The Role of Paracetamol in Chronic Pain: An Evidence-Based Approach

JOBNAME: ajt 12#1 2005 PAGE: 1 OUTPUT: Tue January 11 07:09:39 2005 Prod#: 04 American Journal of Therapeutics 12, 80 91 (2005) The Role of Paracetamol in Chronic Pain: An Evidence-Based Approach C. Jane Nikles, 1 * Michael Yelland, 1 Chris Del Mar, 2 and David Wilkinson 3 Chronic pain is a significant public health burden. Several international guidelines and influential reviews recommend the use of paracetamol (acetaminophen) as the first-line analgesic of choice for the management of chronic pain. These recommendations are based largely on the balance of evidence, which favorably demonstrates the efficacy, safety, and low cost of paracetamol relative to other analgesics. A decade ago, March et al suggested that because of the dangers associated with conventional nonsteroidal antiinflammatory (NSAID) use, particularly in the elderly, they should ideally not be used without an individual n-of-1 trial to show that they are more effective than paracetamol. Today, the results of our investigations into the individualization of pain management options continue to support this suggestion. Based on the data available to date, it still seems prudent to use NSAIDs only in those patients in whom there is good evidence of improved efficacy over paracetamol. In patients with chronic pain, paracetamol can play an important role as an NSAID sparer, with resultant benefits in terms of reduced adverse effects and cost savings. Keywords: paracetamol, acetaminophen, chronic pain, osteoarthritis, n-of-1 trial INTRODUCTION 1 Discipline of General Practice, The University of Queensland, Herston, Queensland, Australia; 2 Bond University, Gold Coast, Queensland, Australia; 3 School of Medicine, The University of Queensland, Herston, Queensland, Australia. *Address for correspondence: Discipline of General Practice, The University of Queensland, Herston Road, Herston, Queensland, Australia, 4006. E-mail: j.nikles@uq.edu.au Much research has been conducted to define and understand pain, with the accepted definition from the International Association for the Study of Pain being an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. 1 Pain can typically be classified clinically into 2 types: neuropathic (stemming from a primary lesion or dysfunction in the central nervous system) or nociceptive (arising from stimulation of nociceptors by noxious stimuli). When described in terms of its duration, acute pain is regarded as being relatively short-lived and can be linked to readily identifiable nociceptive processes (eg, postoperative pain). However, when pain persists beyond 3 months or beyond the time when an acute injury would be expected to have healed, it is regarded as persistent or chronic pain. 2,3 Chronic pain is not only a common problem but also a significant and increasing public health burden in virtually all developed countries. It has recently been estimated that 1 in 5 Australians, including the workingage population, suffer from chronic pain. 4,5 Data collected from a random sample of 17,543 adult Australians have shown that the prevalence of chronic pain peaked in the 65 69-year age group for men (27% of men affected) and the 80 84-year age group for women (31% of women affected). Importantly, these data also highlight that the occurrence of chronic pain is significantly associated with older age, female gender, lower levels of completed education, and not having private health insurance. 4 Disability from chronic pain is substantial. A recent telephone survey of more than 2000 Australians aged 18 years and older revealed that 22.1% were affected by chronic pain and that pain-related disability was high, being observed in 27% of survey respondents. 5 Almost 80% of people with chronic pain had consulted a health 1075 2765 Ó 2005 Lippincott Williams & Wilkins

JOBNAME: ajt 12#1 2005 PAGE: 2 OUTPUT: Tue January 11 07:09:40 2005 Role of Paracetamol in Chronic Pain 81 care provider in the previous 6 months. Furthermore, the majority (70%) of patients with chronic pain took oral analgesics; with nonsteroidal antiinflammatory drugs (NSAIDs) and paracetamol being the most commonly used medications. The substantial use of overthe-counter (OTC) analgesics (typically paracetamol and NSAIDs, such as ibuprofen) highlights the importance of self-medication and pharmacist advice as important components of the management strategy in chronic pain. The undertreatment of pain can result in serious adverse outcomes, including negative physiologic, psychologic, and immunologic sequelae 6 and a subsequent decreased quality of life. 7 The provision of adequate analgesia that is cost-effective while being appropriate to both the patient and his or her condition is therefore fundamental in ensuring positive outcomes in patients with chronic pain. The ongoing challenge in providing optimal treatment is striking a balance between efficacy, safety, and cost. This article examines the role of paracetamol in the management of chronic pain in adults that is not controlled by nonpharmacologic methods. It examines the empirical data that compare paracetamol with NSAIDs and with other analgesics and draws on accumulating data from randomized, controlled trials, systematic reviews, metaanalyses, and n-of-1 trials (using patients as their own control when testing a treatment, in a randomized, double-blind crossover design 8 ). PARACETAMOL: OVERVIEW AND EFFICACY IN MANAGING PAIN Paracetamol has a long history of use as an analgesic; it is effective, well tolerated, and suitable for use by essentially all segments of the population. 9,10 The exact mode of action of paracetamol remains to be confirmed. However, it is thought to act by selectively inhibiting the release of prostaglandins within the central nervous system as well as having some peripheral analgesic effect. Graham and Scott provide the latest data on the possible mechanism of action in their article in this issue of the Journal. Paracetamol has been used extensively for the relief of mild to moderate pain. It is effective in both acute and chronic conditions such as headache, migraine, dysmenorrhea, sore throat, musculoskeletal pain, softtissue injury, pain after vaccination, pain after dental procedures/tooth extraction, toothache, and the pain of osteoarthritis (OA). Paracetamol is widely used as a supplement to or in combination with opioid analgesia in the management of more severe pain states (such as cancer pain) as well as being an accepted treatment of the relief of fever. The efficacy of paracetamol in acute and postoperative pain has been established in many clinical trials, with single doses of 600 1000 mg showing greater activity than placebo. 11,12 Managing mild to moderate chronic pain Despite the availability of a wide range of alternate analgesics, clinical guidelines for the management of pain [eg, those of the American College of Rheumatology (ACR), the European League of Associations of Rheumatology (EULAR), and the National Prescribing Service in Australia] advocate paracetamol as the agent of first choice and, if successful, for long-term use in a variety of mild to moderate chronic pain states, including lower limb OA 13,14 and low back pain. 15 NSAIDs may be considered for use in moderate to severe OA pain (ACR guidelines) or where the pain is unresponsive to paracetamol (EULAR). Osteoarthritis Despite clinical guidelines advocating first-line use, in recent times, the advantages of paracetamol over NSAIDs in managing OA pain have been questioned. 16,17 Those clinical trials that have been conducted to date have utilized total daily doses of paracetamol ranging from 2.6 to 4 g over 3 weeks to 2 years and demonstrated variable findings (Table 1). Of the 6 randomized, controlled trials evaluating the efficacy of paracetamol versus placebo in patients with OA, 18 23 2 trials 19,23 have shown no difference, while 4 trials 18,20 22 have shown paracetamol to provide superior pain relief. Similarly, of those trials that compared paracetamol with NSAIDs (conventional or COX-2 selective NSAIDs) most have shown the NSAID to afford better pain relief, 19,20,22,24 29 while only 1 has shown equal efficacy. 30 Interestingly, in the randomized, double-blind trial by Bradley et al, 30 paracetamol 4 g/d for 1 month, was as effective as both analgesic (1.2 g/d) and antiinflammatory (2.4 g/d) doses of ibuprofen in patients with OA of the knee. These findings have recently been challenged by the IPSO study that was conducted to compare the analgesic efficacy of ibuprofen (single dose, 400 mg; multiple doses, 1200 mg/d) with that of paracetamol (single dose, 1000 mg; multiple doses, 3000 mg/d) in hip and knee OA over 14 days. It demonstrated that ibuprofen was more effective than paracetamol in terms of pain relief and functional improvements. 29 However, the paracetamol dose used in the IPSO trial was less than that used by Bradley et al and lower than the daily dose recommended in the currently published EULAR and ACR guidelines. Factors not mentioned in the IPSO report (such as previous therapy and whether patients with recent

JOBNAME: ajt 12#1 2005 PAGE: 3 OUTPUT: Tue January 11 07:09:40 2005 82 Nikles et al Table 1. Characteristics of clinical trials evaluating the efficacy of paracetamol in osteoarthritis. Study Design Type of OA Duration Treatment groups Paracetamol vs placebo Miceli-Richard et al (2004) 23 parallel Amadio and Cummings (1983) 18 Zoppi et al (1995) 21 Paracetamol vs NSAID vs placebo Case et al (2003) 19 Pincus et al (2003) 20 Pincus et al (2004) 22 Paracetamol vs NSAID Boureau et al (2004) 29 Pincus et al (2001) 24 Geba et al (2002) 25 Williams et al (1993) 27 Shen et al (2003) 28 Bradley et al (1991) 30 crossover parallel parallel crossover crossover parallel crossover parallel parallel Randomized, controlled trial parallel Knee 6 wk Paracetamol 4000 mg/d (n = 405) Placebo (n = 374) Knee 6 wk Paracetamol 4000 mg/d (n = 25) Placebo (n = 25) Hip/knee 1 wk Paracetamol 3000 mg/d (n = 30) Placebo (n = 30) Knee 12 wk Paracetamol 4000 mg/d (n = 29) Diclofenac 150 mg/d (n = 25) Placebo (n = 28) Hip/knee 6 wk Paracetamol 4000 mg/d (n = 168) Celebrex 200 mg/d (n = 178) Placebo (n = 169) Hip/knee 13 wk Paracetamol 4000 mg/d (n = 356)* Celebrex 200 mg/d (n = 370)* Placebo (n = 354)* Hip/knee 14 d Paracetamol 3000 mg/d (n = 111) Ibuprofen 1200 mg/d (n = 111) Hip/knee 6 wk Paracetamol 4000 mg/d (n = 115) Diclofenac 150 mg/d (n = 112) Knee 6 wk Paracetamol 4000 mg/d (n = 94) Celebrex 200 mg/d (n = 97) Rofecoxib 12.5 mg/d (n = 96) Rofecoxib 25 mg/d (n = 97) Knee 2 y Paracetamol 2600 mg/d (n = 75) Naproxen 750 mg/d (n = 73) Knee 3 m Paracetamol 4000 mg/d (n = 10) Rofecoxib 25 mg/d (n = 10) Knee 4 wk Paracetamol 4000 mg/d (n = 61) Ibuprofen 1200 mg/d (n = 62) Ibuprofen 2400 mg/d (n = 61) March et al (1994) 26 N-of-1 Any 6 wk Paracetamol 2000 mg/d vs Diclofenac 100 mg/d (n = 15) Nikles et al (2000) 8 N-of-1 Any 12 wk Paracetamol 3000 mg/d vs Ibuprofen 1200 mg/d (n = 14) Nikles et al (2005) 91 N-of-1 Any 12 wk Paracetamol 3000 mg/d vs Ibuprofen 1200 mg/d (n = 77) Wegman and van der Windt (2003) 88 N-of-1 Any 4 wk Paracetamol 3000 mg/d vs Ibuprofen 1200 mg/d (n = 3) Diclofenac 25 100 mg/day (n = 9) Naproxen 250 500 mg/day (n = 1) *N values represent combined patient numbers from PACES-a and PACES-b. Annals of Rheumatic Disease 2004;63:901 907, adapted and reproduced with permission from the BMS Publishing Group. flare of symptoms were included), the very high baseline pain scores (71.3 and 72.2 in the ibuprofen and paracetamol treatment groups, respectively, as measured by a 100-mm visual analogue scale), and the fact that on average only 7 patients were recruited in each of the 31 centers are suggestive of selection bias and cast doubt as to the generalizability of the study results to clinical practice. Neame et al 31 made similar comments with regard to similar methodological inadequacies in the Miceli-Richard et al study 23 (discussed later), pointing out that, while this study affords lessons that can be learned for future OA trial design, the relevance of its results to the clinical management of common knee OA is questionable.

JOBNAME: ajt 12#1 2005 PAGE: 4 OUTPUT: Tue January 11 07:09:41 2005 Role of Paracetamol in Chronic Pain 83 A Cochrane review has been conducted to assess paracetamol s role in chronic pain associated with OA. 32 Towheed et al 32 found that it was less effective overall than NSAIDs in terms of focal pain reduction and global pain assessments, although the effect sizes for these differences were modest at 0.2 to 0.5. The relative superiority of NSAIDs over paracetamol appears to be more marked in OA patients with more severe pain. Indeed, the ACR guidelines recommend NSAIDs as an alternative first-line medication for moderate to severe OA pain. The EULAR guidelines are more cautious about NSAIDs, recommending that they be reserved for pain that is unresponsive to paracetamol. The Cochrane review noted similar efficacy for both paracetamol and NSAIDs in terms of improvement in functional status. It is of note that the mean duration of clinical trials was only 6 weeks, leading the authors to caution that care should be taken when interpreting the results and extrapolating them to long-term use. 32 Most recently, Zhang et al 33 conducted a metaanalysis of available evidence (to July 2003) to reassess the rationale for using paracetamol in the treatment of OA. As with the Cochrane review, this analysis found that paracetamol does provide effective pain relief, although it is less effective than NSAIDs. Nonetheless, based on its superior safety profile, these authors recommend that paracetamol be used as first-line treatment and that NSAIDs be reserved for those patients who do not respond. Due to the cutoff point for data inclusion, this metaanalysis did not account for the recently published studies of Pincus et al 22 and Miceli-Richard et al. 23 In light of this, Neame et al 31 have provided an updated analysis of the data, concluding that despite the negative findings of the Miceli-Richard et al study, the aggregated research still supports paracetamol as being more effective than placebo in OA pain. Glucosamine may also be a useful treatment option for osteoarthritis. In short-term clinical trials, it has provided effective symptomatic relief for mild to moderate pain due to knee osteoarthritis. 17,34,35 Chondroitin may also be worth recommending in this group. 36 However, there were no trials found directly comparing paracetamol and these agents. Low back pain Despite the more favorable safety profile and preferred first-line status of paracetamol, NSAIDs are widely used for patients with low back pain. 37,38 However, to date, there is still a surprising lack of sufficient evidence of the relative utility of paracetamol versus NSAIDs (or other single agents) in chronic mild to moderate low back pain. 37 Options for managing moderate to severe chronic pain The role of paracetamol, while the first-line analgesic of choice, is limited to the management of mild to moderate pain states. In patients with more severe pain or pain that is unresponsive to nonnarcotic analgesia, alternative options should be sought. The model of the World Health Organization for treatment of cancer pain, a stepwise approach in which mild opioids (eg, oxycodone, codeine, tramadol) and then stronger opioids (eg, morphine) are used until the patient is free of pain, 39 is also recommended for persistent noncancer pain 40 and moderate to severe low back pain. 41 Initial patient evaluation is essential to ensure that adequate pain relief can be achieved via the least toxic means. Analgesics should be given on a fixed time schedule ( by the clock ), 39 and possible adverse effects and interactions should be carefully monitored. Adjuvant drugs (eg, antidepressants, anticonvulsants) may also be considered and are of particular value in the treatment of certain types of pain, such as in diabetic neuropathy. 40 Chronic pain unresponsive to nonnarcotic analgesics In the past, there has been little support for the routine use of opioids in chronic nonmalignant pain; largely because of misunderstandings about opioid-induced addiction, tolerance, and dependence. However, clinical data confirm that they can offer an effective treatment option, 6 especially when combined with paracetamol or NSAIDs. For example, the daily addition of codeine 180 mg to paracetamol 3 g has been shown to significantly reduce chronic pain due to osteoarthritis of the hip joint compared with paracetamol alone. 42 Tramadol has previously been recommended as a useful therapy for patients who do not receive adequate pain relief with paracetamol and are at risk of NSAIDrelated side effects. 43 Interestingly, studies with tramadol (a weak m-opioid agonist and mixed serotoninnorepinephrine reuptake inhibitor) in OA have had mixed results, presumably because it is not as effective as a pure m agonist. For example, one trial suggests that tramadol is no more effective than an NSAID 44 and another that tramadol is as effective as combined paracetamol/codeine but has more side effects. 45 More recently, studies have demonstrated positive results with a once-daily tramadol formulation 46,47 and a tramadol/paracetamol combination. 48,49 However, a comparative double-blind trial in 462 patients with low back pain or OA pain showed no difference in efficacy between paracetamol 325 mg plus tramadol 37.5 mg versus paracetamol 300 mg plus codeine 30 mg. 50 Given that tramadol carries a higher risk of

JOBNAME: ajt 12#1 2005 PAGE: 5 OUTPUT: Tue January 11 07:09:41 2005 84 Nikles et al drug interactions than codeine, it has been suggested that the paracetamol/tramadol combination offers limited advantage relative to standard analgesics. 50 When controlled-release oxycodone was compared with immediate-release oxycodone-acetaminophen in 167 patients with moderate to severe OA pain, pain intensity and quality of sleep were significantly improved in both active treatment groups compared with the placebo group (P # 0.05). 51 However, a short term (2 weeks) trial of controlled-release dihydrocodeine showed that it provided better pain relief than dextropropoxyphene/paracetamol with no difference in side effects. 52 There is a paucity of literature comparing paracetamol combinations with paracetamol alone in neuropathic pain. ADDITIONAL CONSIDERATIONS IN ANALGESIC CHOICE FOR CHRONIC PAIN Efficacy represents an essential aspect of appropriate analgesic use; however, optimal clinical management must account for a variety of additional factors, including safety profile, patient characteristics, cost, compliance, the patient s treatment preferences, and the clinician s professional judgment. Comparative safety profiles Paracetamol is well tolerated at recommended therapeutic doses (1 g orally, 4 times daily as required), and side effects are uncommon. Wide acceptance of the safety of a 4-g daily dose is implicit in the clinical guidelines. 12 14,53 56 Skin rashes and other allergic reactions have occasionally been reported, but generalized anaphylactic type reactions are very rare. 57,58 There have been isolated reports of blood dyscrasia, and a link with analgesic nephropathy has been suggested, although paracetamol does not affect renal function at recommended doses. 59,60 There are no consistent population-based studies that link paracetamol to hepatotoxicity 61 or gastrointestinal (GI) toxicity 62 at therapeutic doses. There have been inconsistent results from the few studies examining the association between paracetamol use and risk of serious upper GI complications. One study found a relative risk (RR) for paracetamol users of 1.4 with a 95% confidence interval (CI) of 1 2. 32 A large study using a computerized general practice database found a small increased risk of GI complications for users of paracetamol (RR, 1.3; 95% CI, 1.1 1.5) with a dose-related response. 63 No increased risk was observed with doses less than 2 g/d, whereas at doses greater than 2 g/d, the RR was 3.7 (95% CI, 2.6 5.1). This may be related to the ability of paracetamol to act as a weak inhibitor of the cyclooxygenase-1 enzyme. 64 However, these findings have subsequently been attributed to bias and confounding (patients known or suspected to be at higher risk of GI complications are more likely to receive paracetamol than NSAIDs 65 ) and incomplete information on predisposing factors for GI complications. In addition, the findings conflict with those of other studies in which drug histories were obtained directly from patients. 62 In contrast, it is well established that NSAIDs are not without risks and their use requires careful risk:benefit assessment. A great deal of data has been published regarding the adverse effects of NSAIDs when administered at prescription doses for the management of chronic conditions; such effects include serious GI, renal, and cardiovascular complications. 59,66,67 Despite the conclusions in the recent metaanalysis of Zhang et al, 33 that for safety reasons paracetamol should be the first line treatment [of OA], with NSAIDs reserved for those who do not respond, the authors of a recent study 29 have claimed that ibuprofen and paracetamol have similar tolerability profiles and use this as a means of challenging the first-line position of paracetamol in the management of OA. However, this conclusion is drawn from data from their own study (of only 14 days duration) and that of 2 other studies, 68,69 both of which evaluated the tolerability of OTC doses of ibuprofen over only a very short time (,10 days of treatment). While these studies have shown equivalent tolerability, they may not be relevant to everyday treatment as they have carefully screened out all patients at risk of any adverse events from NSAIDs. The applicability of such tolerability data to the role of NSAIDs in the management of chronic pain states such as OA is obviously questionable. There is accumulating evidence to suggest a number of concerns when lower, OTC doses are used. For example, in patients with rheumatoid arthritis, the risk of serious GI complications was significantly higher among users of aspirin, ibuprofen, and naproxen (at OTC doses) compared with nonusers, but no such association was apparent with paracetamol. 70 72 This is further supported in a recent review showing the RR of a GI bleed to be twofold for NSAID doses below the standard recommended daily levels (eg, 1200 mg for ibuprofen), fourfold at doses around the standard recommended daily levels, and sixfold at higher doses. 73 The RRs associated with NSAID use have been widely published. However, to fully understand the clinical impact of this risk, Tramer et al 74 conducted an extensive analysis of the available data to estimate the absolute risks of adverse GI events associated with

JOBNAME: ajt 12#1 2005 PAGE: 6 OUTPUT: Tue January 11 07:09:42 2005 Role of Paracetamol in Chronic Pain 85 NSAID use. They found that taking an NSAID for 2 months or more is linked to a 1 in 5 chance of developing an ulcer that can be seen endoscopically, a 1 in 70 chance of developing a symptomatic ulcer, a 1 in 150 chance of a GI bleed, and a 1 in 1200 chance of dying of a bleeding ulcer. The COX-2 specific NSAIDs (coxibs), such as celecoxib and rofecoxib, offer an alternative for the treatment of mild to moderate pain in patients with a history of gastric ulcers or bleeding. 40 Given the accessibility to nonprescription doses of ibuprofen in many countries and the increasing propensity for people to self-medicate with such OTC analgesics, it is important that these also be considered as a potential source of adverse effects, either directly or as a result of interactions with other drugs. PATIENT CHARACTERISTICS: SPECIAL CONSIDERATIONS REGARDING ANALGESIA IN THE ELDERLY The prevalence of chronic pain increases with increasing age, 2 and, as such, the elderly represent a significant proportion of patients requiring management of chronic painful conditions. Chronic pain is common among older people because of the high prevalence of OA and other degenerative disorders in this population and has numerous consequences including depression, sleep disturbance, impaired ambulation, and increased health care utilization and costs. 53 However, physiologic changes with advancing age lead to alterations in the pharmacokinetics of analgesics, leaving older people at increased risk of certain side effects, for example they are at particular risk of NSAID-related GI and renal side effects. Additionally, people aged older than 65 years are the greatest users of medicines; Australian prescribing statistics indicate that 20% of people aged 65 years and older are taking 4 or 5 different drugs, while 17% are taking 3 drugs, 75 and are at increased risk of experiencing medicine-related adverse effects. Not only are older people at greater risk of adverse effects related to polypharmacy, but their recovery from these events can be poorer; for example, hip fracture in older people is significantly more likely to end in death or placement in an aged-care facility. 76 Because of safety concerns regarding the long-term use of NSAIDs in the elderly, paracetamol is recommended by the American Geriatrics Society Panel on Chronic Pain in Older Persons as the drug of choice for treating mild to moderate musculoskeletal pain. 53 COST OF TREATMENT Cost is becoming an increasingly important factor in the effective management of pain. Recently published data from Europe indicate that the average annual disease-related total societal costs of chronic low back pain amount to V8533 per patient. 77 In Australia low back pain accounts for approximately 5% of all general practitioner visits, and in 2001, the health care costs of back pain alone amounted to AU$1.02 billion. 78 In the same year, the estimated cost of the management of OA also amounted to over AU$1 billion. 79 The hidden costs of treatment, arising from adverse effects, must also be taken into account when making treatment decisions. In the United Kingdom, Moore 80 recently proposed that the cost of preventing 1 death from NSAID-related GI side effects is over 20,000. Recently published cost-utility data on the management of OA in Australia indicate that the individual costs of therapy are AU$104 per year for NSAIDs versus AU$391 per year for coxibs. 81 Interestingly, the per-person cost of morbidity was the same (AU$70) in both treatment groups. Based on the evidence and guidelines discussed above, paracetamol should be used as first-line therapy for mild to moderate pain, providing an optimal balance of efficacy, safety, and cost. It is noteworthy, therefore, that since being listed on the Australian Pharmaceutical Benefits Scheme (PBS), the coxibs celecoxib and rofecoxib (the latter now withdrawn) have become 2 of the highest volume drugs in terms of prescriptions written, with 3.1 million prescriptions for celecoxib and 2.8 million for rofecoxib being written in 2003 at a total cost to the PBS of over AU$160 million. In the same year, 4 million paracetamol scripts were written at a total cost of AU$21 million. A preference for the use of coxibs over paracetamol is suggested by data from a recent survey of patients on coxibs who were admitted to a large Australian teaching hospital. 81 Only 16% of patients had symptoms or signs of an inflammatory arthropathy (and therefore met the PBS criteria for prescribing a coxib), while 84% had chronic OA, degenerative spinal disease, injury, or malignancy (without overt active inflammation). Additionally, this study revealed that regular paracetamol had been tested in only 20% of patients prior to using an NSAID. COMPLIANCE ISSUES Regular use of therapeutic doses of paracetamol provides relief from mild to moderate pain. In the management of chronic pain states, it is recommended that paracetamol 4g/d be continued for at least 1 week

JOBNAME: ajt 12#1 2005 PAGE: 7 OUTPUT: Tue January 11 07:09:42 2005 86 Nikles et al before being abandoned or another drug added, 2 while in the management of OA, the trial period for paracetamol may be extended. However, lack of compliance with this 4-times daily dosing regimen means that the dose of paracetamol actually consumed is often less than this, leading to perceptions that it is ineffective. Both patients and doctors may prefer the convenience of NSAIDs and coxibs, many of which have once- or twice-daily dosing schedules. Paracetamol is rapidly absorbed from immediaterelease formulations, with maximum concentrations in plasma typically occurring between 0.25 and 2.0 hours, and an onset of action within about 30 minutes. 82 Because the terminal elimination phase half-life of paracetamol in plasma is short, in the region of 1.9 2.5 hours after a therapeutic dose, 83 the recommended time between doses is 4 6 hours, resulting in a 4-times daily dosing schedule. The development of a novel formulation containing sustained-release paracetamol provides a means of maintaining steadier levels of paracetamol and reducing the dosing frequency, with the potential for improved compliance and control of pain. The efficacy of sustained-release paracetamol has been evaluated in 2 pain models; postsurgical dental pain and OA of the knee. 84,85 The 2 treatments (sustainedrelease paracetamol 1.33 g t.i.d., immediate-release paracetamol 1 g q.i.d.) were concluded to be equivalent. Extended-release formulations of paracetamol may improve compliance by enabling a 3-times daily dosing regimen. 84,85 Accordingly, treatment with sustainedrelease paracetamol formulations may be sufficient to at least delay, and possibly prevent, a future need for a more potent analgesic. Individual preferences and expectations Despite data to the contrary, there exists the perception that paracetamol is less effective than NSAIDs in the management of chronic pain states. Patient preference surveys conducted in the United States indicate that patients are more likely to prefer NSAIDs over paracetamol. 22,86,87 A 15-minute telephone survey of 300 patients, including 172 with confirmed OA, found that 24% of patients who took paracetamol rated it as very helpful, compared with 31% for ibuprofen, 30% for naproxen, and 56% for diclofenac. 87 Interestingly, this survey found that paracetamol was significantly less likely to be discontinued because of toxicity than an NSAID. In a mailed questionnaire survey of 1799 patients with OA, rheumatoid arthritis, and fibromyalgia who were participating in a long-term outcome study, 37% of patients who had taken paracetamol found it to be moderately or very effective. 86 When both effectiveness and side effects were considered together, 25% of the patients had no preference, 60% preferred NSAIDs, and 14% preferred paracetamol. The authors concluded that if safety and cost are issues, then the first-line position of paracetamol is warranted since 38.2% found paracetamol to be as effective as or more effective than NSAIDs. The reasons behind patient preferences are multifactorial and include subjective benefit, side effects, doctor or patient beliefs and interactions, severity of disease, and ease of administration of the medication. 88 Nevertheless, managing the preferences and expectations of an individual patient is an important component of the management of chronic pain. EVALUATING INDIVIDUAL PATIENT RESPONSES TO ANALGESICS Access to evidence about the effectiveness, safety, and cost of different pain management strategies is important; however, it is equally important that that evidence be applied to individual patients. Individual patient differences, for example, in comorbidities and drug metabolism, can lead to differences in the way that patients respond to medication. As mentioned, clinical guidelines suggest paracetamol for first-line therapy for chronic pain, with the addition of NSAIDs for added therapeutic efficacy where necessary. But can those patients who will get a satisfactory response from paracetamol be differentiated from those who might get additional benefit from NSAIDs? One method is to use n-of-1 trials to provide an empirical test of an individual s response to treatment. N-of-1 trials are within-patient, randomized, doubleblind, crossover comparisons designed such that a patient acts as his or her own control in a study comparing the effectiveness of a drug with placebo or another drug. 8 This process, illustrated in Figure 1, provides scientifically rigorous information relevant to a specific individual patient. Several n-of-1 trials designed to evaluate individual responses to paracetamol and NSAIDs in OA with respect to relief of symptoms and immediate side effect profile have been described in the literature. 8,26,88,89 This comparison is of particular interest because (1) the individual response to NSAIDs in OA is unpredictable; (2) the risks and side effects of NSAIDs in long-term use, particularly in the elderly, are well documented; and (3) NSAID prescribing represents a major health care burden. Wegman et al 88 investigated whether paracetamol (3000 mg/d) was as effective as NSAIDs (ibuprofen 1200 1600 mg, diclofenac 75 100 mg/d, or naproxen 750 mg/d) in a series of 13 patients with OA who had

JOBNAME: ajt 12#1 2005 PAGE: 8 OUTPUT: Tue January 11 07:09:43 2005 Role of Paracetamol in Chronic Pain 87 FIGURE 1. Example of treatment order for an individual n-of-1 trial where there are 2 possible treatments and 3 pairs of treatment periods. In this randomized, double-blind, crossover design, there are 8 possible different combinations of treatments, one of which is illustrated in the diagram, together with some examples of graphed VAS scores (Pain VAS: 0 = no pain, 5 = worst pain, Stiffness VAS: 0 = no stiffness, 5 = worst stiffness). Reproduced from Nikles et al, 8 with permission. previously been using NSAIDs. Seven patients completed 20 weeks of therapy; in 5 of these patients, little or no difference in efficacy was found between the 2 treatments. Based on their results, it was recommended that 6 patients change to paracetamol, while the others continued with NSAIDs. In another series of patients with OA, March et al 26 compared the efficacy of paracetamol (2000 mg/d) with that of diclofenac (100 mg/d) over three 4-week cycles (total 12 weeks treatment). Twenty-five patients were recruited, 20 of whom were already taking NSAIDs. Fifteen patients completed the study, 5 withdrew early (having made a treatment decision after 2 treatment cycles) and 5 dropped out of the study. Clinically useful decisions were made for 19 of the 20 patients who had completed at least 7 weeks of the study; 8 patients found that their symptoms were being adequately controlled by paracetamol. At 3 months, equal numbers of patients were taking NSAIDs (n = 9) and paracetamol (n = 9); however, almost all (7 of 8) patients who changed treatment from baseline changed to paracetamol. It was concluded that many OA patients currently receiving or being considered for NSAIDs may achieve adequate pain control with paracetamol. 26 In another series (Nikles et al 8 ), the efficacy of paracetamol (3000 mg/d) was compared with that of ibuprofen (1200 mg/d) in a 12-week trial (involving 3 pairs of 2-week treatment periods). Fourteen patients were recruited into the study, 10 of whom had taken NSAIDs in the past 6 months. Eight of 14 patients completed the trial, which showed that 1 patient was a clear NSAID responder, 5 were nonresponders (ie, paracetamol was as effective or more effective), and 2 were indefinite; clinically useful treatment decisions were made for all 8 patients (Table 2). 8 The dropout rate (43%) was comparable with those reported in other Australian n-of-1 trials 26,90 ; reasons cited for withdrawal included NSAID intolerance, side effects, lack of efficacy, and issues with the number of tablets. A later article reporting more data from the same study (published in this issue of AJT) confirmed these findings. Fifty-four of 77 patients completed the paracetamol versus ibuprofen n-of-1 trial, resulting in 3 NSAID responders, 1 paracetamol responder, 31 in whom the 2 drugs were equivalent, and 19 possible responders (ie, 1 drug possibly better than the other) with a withdrawal rate of 30%. 91 Overall, n-of-1 trials for OA have resulted in an encouraging shift toward increased use of paracetamol and reduced use of NSAIDs; this management approach is in line with treatment guidelines that suggest that patients first be given an adequate trial of paracetamol before resorting to NSAID use. The n-of-1 trial may be a useful tool that has a significant and lasting impact on clinical management of chronic pain. CONCLUSION Pain management is an increasing public health concern. Data from the Australian Bureau of Statistics

JOBNAME: ajt 12#1 2005 PAGE: 9 OUTPUT: Tue January 11 07:09:47 2005 88 Nikles et al Table 2. Clinically useful treatment decisions for 8 osteoarthritis patients completing a 12-week n-of-1 trial. 8 Patient no. Medication immediately prior to trial Response status to ibuprofen Treatment decision after trial 1 Paracetamol Clear responder Ketoprofen 2 Paracetamol Indefinite Ibuprofen 4 Diclofenac Nonresponder Diclofenac 5 Ketoprofen Nonresponder Paracetamol 7 Paracetamol Indefinite Paracetamol and ibuprofen, as required 9 Ibuprofen Nonresponder Paracetamol 10 Piroxicam Nonresponder Paracetamol 11 Tiaprofenic acid and paracetamol Nonresponder Tiaprofenic acid and paracetamol Nikles CJ et al. Preliminary experiences with a single-patient trials service in general practice. MJA 2000;173:100 103. ª Copyright 2000. The Medical Journal of Australia, reproduced with permission. indicates that analgesics are the most commonly used medication in Australia, being used by almost one fourth of the population. 92 Importantly, most people (65%) using analgesics did not do so on the advice of a physician or other health professional, despite the fact that approximately 20% of people using analgesics used the medication regularly. Of the latter, 83% used analgesics every day and/or night and 92% had regularly used the medication for 6 months or more. Several international guidelines (EULAR, ACR) and influential reviews recommend the use of paracetamol as the first-line analgesic of choice for the management of chronic pain, as it provides cost-effective analgesia without the risks associated with NSAID use, particularly in the elderly. Based on currently available data, the use of alternative analgesics, such as tramadol and opioids, either alone or in combination with paracetamol, is warranted in those patients whose pain does not respond to nonnarcotic analgesics. While these recommendations are based on a vast amount of clinical data, they do not account for individual patient responses. N-of-1 trials can be used to determine analgesic suitability based on individual responses. In 1994, March et al 26 suggested that ideally NSAIDs should not be used without an individual trial to show that they are more effective than paracetamol. The results of more recent n-of-1 trials investigating individual responses to paracetamol and NSAIDs in patients with chronic pain continue to support this finding. Future n- of-1 trial studies to further delineate the relative benefits of other analgesic options in individuals are warranted. Incorporating this approach into the management of chronic pain may provide a rational basis on which to prescribe analgesia that is cost-effective and optimized to meet individual needs. REFERENCES 1. IASP Task Force of Taxonomy. In: Merskey H, Bogduk N, eds. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd ed. Seattle: IASP Press, 1994. pp. 209 214. 2. Mashford ML. Therapeutic Guidelines: Analgesic. North Melbourne: Therapeutic Guidelines, 2002. 3. Goucke CR. The management of persistent pain. Med J Aust. 2003;178:444 447. 4. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain. 2001;89:127 134. 5. Blyth FM, March LM, Cousins MJ. Chronic pain-related disability and use of analgesia and health services in a Sydney community. Med J Aust. 2003;179:84 87. 6. Lipman AG. Treatment of chronic pain in osteoarthritis: do opioids have a clinical role? Curr Rheumatol Rep. 2001; 3:513 519. 7. Kerr S, Fairbrother G, Crawford M, et al. Patient characteristics and quality of life among a sample of Australian chronic pain clinic attendees. Intern Med J. 2004;34:403 409. 8. Nikles CJ, Glasziou PP, Del Mar CB, et al. Preliminary experiences with a single-patient trials service in general practice. Med J Aust. 2000;173:100 103. 9. Day RO, Graham GG, Whelton A. The position of paracetamol in the world of analgesics. Am J Ther. 2000;7: 51 54. 10. Bannwarth B, Pehourcq F. [Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues]. Drugs. 2003;63:5 13. 11. Moore A, Collins S, Carroll D, et al. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain. 1997;70:193 201. 12. Moore A, Collins S, Carroll D, et al. Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain. The Cochrane Library, 1st ed. Oxford: Update Software, 2003.

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