Multi-disciplinary Osteoarthritis Pain Management Introduction Osteoarthritis (OA) is a group of common age-related disorders, possibly of diff ering aetiology,

that occur due to dysregulation of normal tissue turnover and r epair. A localized joint disease, osteoarthritis involves a dynamic interplay of cytokines and chemokines, in which all the components of the joint are affected , resulting in total joint failure. In Singapore, osteoarthritis is among the 10 leading causes of specific disease, and as the population ages its incidence is predicted to rise. In the United St ates, an estimated 15% of adults suffer from osteoarthritis; and osteoarthritis healthcare utilises 1 2% of the gross national product (GNP) of several Western co untries and 0.28% of GNP in Hong Kong. A variety of factors predispose individuals to developing osteoarthritis; these include ethnicity, gender, age, heredity, hypermobility, low estrogen levels, ob esity, smoking, osteoporosis, and possibly nutrition. Biomechanical factors act locally at the level of the joint and may be aggravated by obesity, joint injury or deformity, intensive sports, and weak muscles among others. The different pathophysiological processes in osteoarthritis include muscular at rophy, cartilage breakdown, meniscal damage, presence of osteophytes, ligament d ysfunction, altered fat metabolism and leptin. Although the pathogenesis of oste oarthritis is multifactorial, it is primarily mechanically driven and biochemica lly mediated, with mechanical pressure on the joint initiating a pathological cy cle of events. Concurrently at onset, an imbalance of cytokines and growth facto rs, prostaglandin E2, cartilage matrix fragments, neuropeptides, free oxygen rad icals, proteolytic enzymes and protease inhibitors occurs; this leads to proteol ytic destruction of cartilage matrix and chondrocyte death and subsequent remode lling of bone by the formation of osteophytosis, angiogenesis and subchondral sc lerosis. This process results in abnormalities and reduced viscosity in synovial fluid, causing peripheral and central sensitisation and nociceptor activation. The ensuing pain is instrumental in reducing the patient s ability to exercise, le ading to muscle weakness, impaired propioception and joint laxity that in turn a lters the mechanical loading of cartilage, bone and ligaments, which further acc entuates joint destruction. Disease outcomes include joint destruction, severe p ain that persists even at rest, loss of joint function and disability that resul ts in social isolation, depression and reduced quality of life, and overall pose a major economic burden.1,2 The hallmark symptomatology of osteoarthritis is mechanical pain and movement li mitation. Clinical signs include crepitus, bony hypertrophy and tenderness, limi tation of range of motion and malalignment leading to altered gait. The source o f pain in osteoarthritis can be attributed to either inflammation in the synoviu m, medullary oedema, subchondral fracture of the bone, or periosteal reaction an d nerve compression by osteophytes. Other causes of pain include distension of t he capsule and spasm or strain of muscles/ligaments. Osteoarthritis pain can als o be accentuated by anxiety or other contributory factors. The diagnosis of oste oarthritis is confirmed on X-ray as loss of cartilage and new bone formation (os teophyte) beneath cartilage and at joint margins. There is no known cure for osteoarthritis, but its symptoms can be controlled. P ain is a major problem in osteoarthritis and the major management goals are to r educe pain, maintain or improve joint mobility and limit functional impairment. A tailored approach adapted to the needs of individual patients is recommended. In particular, it is imperative to control chronic pain adequately as chronic pa in can result in functional and structural changes in the brain. The search for disease-modifying osteoarthritis drugs that can slow disease progression continu

es, but results to date have been disappointing. Weight control is another important factor in managing osteoarthritis patients, and the obesity epidemic is central to the rising prevalence of osteoarthritis. Optimal weight control prevents and slows the progression of osteoarthritis affe cting the weight-bearing joints such as the knees, hips and lower back; for each pound of weight loss there is a 4-pound reduction in the load exerted on the kn ee during ambulation.3 Treatment Guidelines The key objectives for the management of osteoarthritis are to educate patients about osteoarthritis and its management, alleviate pain, improve function and de crease disability and prevent or retard progression of the disease and its conse quences. Major international clinical guidelines for the management of osteoarth ritis advocate a combination of non-pharmacological and pharmacological treatmen t modalities. Non-pharmacological measures such as education, exercise, weight-r eduction and lifestyle changes form an integral component of care for osteoarthr itis. Exercise is particularly important, because quadriceps weakness is common in osteoarthritis of the knee, and regular exercise has been found to improve pa in control and functional ability. Moreover, both physical and occupational ther apy play key roles in the management of patients with functional limitation. The American College of Rheumatology (ACR)-recommended treatment agents for oral pharmacotherapy of patients with osteoarthritis include paracetamol (acetaminop hen), cyclo-oxygenase 2 (COX-2)-specific inhibitors, nonselective non-steroidal anti-inflammatory drugs (NSAIDs), non-acetylated salicylate and other pure analg esics such as tramadol. Other treatment alternatives include intra-articular glu cocorticoids or hyaluronan injections and topical capsaicin and methylsalicylate .4 All major international guidelines recommend paracetamol as a first-line analges ic. The ACR statement regarding paracetamol is that, for many patients with oste oarthritis, the relief of mild-to-moderate joint pain afforded by the simple ana lgesic, paracetamol, is comparable with that achievable with an NSAID, and that the daily dose of paracetamol should not exceed 4 g.4,5 The European Union for the League of Arthritis and Rheumatism (EULAR) 2003 guide line recommendation for knee osteoarthritis states that paracetamol is the oral analgesic to try first and, if successful, is the preferred long-term oral analg esic, because there is evidence that paracetamol is effective in the treatment o f knee osteoarthritis and in many patients, is comparable with ibuprofen in the short-term, and almost as efficacious as naproxen. There is also evidence that p aracetamol can be taken over the long-term. For hip osteoarthritis, EULAR 2005 s tates that although there is no direct evidence to support the use of paracetamo l in hip osteoarthritis, evidence in osteoarthritis of any site demonstrates tha t paracetamol is effective in relieving pain arising from osteoarthritis. Import antly, a study in knee osteoarthritis shows that paracetamol is better than NSAI Ds, NSAIDs plus gastroprotective agents, and COX-2 specific inhibitors for the c ost of each gastrointestinal (GI) adverse event avoided.6,7 The United Kingdom National Institute for Health and Clinical Excellence clinica l guideline for osteoarthritis recommends that paracetamol should be considered for pain relief in addition to core treatment, and that regular dosing may be re quired. Furthermore, paracetamol and/or topical NSAIDs should be considered ahea d of oral NSAIDs, COX-2 specific inhibitors or opioids.8 The Osteoarthiritis Research Society International (OARSI) has developed updated , patient-focused, evidence-based, expert consensus recommendations for the mana gement of hip and knee osteoarthritis. They recommend paracetamol (up to 4 g/day

) as an effective initial oral analgesic for treatment of mild-to-moderate pain in patients with knee or hip osteoarthritis.9 The Clinical Practice Guidelines for Osteoarthritis of the Knees, Singapore, und erscores that pain medications are important in managing osteoarthritis symptoms and should be used concurrently with nutritional, physical and educational inte rventions, and that doctors should consider efficacy, adverse side effects, dosi ng frequency and cost to the patient when recommending osteoarthritis treatments . For mild-to-moderate osteoarthritis pain, paracetamol is the drug of choice fo r first-line pain relief and improving physical functioning in osteoarthritis. I n clinical trials, paracetamol has been found to provide similar efficacy to low - and high-dose ibuprofen in knee osteoarthritis. Furthermore, paracetamol is co st-effective and has minimal side-effects.10 In treating moderate-to-severe osteoarthritis pain, the use of NSAIDs and COX-2 specific inhibitors (for a patient who is at high risk of adverse upper GI event s) should be considered only if the patient is not responding to paracetamol. Id eally, NSAIDs should be used for the acute relief of pain and improvement in fun ction for as short a period as possible, and the benefits of using NSAIDs should be weighed against the potential adverse reactions, especially, with long-term use, in at-risk individuals. Notably, patients with moderately high risk for gas troduodenal bleeds should receive concomitant gastroprotective agents when using NSAIDs. Risk factors for GI complications include age greater than 60 years, pr evious history of GI events and concomitant corticosteroid use.6 COX-2 specific inhibitors may be used acutely for the reduction of pain from ost eoarthritis of the knees. Although these drugs have relatively lower risk of GI adverse events, long-term use has been associated with myocardial and cerebral i nfarction. When NSAIDs and COX-2 specific inhibitors are needed for the manageme nt of an individual patient, they should be prescribed at the lowest effective d ose. The duration of treatment should be periodically reviewed and kept as short as possible. Opioid analgesics with or without paracetamol are a suitable alter native in patients in whom NSAIDs, including COX-2 specific inhibitors, are cont raindicated, ineffective, and/or poorly tolerated. Topical NSAIDs and capsaicin have been found safe and effective, and can be used as adjunctive or alternative s to oral analgesic/anti-inflammatory agents. Intra-articular injection of long-acting corticosteroid is recommended in patien ts with flares of knee pain, especially if accompanied by effusion. Finally, joint replacement surgery may be considered in patients with hip or kne e osteoarthritis who are not obtaining adequate pain relief and functional impro vement from a combination of non-pharmacological and pharmacological treatment. Notably, replacement arthroplasties have proven an effective and cost-effective intervention for patients with significant symptoms, and/or functional limitatio ns associated with a reduced health-related quality of life, despite conservativ e therapy.6 Efficacy and Safety of Paracetamol Paracetamol has been used for more than 50 years as a leading over-the-counter a nalgesic and antipyretic. It has a very good safety profile and is used as a fir st-line analgesic for management of acute and chronic pain. The absorption of pa racetamol is not affected by food intake. And no renal, GI, or cardiac side effe cts have been reported with paracetamol. Furthermore, it tends to have fewer dru g-drug interactions and has been confirmed to be safe for long-term use. Paracet amol also offers low cost and convenient dose regimens in the form of slow-relea se and standard formulations.11,12 Paracetamol is indicated for the relief of mild-to-moderate acute pain as well a

s in chronic pain management and for the relief of fever. Its efficacy in acute and chronic pain management has been confirmed in several randomized controlled trials and the maximum daily dose of 4 g maximizes efficacy. Importantly, parace tamol is recommended as a first-line agent for osteoarthritis pain management by several international guidelines. In single-dose response studies, paracetamol 1,000 mg has been associated with greater pain reduction than 500 mg. (Table 1) Similarly, a meta-analysis of 21 randomized controlled studies demonstrated that paracetamol provides 40% pain relief that lasts for 4 to 6 hours. With 1,000 mg having greater benefit than <1,000 mg tablets. Sustained-release paracetamol fo rmulations provide greater convenience and better efficacy in osteoarthritis pai n management. In addition, paracetamol has a good safety profile and GI tolerability. It has n ot been associated with any renal or cardiac side-effects and has less drug-drug interaction. A 4 g daily dose of paracetamol is safe for long-term use, and stu dies with 4 mg of paracetamol in osteoarthritis patients for 12 months have reve aled no evidence of hepatic failure, no clinically significant alanine aminotran sferase/aspartate aminotransferase (ALT/AST) elevation, no renal failure or incr eased creatinine levels. In addition, extensive real-world data with widespread use of paracetamol in 82 countries for over 10 years have confirmed its safety. Compared to NSAIDs, paracetamol has the best risk/benefit ratio in more populati ons. Challenges and Treatment Gaps in Clinical Practice Guideline recommendations indicate that paracetamol should be considered as the first line of treatment for relieving pain and improving physical functioning in osteoarthritis. Nevertheless, despite guideline recommendations, there exists a gap between the recommended standard of care and real-life practice setting, an d misconceptions regarding the dosing of paracetamol and duration of treatment r equired, continue to exist. A survey of registered Singapore family physicians conducted between April and A ugust 2007 to obtain information regarding knowledge, attitudes and practices of general practitioners (GPs) in Singapore revealed that overall first-line presc ription of NSAIDs/COX-2 specific inhibitors (49.6%) far outstripped that of para cetamol alone or in combination (36.2%). The survey showed that 35% of Singapore GPs opted for NSAIDS as first-line treatment, while 20.6% prescribed paracetamo l combinations, 15.6% paracetamol, 14.6% COX-2 specific inhibitors, 8.5% glucosa mine/chondroitin sulphate and 4.5% topical NSAIDs. Most (74.6%) GPs cited effect iveness as their reason for choosing an NSAID, while 39.4% and 8.4% of GPs respe ctively selected NSAIDs for their affordability and safety profile. Similarly, t he primary reason for prescribing a COX-2 specific inhibitor was effectiveness ( 58.6%), other reasons included better GI tolerance (37.9%), less side-effects (2 4.1%) and favourable safety profile (20.6%). Paracetamol and paracetamol plus co mbinations were selected for their better overall safety profile (48.3%), GI tol erance (32.3%), effectiveness (32.3%), affordability (22.5%) and less side-effec ts (19.4%). Most respondents considered paracetamol and paracetamol combination tablets to b e of moderate effectiveness when used for osteoarthritis knee pain. Paracetamol was perceived to have very mild side effects, even less than those of paracetamo l combination tablets. Conversely, NSAIDs were rated as more effective than para cetamol, albeit with moderate side-effects. COX-2 specific inhibitors were thoug ht to be more effective than NSAIDs and with fewer side-effects, and opioids wer e rated as effective as NSAIDs, but were also associated with moderate side-effe cts. Overall, 57.8% of respondents reported that they would use paracetamol as a first-line agent for knee OA pain management. The main reasons for not using pa racetamol as first-line agent were the perceived ineffectiveness (47.9%), and th e fact that patient was expecting stronger medicine from the doctor (40.2%). The

survey revealed a common pattern of paracetamol use. The most common starting d ose of paracetamol was 2,000 mg (48.7%) per day, followed by 2,500 mg per day (2 8.8%). Most respondents prescribed paracetamol at three (58.9%) to four times (3 6.0%) a day. However, approximately 10% of respondents prescribed less than 1,20 0 mg of paracetamol a day, which might be a subtherapeutic dose. In addition, tw o-thirds stated that they would use paracetamol on an as-needed basis. The surve y findings underscore the urgent need to take proactive steps to translate theor y into practice. Consensus on Osteoarthritis Pain Management An expert panel on osteoarthritis pain management convened to develop a consensu s recommendation for a multidisciplinary approach to pain management in osteoart hritis. The panel included members of diverse specialities including family prac tice, geriatrics, rheumatology, physiotherapy and pharmacy. The panel set out to outline multidisciplinary actions that would contribute towards improved patien t outcomes, with a focus on identifying and confirming the place of paracetamol in the treatment algorithm of osteoarthritis, bridge the gap between standard car e and real practice by implementing counselling strategies and educational initia tives, and elucidate the role of different health specialties in osteoarthritis pain management. From a family practice perspective, local culture and the patient mind-set were found to dictate prevalent practices. In addition, patients were prone to seek i nstantaneous pain relief and were not amenable to taking pain medication in the long-term as recommended, and instead discontinued medication once their pain ha d abated. Education of patients by healthcare providers could help to overcome b arriers of patient misconceptions and expectations. Primary care physicians also need to ensure that patients are taking the right dose on a long-term basis to obtain adequate pain relief. For older patients, polypharmacy is of particular concern, as most of these pati ents have one or more co-morbid conditions, for example, hypertension, diabetes, stroke, renal disease and dementia. Treatment should therefore be selected care fully bearing in mind the potential for drug-drug interactions and should be specifi cally tailored for individual patients. Paracetamol is one of the safest analges ics for older individuals who are more prone to GI side-effects with NSAIDs. Mor eover, these patients are often renally compromised and are liable to develop re nal failure with a COX-2-specific inhibitor. In addition, older people are often unable to tolerate opioid drugs. Importantly, osteoarthritis is primarily a mechanically-induced disorder, with s everal mechanical factors including knee alignment and obesity, influencing join t loading and contributing to the development of abnormal mechanical environment and articular destruction. For this reason, the use of balance and strength tra ining through physiotherapy which promotes joint stability and dynamic alignment s at the affected joint has proven to be beneficial in reducing pain. An optimal balanced approach to the management of osteoarthritis, therefore, is to use a c ombination of physiotherapy and pharmacological intervention. Pharmacists also play an important role in the management of osteoarthritis, as patients often have misconceptions regarding pain medications. Proper counsellin g empowers patients to use their medication appropriately, which can improve eff icacy and reduce the side-effects. In particular, misconceptions regarding dosin g, frequency of administration, and when the drug has to be taken in relation to meals, can result in poor efficacy, increased side-effects and even toxicity. T his is especially important when patients are taking more than one medication, a s patients may have difficulty understanding the different categories of analges ics. For paracetamol, it is important to stress that patients can take two table ts four times a day irrespective of meals. Many patients are unaware that they c

an take up to two tablets of paracetamol and have been taking inadequate doses o f it; as a result they step-up to taking stronger medications such as NSAIDs, an d become over-reliant on stronger analgesia at an earlier stage when paracetamol alone could have sufficed. Strategies and Priorities for Action Key issues identified by the panel members included the need to empower doctors with knowledge of the indications for paracetamol and help overcome misconceptio ns regarding the safety of long-term use. Other areas that require attention inc luded educational vehicles that could help change the way doctors think. The role of pharmacists is integral, as they are the front-line care providers, especially given that paracetamol is an over-the-counter product. Consequently, it is important for pharmacists to have a clear understanding of patient s require ments, the reason for the pain and its level of intensity. Furthermore, when doc tors and pharmacists are counselling patients it is important for them to presen t information in a manner that patients are able to relate to, which may help ov ercome reservations about the side-effects of therapy. Similarly, it is importan t to customise patient education tools to their level of comprehension to make t hem more applicable. The ACTIV-8 Programme is an initiative, developed in collaboration with Singapor e National Arthritis Foundation, that can help improve patient understanding and compliance. Its goals are to educate patients and encourage them to take an act ive role in the management of their osteoarthritis. The name ACTIV-8 reflects ei ght steps to managing osteoarthritis. It comprises eight sections, available in English and Chinese: The power of exercise Joint action Eating for health Learning to relax Managing the pain using various options Making life easier for yourself Learning to protect by using aids to alleviate the pain Monitoring the progress by using a 12-week suggested programme Osteoarthritis pain is primarily of mechanical aetiology with only intermittent flares. Therefore, when evaluating osteoarthritis treatment options, use of long -term NSAIDs is not appropriate, especially for older patients who are at increa sed risk. For this reason, international guidelines and local guidelines concur in recommending paracetamol as first-line treatment to manage pain in osteoarthr itis patients. A local survey suggests that half of all GPs are aware that clini cal practice guidelines indicate paracetamol as first-line. Nevertheless, the us e of paracetamol is associated with perception issues regarding efficacy, primar ily due to inadequate dosing. A need therefore exists to overcome knowledge gaps in doctors and patients on the nature of osteoarthritis and the requirement for long-term treatment, with attention to particular issues for special population s such as co-morbid conditions and polypharmacy. Proper patient counselling with the support of appropriate counselling tools and improved communication between healthcare service providers and patients, can g

reatly improve the standard of care of osteoarthritis patients. New initiatives in collaboration with Singapore National Arthritis Foundation for development of both patient- and healthcare-professional education have been planned, and are a step forward to help overcome some of the knowledge gaps. In particular, the A CTIV-8 Programme is an exciting tool that includes both pharmacological and nonpharmacological interventions for osteoarthritis management; it is written in a step-wise manner that is easy for patients to understand, and it explains how os teoarthritis can be treated systematically. ACTIV-8 is a balanced initiative tha t advises on diet, exercise and drug treatment options so that patients are able to comprehend the overall treatment strategy for osteoarthritis, resulting in i mproved patient compliance and better treatment outcomes.