population that includes both RA and OA patients.

Patients and methods

Patient Selection

All patients were outpatients requiring supplementary analgesic treatments because of moderate or severe pain, which was not adequately controlled with paracetamol, anti-inflammatory agents or weak opioids. Patients with RA were required to meet the RA criteria of the American College of Rheumatology (ACR)38. If the subjects were taking disease modifying anti-rheumatic drugs, corticosteroids or anti-inflammatory agents they must have been on a stable dose for at least 3 months before screening and expected to remain on a stable dose for the duration of the trial. Patients with OA had to have OA of the knee or hip and meet the OA criteria of the ACR39- 41. They had to have radiographic evidence, and need and be waiting for hip or knee replacement as indicated by an orthopaedic surgeon.

Excluded were those who had received regular treatment with a strong opioid in the 4 weeks before the study, including those taking weaker analgesics or weak opioids exceeding the maximum recommended dose. Concomitant analgesic opioid medication or supplementary weak opioids, and treatments that might alter the degree or nature of pain were not allowed to be started during the study. Patients were excluded if they had continuous pain of non- arthritis origin, or had undergone surgery/arthroscopy, intra/peri- articular injections and arthrocentesis within 3 months, 6 weeks and 4 weeks of study start, respectively. Those with RA in acute flare at trial entry were also excluded.

Study Design

Screened patients satisfying the selection criteria were to be recruited to this international, open, prospective trial and each gave written informed consent before inclusion. The study was carried out in accordance with the latest revis\ion of the Declaration of Helsinki, and Good Clinical Practice and was approved by local Independent Ethics Committees.

Non-opioid analgesia is not always taken at the dose necessary to achieve pain control42, therefore, the run-in period was designed to achieve this. During a run-in period of 1 week, non-opioid analgesic treatment was optimised or increased to the maximum tolerated dose or maximum recommended dose, while weak opioids were kept stable. All patients with insufficiently controlled pain (poor or very poor pain control on a five-point scale) at the end of this period were to begin treatment for 28 days with the fentanyl transdermal patch (TDF), Durogesic 25 g/h (Durogesic 25, Janssen-Cilag), which was replaced every 72 h (3 days). Previous non-opioid analgesia -was continued and kept stable while, weak opioids were discontinued. If required, the dose of TDF was titrated upwards in steps of 25 g/h every 72 h (no maximum dose specified) until adequate pain control was achieved. Supplementary analgesia could be provided using paracetamol 500 mg tablets up to 4 g/day. After 28 days or should it be necessary, e.g. if side effects occurred or the treatment was not effective within 1 month, a similar downward titration regimen was employed. With the exception of paracetamol that was permitted, other non-opioid analgesics were kept stable and no short acting opioids were added during down-titration.

Metoclopramide 10 mg three times a day was given concurrently to all patients for the prevention of nausea and vomiting during the first week of treatment, after which it was taken as needed.

Assessment Procedure

Patients were evaluated at screening (day -7), at baseline (days 0), 7 days, 14 days (optional) and 28 days (trial end), and on other days if dose adjustment was necessary, and at the end of a 1 week or 2 week tapering off period.

The primary efficacy variable, pain control, was evaluated weekly by each patient on a five-point pain control assessment scale (very poor to excellent). For this assessment, the investigator presented the following question 'would you rate your pain control today as being excellent, good, moderate, poor or very poor?' Secondary to this, patients also completed a pain assessment questionnaire [shortened version of the Wisconsin Brief Pain Inventory (WBPI)43] (10-point rating scale: 0, best to 10, worst). The degree of pain after 24 h of treatment was assessed by asking the patient one question on the amount of pain that they had 'right now'. Patients also recorded pain intensity in a diary on a five-point scale. Evaluations of nausea, vomiting and the use of prophylactic anti- emetic treatment were also recorded in the diary.

Patients completed a treatment assessment questionnaire consisting of 10 items, which were scored on a Likert scale. The acute version of the SF-36 quality of life questionnaire44 including eight quality of life domains (physical functioning, physical role limitations, emotional role limitations, social functioning, body pain, general mental health, vitality and general health perceptions) was completed after the run-in phase and at day 28. Functionality of patients was assessed at the same time points using the HAQ (Health Assessment Questionnaire)45 in RA patients and the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index)46 in OA patients.

Statistical Analysis

As this was a pilot study, there was no formal sample size calculation; 292 patients entered the trial. A total of 263 patients were treated at least once with the study medication (all patients). An intent-to-treat analysis, comprising all patients with at least one post-baseline measurement of the primary endpoint (pain control) and treated at least once with the trial medication, was performed (n = 240; 97, RA; 91, OA knee; 52, OA hip)47.

Descriptive statistics were calculated for patient demographic details and baseline characteristics, and for all study assessments. The ANCOVA model was used to analyse the change from baseline to endpoint, and the influence of baseline values. The Wilcoxon signed- rank test was used to compare intragroup results and results at each time point or endpoint with baseline, where applicable. Statistical tests were interpreted at the 5% significance level (two-sided).

With the exception of safety data, where events from all patients are reported, intent-to-treat analysis data are reported for other measurements (per-protocol results were very similar to those from the intent-to-treat analysis).

Results

Patient Characteristics

From the 292 patients screened, a total of 263 patients with RA (n = 104) and OA of the knee (n = 102) or hip (n = 57) were recruited into the study from 50 main centres in 11 countries and started treatment with TDF. Demographic data of the 263 patients are shown in Table 1.

Eighty per cent of the patients had used non-opioids in the month before screening (mostly paracetamol 26%, diclofenac 18% and celecoxib 11%), 58% had used weak opioids (mostly tramadol 35%, and paracetamol-codeine combination 9%), and 1% had not used any analgesic treatment. At this time 38% of the patients had used a combination of a non-opioid and weak opioid.

Concomitant medication with possible analgesic effects used during the treatment phase included paracetamol (74%), traditional NSAIDs (50%), weak opioids (46%), steroids (25%), immunomodulating drugs (25%), Cox-2 selective inhibitors (21%), analgesics (6%) and strong opioids (1%). Of those taking weak opioids, the vast majority took them on the first day of treatment only. Two patients continued with weak opioids as rescue medication throughout the trial and had to be considered as protocol violators. Notably, the use of anti- inflammatory agents, and to a lesser extent, paracetamol and 'analgesics' also reduced after the first 24 h of treatment. This was particularly the case for those with OA. Rescue medication was required by 66% patients, of whom almost all used non-opioids, particularly paracetamol.

Table 1. Characteristics of the patients and their pain at study initiation

The majority of patients suffered from concomitant diseases: 54% of the patients had currently active cardiovascular diseases, 56% genitourinary, 52% musculo-skeletal, 35% endocrine, and 20% had gastrointestinal disease. The most frequently used non-analgesic concomitant therapies (in at least 10% of patients) during treatment were metoclopramide 53%, methotrexate 18%, folic acid 11% and omeprazole 10%.

Discontinuations

Twenty-three per cent of patients discontinued the trial during the treatment phase, most frequently because of adverse events, with half the drop-outs occurring during the first week of TDF treatment (Figure 1). Ninety patients started the optional tapering off phase, most of them either after dropping-out prematurely or due to organizational reasons.

Study Medication

Individuals started TDF at 25 g/h and daily doses ranged from 25 g/h to 125 g/h. The highest dose was used only by two patients. The average mean daily dose for week 1 was 26.9 g/h, and increased slightly in week 4 to 37.3 g/h, respectively. Fifty-one per cent of all patients used 25 g/h as a maximum dose during the study. Patients were treated for an average of 22.5 0.68 days.

Primary Efficacy Variable

Pain control was defined as a score of 'moderate', 'good' or 'excellent' on the pain control assessment scale. There were some protocol violators, who had good pain control already at screening. The proportion of patients with adequate pain control increased during the 1-week run-in period from 4% at screening to 29% by optimising the dose of non-opioid analgesia. As the study was continued in these patients, they accounted for the majority of protocol violators. Seventy-five per cent of patients had adequate pain relief in the first week of treatment, with 40% patients reporting moderate, 31% good and 5% excellent pain control. Pain control was achieved in 80% and 88% of patients on days 14 and 28, respectively. At endpoint, 80% of patients considered their pain controlled (Figure 2). Of the patients who already experienced adequate pain control after the run-in phase (24 patients -with moderate and one patient with good pain control), 50% improved further during TDF treatment.

Figure 1. Study population analysis

After week 1 of treatment, 70% considered their pain control better than it had been at baseline, with 81% and 74% of patients indicating this to be the case at day 28 and endpoint, respectively. Improved pain control was reflected in the mean pain scores, which increased from 2.1 0.05 (poor) at baseline to 3.3 0.06 (above moderate) at endpoint, and were statistically better (p < 0.001) at all time points compared to baseline. Efficacy was maintained over the 4-week treatment period. The change in pain control between baseline and endpoint was also significantly related to the baseline value (p < 0.001), with greater pain relief for those with poorer pain control at baseline.

Secondary Efficacy Variables

Pain Control

Using the WBPI, patients described a significant reduction in pain from baseline to endpoint for each item at every time point (p < 0.001). Thus, the mean reduction in 'pain at its worst' was 2.0 points (from 8.0 to 6.0), 'pain at its least' was 1.7 points (from 4.5 to 2.8), and 'pain on average' was 2.0 points (from 6.3 to 4.3). The amount of trouble or bother the pain was causing also decreased by a mean 2.7 points (from 7.1 to 4.4). The mean reduction in 'pain right now' was 2.5 points (from 6.2 to 3.7) from baseline to endpoint. A significant reduction in 'pain right now' was reported as early as 24 h after baseline (1.3 points, from 6.1 to 4.8). From patients' diaries, the mean pain score for degree of pain was significantly decreased at each time point, and from severe pain (score 3) to moderate pain (score 2) from the run-in period to endpoint (p < 0.001).Results were similar for the patients' highest score for their degree of pain.

Figure 2. Pain control assessment. Number of subjects at each time point is indicated

Nausea and Vomiting

During the run-in period, 19% of patients reported nausea. This increased to 53% in week 2 and decreased to 44% of patients in week 4 of treatment. Nausea was rated as mild on a 10-point scale and decreased further after the first weeks of treatment (mean scores: run-in, 0.73; week 2, 2.14; week 4, 1.55) A greater number of patients (25%) who used weak opioids during the run-in period reported nausea at baseline compared to those who did not (11%). However, a slightly higher mean nausea score was reported during the first week of treatment for those who did not use weak opioids during run-in than for those patients who used them (2.33 vs 1.74), this difference disappeared in the second week. The majority (78%) of all patients did not suffer from vomiting during the treatment period. The remaining 60 subjects reported a total of 78 events of vomiting.

Sixty-two per cent of patients used metoclopramide at least once after the first week. However, the number of individuals taking this treatment decreased from 56% during week 2 to 40% at endpoint, and its use was not regular: the mean SE number of times it was used in a week reduced from 6.1 0.56 to 4.1 0.48.

Treatment Assessment

In their assessment of treatment, 64% of patients rated the treatment positively with respect to pain control and, with over 80% satisfied with its convenience of use (89% thought it easy/ extremely easy to use; 83% were very/somewhat pleased by the way it's used), 82% would recommend the treatment for their type of pain. Side effects were not an issue for half of all patients. In assessing how they had felt over the past week, the percentage of all patients who answered good or very good increased during the study from 5% during the run-in period to 36% in week 4, and their scores at all time points were significantly better than before treatment (p < 0.001). This was also the case for RA and OA groups separately.

By the end of the trial 41% of the patients indicated that they needed help with basic activities; 47% needed less help than before the treatment.

Quality of Life

Not all patients filled in the quality of life questionnaire. There were statistically significant improvements in all domains of the SF-36 from baseline to endpoint, including overall physical health (p < 0.001) and mental health (p < 0.05) (Table 2). Quality of life scores were low at baseline despite optimisation of previous treatment. Role physical, bodily pain and physical functioning were most adversely affected by the underlying condition. Largest absolute improvements were seen for bodily pain, role physical, role emotional and social functioning.

Table 2. Changes in quality of life (SF-36 scores)

Table 3. Adverse events reported during the treatment phase and tapering off phase (> 5% of patients)

Functionality

In RA patients the mean score for the overall disability index improved from 2.07 ( 0.065) to 1.92 ( 0.071). This decrease was statistically significant (p < 0.001). In OA patients the mean WOMAC score improved from 62.1 ( 1.34) to 47.4 ( 1.82). This change was also statistically significant (p < 0.001).

Evaluation of Safety

Adverse events occurring during the treatment phase and tapering off phase were those associated with strong opioid treatment (Table 3). Five per cent of the patients reported adverse events during the run-in period, 67% during the treatment period, and 27% during the optional tapering off period. The study medication was permanently stopped in 26% of cases during the treatment phase particularly because of nausea (46%) and vomiting (33%). Withdrawal syndrome was reported in two cases during tapering-off and was either moderate or mild and resolved without specific treatment. Serious adverse events during treatment or the tapering-off phase were reported in six patients and were mostly not related to the study drug. Vital signs, including pulse rate, diastolic blood pressure and systolic blood pressure, remained stable between baseline and endpoint.

Discussion

This study investigated the use in clinical practice of TDF for pain associated with RA and OA (knee and hip), which was poorly controlled by traditional NSAIDS, Cox-2 selective inhibitors, paracetamol or weak opioids at optimal doses. It confirmed that the recommended 1-month test period25 in this particular patient population was of adequate duration to achieve pain control.

This trial aimed to include patients who were severely under- treated for pain: all of them rated their pain control as poor or very poor at the beginning of treatment. The patients had either been treated with non-opioid analgesics, anti-inflammatory agents or weak opioids. The analgesic effect of anti-inflammatory agents and non-opioid analgesics is limited10 and people with RA and with OA may continue to suffer in spite of optimal dosing. About one- quarter of patients entering this study were not even receiving adequate doses of their current non-opioid analgesic agent, as the number reporting pain control was increased during the run-in phase when doses of these medications were optimised. However, even with dose increases, there is a need to recognize the ceiling effect of these drugs48. This means that beyond a certain dosage there is no additional benefit and, therefore, a limit to the degree of pain control achieved. The majority of patients benefited from treatment with TDF. After 1 month, TDF provided nearly a 60% increase in the number of patients with their pain adequately controlled over that achieved with non-opioid analgesics. For the majority (75%), pain control was achieved during the first week of treatment, with a significant improvement in their degree of pain evident after 24 h.

On the first day of TDF treatment during the lag-period when serum levels of fentanyl had not yet achieved steady-state, about half of patients needed tramadol as add-on treatment. From day 2 onwards, paracetamol was sufficient to control breakthrough pain. Reduction in the use of other analgesics, especially traditional NSAIDs and selective Cox-2 inhibitors, following the start of TDF suggests that with adequate pain control clinicians appear to be able to reduce these medications, when they are used mainly as analgesics and not because of their anti-inflammatory properties. Good pain control was maintained over the 4-week treatment period.

The patients entered into this study reflect the average population of patients with RA or with OA with regard to age and sex distribution27. Not surprisingly, the majority of the patients suffered from other concomitant diseases requiring additional concomitant medication. The use of a medication, which provides adequate pain medication but which does not cause organ damage or have major interactions with other drugs, is, therefore, very important. Pain from arthritis may be caused by a number of interactive biochemical pathways and is only partly related to inflammation7. Use of TDF may relieve pain and decrease the risk of life threatening gastrointestinal events by reducing the need for traditional NSAIDs.

Physical dependence is a normal and predictable neurophysiological response to regular treatment with opioids for more than 1 week-2 weeks duration, which is characterized by withdrawal syndrome that occurs when the opioid is abruptly discontinued. However, withdrawal syndrome can be prevented by gradually reducing the dose of opioid before discontinuing the drug. Withdrawal syndrome was not a major issue in this patient population; TDF can be easily tapered off should it be necessary. Withdrawal syndrome should not, therefore, be considered a barrier to TDF treatment in OA or RA patients.

Nausea and vomiting are also recognized side effects of strong opioids, particularly occurring at the start of treatment. Opioids are thought to induce nausea and vomiting by a direct action on the chemoreceptor trigger zone in the hind brain49. Although nausea and vomiting are usually self-limiting and not harmful, they can be cumbersome to those who may otherwise benefit from opioid use. These symptoms were explicitly requested in the patient diaries thus drawing attention to them; unsurprisingly, nausea and vomiting were the most frequently observed side effects. Metoclopramide, indicated for the symptomatic treatment of nausea and vomiting, acts by antagonism of peripheral dopaminergic receptors that decrease the sensitivity of the visceral nerves supplying afferents to the vomiting centre. Metoclopramide was used to help patients overcome nausea and vomiting, and thus remain on treatment and potentially achieve pain control. Overall findings suggest that metoclopramide 10 mg tid was of little value in the prevention of nausea and vomiting in patients with RA and OA using strong opioids for pain control. Improvement in anti-emetic treatment, either by increasing the metoclopramide dose or replacing it with an alternative agent, would enable more patients to continue to use TDF and, with or without up-titration; achieve adequate pain control.

There has been concern that the initiation of TDF treatment directly after non-opioid therapy might cause unbearable nausea. This trial shows that skipping step two of the World Health Organization analgesic ladder leads to a somewhat higher amount of nausea during the first week of TDF treatment, although this levels off at week 2 and is similar to that of patients pre-treated with weak opioids. On the other hand, patients skipping step two of the World Health Organization analgesic ladder do not suffer nausea induced by weak opioids. This trial, therefore, shows that the effects of pre-treatment with a weak opioid are minor, and apparent only in the first week of TDF treatment. It is noteworthy, that takin\g a combination of non-opioids and weak opioids in the month before screening did not increase the proportion of patients continuing treatment when compared to the proportion discontinuing the trial due to an adverse event.

Constipation is commonly associated with opioid treatment but in this study was noted infrequently, by 6% of patients only. A significantly lower incidence of constipation has previously been detected in patients receiving fentanyl for chronic non-cancer pain in addition to cancer pain compared with oral morphine29,50,51.

Dissatisfaction with treatment is reported to be the most common reason for patients on an anti-inflammatory agent to re-present to their GP, and this is specifically because of breakthrough pain and incomplete pain relief on current painkillers50,51. Patients were generally satisfied with TDF as they felt significantly better than before using it, with over 80% of them reporting that they would recommend this treatment to others with similar pain. Patients found the patch particularly easy to use, giving at least better pain relief than their previous medications. Patients with chronic non- cancer pain have previously been shown to prefer treatment with TDF than with sustained release oral morphine33.

Aspects of quality of life and functionality, which were compared bet-ween baseline (after optimisation of previous treatment) and the end of the study, indicated that the improvement in pain control is translated into an improved quality of life as well as into improved functionality for the combined RA and OA population. This improvement will be detailed in further publications reporting data from the RA population and the OA population separately.

This study has certain limitations owing to the use of an open design, which might bias efficacy findings towards TDF and other factors causing improvement unrelated to the change in medication. Nevertheless, the study showed substantial additional pain relief in patients already up-titrated to optimal doses of non-opioid treatment, thus demonstrating to clinicians a further step in the treatment of pain from musculoskeletal disease.

There is dissatisfaction with currently used treatment regimens for OA, RA and unspecified arthritis from both GP and patient perspectives52. Since there has been great change in the way some pain specialists view the use of opioids for the management of chronic non-cancer pain53, the role of opioids in this area is rapidly evolving48. This study showed that TDF is efficient in chronic RA and OA pain that is inadequately controlled by non- opioid analgesics or weak opioids. TDF should, therefore, be considered as a valuable treatment option in chronic pain due to musculo-skeletal diseases.

Acknowledgements

This study was funded by Janssen-Cilag. We would like to thank Dr Susan Libretto for help in preparing the manuscript. We would also like to acknowledge the FEN-INT-30 Study Group, which comprised the following other investigators:

Belgium: Arlon - C. Pater (private practice); Brussels S. Di Romana (Saint-Pierre University Hospital), L. Fabeck (Saint-Pierre University Hospital), M. Lambert (General Hospital - Free University Brussel), A. Peretz (Brugmann University Hospital), V. Siderova (Brugmann University Hospital); La Louvire - S. Schreiber (Tivoli University Hospital).

Croatia: Split - T. Vlak (Clinical Hospital); Zagreb A. Branimir (Clinical Hospital Center), M. Sentic (Clinical Hospital Center), Z. Jajic (Clinical Hospital Sestre milosrdnice), B. Curkovic (Clinical Hospital Center), P. Peric (Clinical Hospital Center), D. Delimar (Clinical Hospital Center).

Czech Republic: Prague - Z. Urbanova (Institute of Rheumatology).

France: Amiens Nord - P. Fardellone (University Hospital Center Amiens Nord), A. Hacene (University Hospital Center Amiens Nord); Gonesse - J. Glowinski (Gonesse University Hospital); Grenoble - J.P. Alibeu (University Hospital Center), A. Dumolard (University Hospital Center); Lyon - E. Vignon (Hospital Center Lyon Sud); Paris - P. Bourgeois (La Piti Hospital), A. Coutaux (La Piti Hospital), O.Meyer (BICHAT Hospital); Rouen - L.F. Da Silva (University Hospital Center); Sainte Adresse - M. Genty (Roseraie Clinic); Tours - J.P. Valat (Trousseau Hospital).

Germany: Lubbeck - A. Ince (University Hospital Orthopedic Clinic); Mainz - J. Muller (St. Vincent- and Elisabeth-Hospital); Ulm - K. Dreinhfer (Rehabilitation Hospital - University Hospital Ulm), B. Jtzold (University Hospital Ulm), H. Koepp (University Hospital Ulm), R. Strohm (University Hospital Ulm).

Ireland: Cork - M. Molloy (Cork University Hospital); Waterford - K.S. Afridi (Waterford Regional Hospital), A. El-Rafie (Waterford Regional Hospital).

Norway: Arendal - K. Holstad (Srlandet Clinic), D. Soldal (Srlandet Clinic); Horten - O. Knudsrod (Horten Helse-Center); Kristiansand - T. Tveit (Srlandet Clinic); Oslo - N. Berner (Aker University Hospital), A. Berntsen (Aker University Hospital), J.H. Rosland (Aker University Hospital); Sandvika - O. Clarke-Jenssen (Martina Hansens Hospital), E. Fjeld (Martina Hansens Hospital); Sarpsborg - S. Angelskar (stfold Clinic), B. Finnanger (stfold Clinic); Skien A. Dietze (Betanien Hospital); Tonsberg - P. Blichfeldt (Private practice).

Poland: Bialystok - S. Sierakowski (Medical University); Katowice - E. Kucharz (Medical University); Lublin - L. Szczepanski (Medical University); Warsaw - A. Filipowicz-Sosnowska (Institute of Rheumatology), A. Zubrzycka-Sienkiewicz (Institute of Rheumatology), W. Tlustochowicz (Central Clinical Hospital).

Spain: Barcelona - A. Rodriguez de la Serna (St. Creu and St. Pau Hospital).

Switzerland: Aarau - P. Siman (Aarau Cantonal Hospital), R. Theiler (Aarau Cantonal Hospital); Bellinzona - G. Mariotti (Rheumatology & Rehabilitation).

Turkey: Ankara - F. Atalay (GAZI Medical Faculty), J. Meray (GAZI Medical Faculty), D Karakus (Ankara Physical Therapy and Rehabilitation Hospital), B. Karaoglan (Ankara Physical Therapy and Rehabilitation Hospital), K. Ozoran (Education & Research Hospital), Y. Karaaslan (Fatih Medical Faculty); Istanbul - U. Akarirmak (Cerrahpasa Medical Faculty), H. Sari (Cerrahpasa Medical Faculty), H. Direskeneli (Marmara Medical Faculty), M. Temel (Marmara Medical Faculty), N. Kotevoglu (Sisli Etfal Education & Research Hospital); Izmir - Y. Akkoc (Ege Medical Faculty), Y. Kirazli (Ege Medical Faculty).

References

1. Hitchcock LS, Ferrell BR, McCafferty M. The experience of continuous non-cancer pain. J Pain Symptom Manage 1994;9:312-8

2. Holman GH. Chronic nonmalignant pain. Clin Geriatr 1997;5:21- 41

3. Arthritis Research Campaign. Factfile - arthritis at a glance. Arthritis Research Campaign, Chesterfield, 2002. Available from: http://www.arc.org.uk/about_arth/astats.htm [accessed 19 October 2004]

4. Anderson KO, Bradley LA, Turner RA, Agudelo CA, Pisko EJ. Pain behaviour of rheumatoid arthritis patients enrolled in experimental drug trials. Arthritis Care Res 1994;7:64-8

5. Buckelew SP, Parker JC. Coping with arthritis pain: a review of the literature. Arthritis Care Res 1989;2:136-45

6. Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;350:503-8

7. Pinals RS. Mechanism of joint destruction, pain and disability in osteoarthritis. Drugs 1996;52(Supp 3):14-20

8. Wolheim FA. Current pharmacological treatment of osteroarthritis. Drugs 1996;52(Supp3):27-38

9. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. New Engl J Med 1984;310:563- 72

10. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and non- steroidal anti-inflammatory drugs. New Engl J Med 1994;331:1675-9

11. Johnson AG, Nguyen Ty Day RO. Do non-steroidal anti- inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289-300

12. Hawkey CJ. COX-2 inhibitors. Lancet 1999;353:307-14

13. Garcia Rodriguez LA, Hernander-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6

14. McQuay H. Opioids in pain management. Lancet 1999;353:2229- 32

15. Jadad A, Carroll D, Glynn C, Moore RA, McQuay HJ. Morphine responsiveness of chronic pain: double-blind randomized cross-over study with patient-controlled analgesia. Lancet 1992;339:1367-71

16. Arkinstall W, Sandler A, Goughnour B, et al. Efficacy of controlled release codeine in chronic non-malignant pain: a randomized, placebo-controlled clinical trial. Pain 1995;62:169-78

17. Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H. Randomized trial of oral morphine for chronic non-cancer pain. Lancet 1996;347:143-7

18. Dellemijn PLI, Vanneste JAL. Randomized double-blind active- placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain. Lancet 1997;349:753-8

19. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837-41

20. 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 knee or hip. J Rheumatol 2000;27:764-71

21. Caldwell JR, Hale ME, Boyd RE, et al. Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to non-steroidal anti- inflammatory drugs: a double blind, randomized, multicentre, placebo controlled trial. J Rheumatol 1999;26:862-9

22. Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to- severe osteoarthritis pain: results from a randomized, placebo- controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage 2002;23:278-91

23. Gonzales GR, Portenoy RK. Selection of analgesic therapies in rheumatoid arthritis: role of opioid medications. Arthritis Care Res 1993;6:223-8

24. Griessinger N\, Sittl R, Jost R, Schaefer M, Likar R. The role of opioid analgesics in rheumatoid disease in the elderly population. Drugs Aging 2003;20:571-83

25. Kalso E, Allan L, Dellemijn PLI, et al. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain 2003;7:381-6

26. Pendleton A, Arden N, Dougados M, et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2000;59:936-44

27. American Pain Society. Guideline for the management of pain in osteoarthritis, rheumatoid arthritis, and juvenile chronic arthritis. American Pain Society, Glenview, IL, 2002. Available from: http://www.ampainsoc.org/pub/arthritis.htm [accessed 19 October 2004]

28. Schug SA, Merry AF, Acland RH. Treatment principles for the use of opioids in pain of nonmalignant origin. Drugs 1991;42:228-39

29. Graziotti PJ, Goucke CR. The use of oral opioids in patients with chronic non-cancer pain. Management strategies. Med J Aust 1997;167:30-4

30. Anon. The use of opioids for the treatment of chronic pain: a consensus statement from the American Academy of Pain Medicine and the American Pain Society. Pain Forum 1997;6:77-9

31. Jeal W, Benfield P. Transdermal fentanyl: a review of its pharmacological properties and therapeutic efficacy in pain control. Drugs 1997;53:109-38

32. Simpson RK, Edmondson EA, Constant CF, Collier C. Transdermal fentanyl as treatment for chronic low back pain. J Pain Symptom Manage 1997;14:218-24

33. Allen L, Hays H, Jensen NH, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. Br Med J 2001;322:1154-8

34. Milligan K, Lanteri-Minet M, Borchert K, et al. Evaluation of long term efficacy and safety of transdermal fentanyl in the treatment of chronic non-cancer pain. J Pain 2001;2:197-204

35. Ringe JD, Faber H, Bock O, et al. Transdermal fentanyl for the treatment of back pain caused by vertebral osteoporosis. Rheumatol Int 2002;22:199-203

36. Theodoridis T, Waap I, Schwalen S, Kramer J. Fentanyl in the treatment of pain caused by arthrosis. Z Orthop 2002;140:217-22

37. Berliner M, Schwalen S, Seidel W, Hanteschel H. Fentanyl-TTS in the treatment of pain caused by rheumatoid arthritis. Akt Rheumatol 2002;27:230-5

38. Arnett FC, Edworthy SM, Bloch DA, et al. The Americam Rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24

39. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, part I: osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40

40. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, part II: osteoarthritis of the knee. Arthritis Rheum 1995;38:1541-6

41. Bierma-Zeinstra S, Bohnen A, Ginai A, Prins A, Verhaar J. Validity of the American College of Rheumatology criteria for diagnosing hip osteoarthritis in primary care research. J Rheumatol 1999;26:1129-33

42. Bellamy N, Bradley LA. Workshop on chronic pain, pain control, and patient outcomes in rheumatoid arthritis and osteoarthritis. Arthritis Rheum 1996;39:357-62

43. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129-38

44. Ware JE, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36). Med Care 1992;30:473-83

45. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patients outcome in arthritis. Arthritis Rheum 1980;23:137-45

46. Bellamy N, Buchanan WW Goldsmith CH, et al. 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 knee or hip. J Rheumatol 1988;15:1833-40

47. Gillings D, Koch G. The application of the principle of intention-to-treat to the analysis of clinical trials. Drug Inform J 1991;25:411-24

48. Portenoy RK. Current pharmacotherapy of chronic pain. J Pain Symptom Manage 2000;19:S16-S20

49. Wang SC. Emetic and antiemetic drugs. In: Root WS, Hofmann FG, editors. Physiological pharmacology II. New York: Academic Press; 1965. p. 255-328

50. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained release oral morphine in cancer pain: preference, efficacy and quality of life. J Pain Symptom Manage 1997;13:254-61

51. Allan LA, Kalso E, on behalf of the FEN-INT-26 Study Group. Randomised trial of transdermal fentanyl and sustained release oral morphine in chronic low back pain. Presented at the 4th Congress EFIC, Czech Republic, Prague, 2-6 September 2003

52. Knott L. Treating osteoarthritis in practice - the TOP study. Curr Med Res Opin 2000;16:147-52

53. Portenoy RK. Opioid therapy for nonmalignant pain: a clinician's perspective. J Law Med Ethics 1996;24:296-309

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2801_3, Accepted for publication: 21 October 2004

Published Online: 19 November 2004

doi:10.1185/030079904X14120

Karel Pavelka1, Xavier Le Loet2, Olav Bjorneboe3, Gabriel Herrero- Beaumont4 and Ute Richarz5

1 Institute of Rheumatology, Prague, Czech Republic

2 Centre Hospitalier Universitaire de Rouen, Rouen, France

3 Martina Hansens Hospital, Sandvika, Norway

4 Fundacion Jimenez Diaz, Madrid, Spain

5 Janssen-Cilag, Baar, Switzerland

Address for correspondence: Dr Ute Richarz, Janssen-Cilag (Europe, Middle East, Asia), Sihlbruggstr. 111, 6341 Baar, Switzerland. Tel.: +41 41 7673421; Fax: +41 41 7673450; email: uricharz@jacgb.jnj.com

Copyright Librapharm Dec 2004

Source: Current Medical Research and Opinion

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