Oxycodone/acetaminophen at low dosage: an alternative pain treatment for patients with rheumatoid arthritis ABSTRACT Objectives: to assess efficacy

y and safety of the association oxycodone/acetaminophen (oxycodone/acetaminophen) for pain treatment and disability improvement in patients with rheumatoid arthritis (RA). Methods: Patients with RA (n = 29), suffering from moderate to severe pain for more than three months, were included in the study, except those under RA therapy with biological drugs. The treatment started with oxycodone/acetaminophen at the dosage of 5 mg/325 mg, and then the dosage was titrated until the attainment of good pain relief. Antiemetic and laxative therapy was used for the prophylaxis of known opioidrelated adverse events. Results: Patients continued their RA therapy without changing the dosages, reported reduced pain intensity and disease activity, and improvement of disability. Forty-two percent of patients had a good clinical response to oxycodone/acetaminophen treatment, according to European League against Rheumatism (EULAR) assessment criteria, and 50% of patients reached the American College of Rheumatology 20% improvement criteria (ACR20). At the end of the study, the mean ( SD) daily effective oxycodone/acetaminophen dose was 13.8 (6.8) mg/ 720.4 (291.0) mg. No serious adverse event was observed. Nausea, vomiting and stipsis of mild-moderate intensity were the most common adverse events. Conclusion: oxycodone/acetaminophen at low dosages for the treatment of chronic pain in RA patients, can be a good alternative to NSAIDs, allowing the reduction of their consumption, while keeping RA therapy stable. Keywords: opioids; pain control; rheumatoid arthritis; association

oxicodone/acetaminophen
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INTRODUCTION Rheumatoid arthritis (RA) is an auto-immune disease, which is characterized by inflammation, altered humoral and cellular immune responses, and synovial hyperplasia, leading to destruction and subsequent loss of joint function, which, in many cases, cause severe pain, disability and poor quality of life (1). Twenty two percent of RA patients have to leave their job, and 10% of them require a continuous assistance (2). In Western countries, RA affects up to 1-3% of the population, and approximately 1% of adults in the United States (3). There is a higher percentage of females than males affected (3:1 female preponderance) (4). Women with RA, moreover, experience a greater degree of disease activity, pain intensity, disability, and psychological distress than men (4). Pain is one of the most important symptoms of rheumatoid arthritis for the majority of people affected by this disease (5). Therapy for rheumatoid arthritis generally includes NSAIDs for control of pain, oral or intra-articular glucocorticoids, and disease modifying antirheumatic drugs (DMARDs) for disease progression control (6). NSAIDs are effective for the treatment of pain, but their chronic use (especially at high dosages) increases the risks of gastrointestinal, and/or cardiovascular side effects, risks that are particularly high for elderly patients and women (7, 8). Steroid also expose patients to high risks of side effects, such as: osteoporosis, cushingoid symptoms, and diabetes or cataract (9). The side effects correlated to both NSAIDs and corticosteroids are extremely relevant and certainly represent an important limitation for pain therapy. Recently the guidelines of the American Pain Society (10) strongly suggest the use of opioids, such as oxycodone and morphine, for the treatment of serious chronic pain that is not responsive to NSAIDs. The efficacy and safety of opioids in chronic cancer pain are well-documented (11, 12). Opioids are effective also for the treatment of non-cancer pain. In the last few years, indeed, clinicians have started to substitute NSAIDs with opioids, obtaining good results,
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as concerning pain relief, in patients suffering from several chronic noncancer pain diseases, including osteoarthritis, rheumatoid arthritis and herpes zoster (13, 14). Because of the low incidence of serious adverse reactions after prolonged administration (15), opioids represent an alternative therapy for the treatment of immuno-dependent painful pathologies, such as rheumatoid arthritis. In this case, the use of opioids would allow the reduction of pain intensity, while reducing the risks connected to the prolonged administration of NSAIDs and corticosteroids. Drugs containing a non-opioid and a strong opioid, moreover, are a potential advantageous pain therapy, because they allow exploiting the synergic analgesia of two molecules with different mechanisms of action, attaining a good pain control at low dosages of the single components. Clinical trials have proved that the treatment with oxycodone/acetaminophen is efficacious and well tolerated by patients with osteoarthritis (16-18). The association opioid/acetaminophen added to regular therapy for rheumatoid arthritis pain was associated with a significant improvement in pain relief and a significant reduction in pain intensity (19-20). For this reason we choose oxycodone in association with acetaminophen as study drug. There are only few studies on oxycodone/acetaminophen treatment of RA pain, this is the reason why we believed it was important to validate the analgesic efficacy and safety of opioids for the treatment of RA pain in an open label case series study with a small number of patients. In this paper we repot the results of our preliminary study on tolerability and safety of oxycodone/acetaminophen association for the treatment of chronic pain in RA patients. MATERIALS AND METHODS Study design: We performed a prospective, open-label case series study of the use oxycodone/acetaminophen combination for the treatment of chronic pain in RA patients, in order to assess efficacy on pain control and safety of the treatment.
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Ethics The study was approved by the Hospital Ethics Committee and conducted according to the Helsinki declaration principles on human clinical studies. All the patients, after a through explanation of the procedure and the aims of the study, gave a written consent. Study Population Inclusion criteria: patients with RA; older than 18 years; informed consent signed; suffering from musculoskeletal pain for more than 3 months; pain intensity 50 on a visual Analogue scale (VAS) 0-100; non responsive to at least two different types of immunosuppressive therapy; NSAIDs use for at least one month without pain relief. Exclusion criteria: patients in treatment with biological drugs, mono-amino-oxydases inhibitors (MAOI) or tricyclic antidepressants; mechanical ileum, central nervous system (CNS) depression, uncontrolled epilepsy, intracranial hypertension, respiratory

insufficiency, asthma, hepatitis and/or renal insufficiency, pregnancy or breast-feeding, hypersensitivity towards the study drugs. Study intervention All prior analgesics were discontinued. The optimal dosage of oxycodone/acetaminophen for clinically meaningful pain relief (VAS 40) was established after a period of titration. The initial oxycodone/acetaminophen dose was 5mg+325 mg once a day, and the maximum dosage allowed was 20+325 mg four times a day. The prophylaxis therapy was prescribed to each participant, and it was assumed as needed. Prophylaxis included polyethlene glycol for stipsis prevention, and metoclopramide for emesis prevention. The study included 5 visits: at 0, 15, 30, 60 and 90 days of treatment. During the study every patient continued its basal RA treatment without changing the dosages. Outcome Measures Quality of Life and Disability: Quality of life was assessed with the global health state (GHS) scale, where 0=the worst possible health status and 100= the best possible health
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status; and the Health Assessment Questionnaire (HAQ 0-3), which is index of disability (21, 22). Patients were also asked to express their perception of disease activity (DAP) on a VAS 0100 scale, where 0=no disease activity, and 100= the highest disease activity. Disease activity: Ritchie score (RI78), number of swollen and tender joints (SW 44 and TEN 44, 0-44), disease activity score (DAS), erythrocyte sedimentation rate (ESR, mm/h), and C-reactive protein (CRP, mg/L) were the parameters used as indexes of disease activity as described in the literature (23). They were assessed at each visit, together with: the type and the intensity of adverse events, drugs intake for adverse events and for pain support, and finally the physician was asked to express its perception of disease activity (DAD) on a VAS 0-100, where 0=no disease activity, and 100= the highest disease activity. Finally the Disease Activity Score (DAS) was calculated as follows: 0,53938x (RAI) +0.06465 x SW44+ 0.330 x ln ESR+ 0.00722 x GHS (23). Tolerability: The profile of tolerability of the oxycodone/acetaminophen treatment was evaluated in terms of number, frequency and intensity of adverse events that were oxycodone /acetaminophen related. Pain relief: A reduction of 20 point of pain intensity in the VAS scale, from the baseline to end of study visit, was considered as index of oxycodone/acetaminophen efficacy as concerning pain relief. Pain intensity was recorded at each visit using the VAS 0-100, which is one of the most validated scale for pain assessment (24), where 0=no pain, and 100=worst possible pain. Clinical responses to oxycodone/acetaminophen treatment were assessed according to the American College of Rheumatology (ACR) criteria and the European League Against Rheumatism (EULAR) criteria, because they are standardized response measurement in rheumatoid arthritis trials (23, 25). The ACR20 criteria define a significant clinical response
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to drug treatment as a 20% improvement in tender and swollen joint counts and 20% improvement in 3 of 5 core set measures: patient global assessment, physician global assessment, pain intensity (VAS), disability (HAQ), and CRP (10). The EULAR response criteria define patients as good responders, moderate responders, or non-responders using individual changes in DAS from baseline levels (23). According to this criteria: a good clinical response is attained if DAS44 <2.4 and its reduction from basal value >1.2; a moderate response is achieved if DAS44 is between 2.4 and 3.7 and the reduction is >0.6 or DAS44>3.7 and reduction>1.2; no response is considered in the other cases. Statistical Analysis Continuous data of the whole sample (N=24) were reported as the mean and standard deviation, and were analyzed with the model analysis of covariance (ANCOVA). Statistical significance was defined as P < 0.05. Proportions were expressed in percentage. RESULTS Description of the sample Fifty-three patients were screened; 14 of them were excluded because did not meet inclusion criteria, 10 did not accept to take part to the study, 29 were enrolled, 5 of these were lost of follow up because they did only the baseline visit. For this reason we did the whole analysis on the remaining 24 patients. Twenty four patients did the first follow up visit (15 days), 20 patients did the second visit (30 days), whereas 13 and 10 were the patients who did the 60 and 90 days control visit respectively. The reasons for discontinuation were adverse events (N = 4), patient choice (N = 4), lack of compliance (N= 3) and lack of effectiveness (N = 1). One patient violated the protocol, and 1 had to leave the study because of worsening (not related to study drug) of a concomitant pathology. The characteristics of patients were summarized in table 1: 22 (76%) were females and 7 (24%) males, with an average age of 64.5313.56 years (range 39-88 years), and their
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baseline average pain intensity was VAS 64.2815.80 (VAS 0-100). Analgesic and RA therapy at baseline visit was reported in table 1. Study drug dosing At the end of the study, the mean ( SD) daily effective oxycodone/acetaminophen dosage was 19.50 (9.26) mg/ 780 (274.6) mg. Oxycodone/acetaminophen dosages at the different time point were reported in table 2. Effective dosage was reached when VAS<40. All previous analgesics were discontinued by the majority of the patients, only three patients continued NSAIDs consumption; two of these reduced the dosage of 60% (average value), whereas one did not change the dosage until the end of the study. Efficacy Average pain intensity at baseline was 65.9 ( 3.2). Significant (p<0.05) pain reduction was observed already after 15 days of therapy, and increased in later time points (table 3). Disease activity, quality of life and disability improved as a consequence of oxycodone/acetaminophen treatment. Average TEN44, RI78, and DAS scores decreased significantly (p<0.05), and DAD, DAP and GSH scores improved (p<0.05) from baseline to end of study (table 3). ACR20 and EULAR assessment According to the EULAR criteria: 50% of patients had a good response and 40% a moderate response to the oxycodone/acetaminophen treatment, without the need to change the basal RA therapy. After three months of treatment, 50% of patients achieved also the ACR20. Only 10% of patients did not show any response to the study drug. Tolerability No serious adverse event was observed as a consequence of oxycodone/acetaminophen treatment. The most common adverse events were those correlated to opioids use: nausea (22%), sleepiness (18%), stipsis (14%), vomiting (12%). Other less frequent

adverse events were: vertigo (8%), inappetence (5%), xerostomy (5). Their intensity was mild or moderate, and they caused the interruption of the study in 21% of patients (n=4). Prophylaxis for stipisis and emesis was used by 4 (13.8%) and 3 (6.9%) patients respectively.

DISCUSSION International rheumatology guidelines indicate the use of NSAIDs as first choice drugs for the treatment of pain, because of their anti-inflammatory properties (26, 27). The risks correlated to prolonged therapies with NSAIDs are well known (28), for this reason we believe that alternative models of pain treatment, involving the use of opioids, should be identified. Our data showed that oxycodone/acetaminophen therapy resulted in adequate pain relief without causing serious adverse effects. This result is supported by the literature (18, 29). In our study oxycodone/acetaminophen induced a 20 points reduction of pain intensity in a VAS scale 0-100 in RA patients. The Health Assessment Questionnaire (HAQ) was developed in the late 1970s, to measure disability and disease activity in patients with arthritis (21) improvements in HAQ scores in patients with early RA are associated with favorable long-term outcomes (22). Sokka and colleagues showed that mean baseline HAQ scores were significantly higher in patients with RA than in controls: 0.71 versus 0.17 (22). Mean baseline HAQ score of our patients were higher than those resulting from the above survey (1.9 versus 0.71). The 0.32 units mean reduction of HAQ from baseline to end of treatment (3 months) was very high, as compared to 0.01 unit increase per year, described in the above registry study (22). This result was very important, because it suggested that oxycodone/acetaminophen may be involved in reducing RA disease activity of our patients, improving patients disability, as confirmed also by the reduction of RI78, TEN and DAS scores. ESR and
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CRP, however, did not change significantly. We believe that this is due to the short period of observation, future work is required to better assess this issue. Attainment of ACR20 and of a good clinical response according to EULAR criteria, was achieved at low dosages of oxycodone/acetaminophen (mean daily dosage at the end of the study= 19.50mg/780mg), maintaining stable the basal RA therapies, during the whole study (3 months). A substantial limitation of our study is that it is an open label case series without an active comparator or placebo control sample. Another limitation can be the number of patients treated, which was relatively small (29 patients), the drop-out rate after 30 days, and the short period of assessment. As concerning the drop out-rate, unfortunately, many patients were geriatric and this limited their compliance and their presence at follow-up visits, and many of them withdrew from the study after 1-2 months. Our results, nonetheless, are important, because they showed that oxycodone/acetaminophen was effective on pain relief already after 15 days and 30 of treatment, and this benefit was maintained until the end of study. However, the primary purpose of this study was to preliminarily test the effectiveness and the safety for the treatment of RA-pain, and the three months of observation are considered enough by the Food and Drug Administration for approval in chronic pain. Conclusion: The positive results attained in our study with oxycodone/acetaminophen suggest that this drug is efficacious for pain and disability management of RA patients. We showed that oxycodone/acetaminophen was well tolerated, induced few adverse events, and had a positive effect on pain, patients general health status and disability. For these reasons opioid can be good alternative to NSAIDs, and we suggest using them as first choice for the treatment of RA pain and/or in association to cyclic use of NSAIDs. Conflict of interest section The authors declare that they have no conflict of interest. Disclosures: None
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2008;8(4):287-313 14. .Solomon, D.H., Avorn, J., Wang, P.S, et. al.. Prescription opioid use among older adults with arthritis or low back pain. Arthritis Rheum, 2006; 55, 35-41. 15. Raffaeli W. et al. The immune system and Analgesics In Management of pain. In A world Perspective ( P. Raj , D.Niv eds) Moruzzi editor, 1995, 85-93. 16. Millett PJ, Gobezie R, Boykin RE. Shoulder osteoarthritis: diagnosis and management. Am Fam Physician. 2008;78(5):605-11. 17. Barron MC, Rubin BR. Managing osteoarthritic knee pain. J Am Osteopath Assoc. 2007;107(10 Suppl 6):ES21-7. 18. Caldwell JR, Hale ME, et. al.. Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. J Rheumatol. 1999; 26(4):862-9. 19. Lee EY, Lee EB, et al. Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, doubleblind, placebo-controlled trial. Clin Ther. 2006, 28(12):2052-60.
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20. Connelly M, Schanberg L.Opioid therapy for the treatment of refractory pain in children with juvenile rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006;2(12):636-7 21. Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum, 1980; 23:13745 22. Sokka T, Makinen H. Improving outcomes in rheumatoid arthritis: what determines decisions to change ineffective therapy? J Rheumatol, 2006; 33:1213-1215. 23. Wells G, Becker JC, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68(6):954-60. 24. Huskisson EC: Measurement of pain. Lancet, 1974, 2:1127-1131. 25. American College of Rheumatology Committee to Reevaluate Improvement Criteria. A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum, 2007; 57, 193-202. 26. Thomas J, Straus WL, Bloom BS. Over-the-counter nonsteroidal anti-inflammatory drugs and risk of gastrointestinal symptoms. Am J Gastroenterol 2002;97(9):2215-9. 27. Adams NJ, Plane MB, Fleming MF, Mundt MP, Saunders LA, Stauffacher EA. Opioids and the treatment of chronic pain in a primary care sample. J Pain Symptom Manage; 2001; 22(3):791-6. 28. Raffaeli W, Salmosky-Dekel B.G. Biological consequences of long-term intrathecal administration of opiods. Minerva Anestesiol 2005; 71:475-8 29. Corsinovi, L., et al., Efficacy of oxycodone/acetaminophen and codeine/acetaminophen vs. conventional therapy in elderly women with persistent, moderate to severe osteoarthritis-related pain. Arch. Gerontol. Geriatr., 2009,

doi:10.1016/j.archger.2008.12.003
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Table 1) Description of the sample

Characteristics Male n (%) Female n (%) Age (meanstd) Age Range Baseline VAS (meanstd) Baseline Pain treatment n (%) None NSAIDS Other Baseline RA treatment None Sulfasalazine (3%), Leflunomide (14%), Methotrexate (45%), Hydroxychloroquine (14% Baseline Steroid treatment None Cortisone Methylprednisolone Prednisone Deflazacort 11 (38) 15 (52) 4 (10) n (%) 9 (31) 1 (3) 4 (14) 13 (45) 4 (14) n (%) 5 (17) 6 (21) 11 (38) 6 (21) 1 (3) Value 7 (24) 22 (76) 64.53 13.56 39-88 65.9 15.80

Table 2) Daily Oxycodone/acetaminophen dosages

Time point Mean daily Oxycodone dosage ( STD) mg 15 days 30 days 60 days 90 days 8.13 ( 3.13) 11.38 (4.83) 17.69 (7.8) 19.50 (9.26) Mean daily acetaminophen dosage ( STD) mg 523.96 (207.92) 723.1 (306.61) 775 (249.58) 780 (274.6)

Table 3) Clinical response to Oxycodone/acetaminophen treatment

Baseline mean std VAS % VAS<40 % VAS reduction >20 GSH DAP HAQ TEN44 RI78 DAS SW44 ESR CRP DAD 65.9 15.8 0 15 days mean std 30 days mean std 60 days mean std 90 days mean std

50.4 22.3** 45.6 22.17 50 50 50 54 62 20.4

43.2 21.2** 44.2 24.7** 45 60 54 50 65.4 18.2 64.3 18.35* 44.8 24.7* 47.5 26.8* 1.5 0.8* 1.5 0.8* 7 6.4* 6.9 6.4* 9 10.5* 9.8 10.2* 2.4 1.1** 2.2 0.8* 5 9.1 5 9.1 32.4 26.8 32.1 27.4 10.8 13.8 10.4 14.0 29.4 18.3* 28.8 18.4*

50.1 23.0 61.1 26.5 1.9 0.7 13.7 10.6 16.5 15.4 3.5 1.1 6.1 7.4 39 27.3 13.6 15.8 38.8 23.3

52.8 18.4

51.3 26.1** 47.3 26.3* 1.7 0.8** 7.4 6.3 1.5 0.8* 7.5 6

11 10.2 10.6 10.5* 3 1.1 6.3 8.5 33.7 25.8** 14.1 14.5 2.7 1.0 5.7 9.0 34.2 26.2 12.3 13.7

31.4 19.3** 31.9 18.1*

*p<0.05
**p<0.01