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Life without COX 2 inhibitors has problems.
- Alexander SD Spiers (3 June 2006)
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Of Pain Clinics and Education
- William G Notcutt (6 June 2006)
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Life without COX 2 inhibitors
- Colette M Reid, Jeremy Horwood, Research Associate, MRC Health Services Research Collaboration (7 June 2006)
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Life without COX-2 inhibitors
- John R May (7 June 2006)
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Life after coxibs – is chaos still ruling?
- Jan M Bjordal, Jan H. Demmink, Rodrigo A.B. Lopes-Martins (14 June 2006)
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The death of COX 2 inhibitors is greatly exaggerated
- Frank McKenna (16 June 2006)
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Alexander SD Spiers, Professor of Medicine (Retired) n/a
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The theme of this Editorial is that COX 2 inhibitors are not a superior option for the management of musculoskeletal pain, and that paracetamol can be equally effective and much safer. From personal experience I suggest that for some of us, COX 2 inhibitors provide significantly better pain relief than can be secured by conventional NSAIDs or by paracetamol. As a result of sports activity I suffer from bilateral shoulder pain of variable severity. It was partially alleviated by ibuprofen in a dose of 800 mg four times a day. I never suffered gastrointestinal side effects from ibuprofen, but when it was demonstrated that the drug could nullify the cardioprotective effects of low-dose aspirin, I switched to rofecoxib, then thought to be a safe drug. I took two tiny tablets of 12.5 mg each, once a day. This more convenient medication produced complete pain relief. Furthermore, the onset of action was in approximately 30 minutes. Thus on three counts - convenience, pain relief and immediacy of action - rofecoxib was definitely superior to ibuprofen. Then came alarming reports (1) that rofecoxib in particular, and perhaps COX 2 inhibitors in general, were associated with an increased risk of myocardial infarction, so I switched to paracetamol. I am now constrained to take two 500 mg tablets four times a day and the control of pain is incomplete. I conclude that rofecoxib is a highly effective drug. Oh for a COX 2 inhibitor that does not promote myocardial infarction! 1 Kearney PM, Baigent C, Godwin J, Emberson JR, Patrono C. Do coxibs and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-5. Competing interests: None declared |
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William G Notcutt, Consultant Anaesthetist James Paget Hospital, Great Yarmouth, NR31 6LA, UK
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The doubts about the safety of NSAIDs are having a significant impact on the ability of doctors to treat acute and chronic pain. It is a pity therefore that Messrs Shaughnessy and Gordon did not mention that there is a specialty of medicine dedicated specifically to managing pain. A large proportion the work of my pain management colleagues and I is spent working with older patients, helping them manage their problems which are primarily degenerative musculo-skeletal. Our focus is partly on the use of therapeutic agents (such as analgesics, acupuncture etc), but more on the understanding of the pain problems, the reality of the underlying situation (we are all getting old) and then addressing the lifestyle changes that need to be made, dealing with the associated depression and so on. Perhaps one of the difficulties is the failure to see chronic pain as a “chronic disease” like COPD, asthma, diabetes, stroke etc. Patients and doctors often think that the pain can be cured with a well-placed injection or a simple treatment. However, commonly the causes not only don’t go away but also may progress. Therefore patients need help with pain management rather than fruitless attempts to find a cure. Pain can also be lethal disease. As examples, depression and despair can lead to suicide and NSAIDs can lead to gastro-intestinal catastrophe. Life without COX2 inhibitors will not change my personal practice. Over the years I have spent much more of my time taking patients off these drugs rather than initiating them. I now worry though that the reduced usage of NSAIDs by GPs is going lead to an increased referral rate to our Pain Clinics as they struggle to help their patients. The authors are wrong to consider that opioids are "the last pharmacological resort". There many other treatments that would qualify for this title. Used appropriately, opioids are probably much safer than NSAIDs even over the long term. However, doctors need to have the appropriate skill and training in their use. This highlights the serious deficiency in teaching about pain management in the curricula of medical schools and postgraduate education programs (1). Personally I feel that no doctor should qualify without being able to demonstrate the ability to use the drug morphine for acute and chronic pain. Yet day after day I and my colleagues see the most basic mistakes being made. Thomas Sydenham, a 17th century physician wrote “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” William Serturner first purified morphine in May 1805. Both must be turning in their graves knowing that even now in the 21st century we still can’t get it right. Reference: 1. Notcutt WG. Purchasers should require providers to set standards for pain relief BMJ, Feb 1997; 314: 442 Competing interests: None declared |
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Colette M Reid, Specialist Registrar in Palliative Medicine Department of Palliative Medicine, BHOC, Horfield Road, Bristol BS2 8ED, Jeremy Horwood, Research Associate, MRC Health Services Research Collaboration
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Shaughnessy and Gordon write in their editorial on the loss of COX 2 inhibitors that “there is good evidence that other pharmacological and non -drug options may be reasonably effective, equally safe and less costly”¹. They go on to give examples of both drug and non-drug measures which have been shown to be effective in osteo-arthritis. However, their discussion of opioids was not referenced. We find the omission of studies supporting the use of opioids surprising, particularly when references for the non- drug measures discussed were included, even when the effect sizes were reported as small, or the data limited by small numbers. Two systematic reviews of opioids in chronic non-cancer pain²,³ report several papers showing efficacy of opioids (morphine and oxycodone) in osteoarthritis, demonstrating an average 30% reduction in pain intensity, a level generally considered to be clinically meaningful4. Whilst the authors of the Kalso systematic review note the worries of addiction and drug diversion (presumably the reason they are referred to as “a last pharmacological resort” by Shaughnessy and Gordon) and caution that not all patients respond to opioids, in a more recent BMJ editorial Professor Kalso observes that the British Pain Society has published recommendations for the appropriate use of opioids in persistent non- cancer pain5. The guidelines offer a framework for the safe prescribing of opioids in conditions such as osteoarthritis6. A recent paper highlighted that a quarter of GP’s sampled did not prescribe opioids for patients with persistent chronic pain, and that prescription patterns were influenced by the doctor’s beliefs about the appropriateness of opioids in chronic pain, in spite of these guidelines7. We are currently conducting a trial focusing on the patient’s acceptability of opioids for osteoarthritis pain, which will add to this debate and highlight the patient’s experience of opioid treatment. In addition, one of us (CR) has recently completed a qualitative study examining the views of patients with cancer pain when offered morphine. Interestingly, the phrase most commonly used by these respondents was “last resort” and this association meant that these patients delayed the use of drugs like morphine for as long as possible, suffering from uncontrolled pain as a consequence. Given the prejudice of this BMJ editorial, perhaps we should not have been surprised that some of these patients seemed to be reflecting the views of their physicians. 1. Shaughnessy, A.F. Gordon, A. E. Life without COX 2 inhibitors BMJ 2006;332: 1287-8 2. Kalso, E. Edwards, J.E. Moore, R.A. and McQuay, H.J. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004; 112: 372-380 3. Bloodworth D. Issues in opioid management. American Journal of Physical Medicine and Rehabilitation 2005;84:S42-S55. 4. Farrar, J.T. Portenoy, R.K. Berlin, J.A. Kinman, J.L. Strom, B.L.Defining the clinically important difference in pain outcome measures. Pain 2000;88: 287-94 5. Kalso, E. Opioids for persistant non-cancer pain BMJ 2005;330: 156 -7 6. The Pain Society. Recommendations for the appropriate use of opioids in persistent non-cancer pain. A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaethetists, the Royal College of General Practitioners and the Royal College of Psychiatrists. March 2004. www.britishpainsociety.org/pdf/opioids_doc_2004.pdf 7. Hutchinson, K. Moreland, A. Williams, A, Wienman, J. and Horne R. (2006) Exploring beliefs and practice of opioid prescribing for persistent non-cancer pain by general practitioners. European Journal of Pain. In Press, Corrected Proof, Available online 17 February 2006 Competing interests: None declared |
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John R May, consultant anaesthetist Raigmore Hospital Inverness IV2 3UJ
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The authors do not mention those patients who suffer severe anaphylactoid reactions to aspirin and conventional NSAIDs (non steroidal anti inflammatory drugs) acting on cyclo-oxygenase-1 pathways. Such patients with arthritis could possibly be disadvantaged by a total withdrawl of these newer anti-inflammatories. Competing interests: None declared |
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Jan M Bjordal, Postdoctoral Research Fellow University of Bergen, Jan H. Demmink, Rodrigo A.B. Lopes-Martins
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EDITOR—In their editorial “Life after coxibs” Shaughnessy and Gordon deliver a narrative clinical review of alternatives to coxibs in arthritis and chronic pain management (1). We agree with the authors that little is lost if coxibs disappear. However, narrative reviews have the inherent methodological weakness that selection of therapies and recommendations may be circumstantial, and this editorial about alternatives to coxibs is no exception to the rule. The editorial lacks substantial information about priority in based on effect sizes, time-effect profiles and power of evidence behind each of the 13 recommended therapies. And it does not seem to make a difference which therapy is chosen. In our opinion, it actually makes a difference which one of these therapies is chosen, and some of the authors´ recommendations do not seem justified by evidence. In the editorial on-drug options, such as exercise and weight loss are rightfully claimed to be efficacious, but we think that they should be mentioned as firstline alternatives in knee osteoarthritis as adviced by Felson & Hunter in a recent clinical BMJ-review (2). The authors recommend combining non-selective cox inhibitors with misoprostol and other recommendations include topical NSAIDs, acetaminophen (paracetamol), opioids and glucosamine sulphate (GS). The above pharmacotherapies in addition to steroid injections and chondrotin are the seven most common pharmacotherapies in Europe (3), and they have recently been systematically reviewed and subjected to meta-analysis (4). Baseline pain levels, effect sizes, time-effect profiles and power of evidence have been thoroughly analysed, and some of these results contradict Shaughnessy & Gordon´s recommendations. Both GS and chondroitin were found in this meta-analysis to exhibit rather small effect sizes of questionable clinical relevance. The Cochrane review cited by the editorial did not find unequivocal positive evidence from GS in general, as 8 out of 15 trials were negative. The positive results came from 7 trials funded by a specific GS manufacturer. The large independently-funded GAITT trial published in February 2006 (5) did not find significant pain-relieving effects from neither GS nor chondrotin. Paracetamol recommendations are common in guidelines in spite of a very poor effect size (4). The authors also claim that S-adenosylmethionine (SAMe) reduces pain in osteoarthritis, but their own review reference and another meta- analysis (6) actually found no pain-relieving effect from SAMe over placebo. Some complementary therapies like therapeutic taping and braces are also claimed to be effective, and acupuncture is suggested to give a small pain-relieving effect, while the authors point out limited evidence in favour of therapeutic touch (TT), and electrical stimulation. There are several question-marks associated with the assessment of non-drug therapies in the editorial. We have found 36 placebo-controlled trials in knee osteoarthritis with eight physical therapies. So why are the authors recommending non-drug interventions with only one or two published trials? For instance, the evidence behind TT is a single Medline -indexed randomized controlled trial with TT with 25 knee osteoarthritis patients (7), and thus has not been subjected to assessment of methodological quality. Therapeutic taping was also recommended in the editorial. But it has only been tested in a single positive monotherapy trial (8), and the effect was lost when combined with other interventions in a later trial by the same group (9). Electrical stimulation is also given a limited recommendation by the authors while citing a Cochrane review with 3 trials (10). This cited reference is in fact a review of electromagnetic fields therapy in osteoarthritis, and not electrical stimulation. The authors also fail to mention non-drug interventions like TENS and low level laser therapy which have been systematically reviewed by Cochrane (11) (12) and others (13) finding clinically relevant pain- relieving effects from samples of 8 and 6 trials respectively. It is becoming increasingly difficult for a general practitioner to navigate towards “best practice” in the plethora of effectiveness claims. The unfortunate truth is that several drug interventions are largely ineffective. This is highlighted by findings where 1 in 4 osteoarthritis patients uses self-medication, 1 in 2 osteoarthritis patients uses two drugs or more for their osteoarthritis pain (OA Nation survey UK, Arthritis Care 2003). In addition, more than half of chronic pain patients (where arthritis is the largest diagnostic group) do not feel that their pain is adequately controlled by drugs (14). Patients expect GPs and other clinicians to give meaningful advice about medical as well as physical and complementary treatment. A comprehensive systematic review comparing physical and complementary therapies in OAK management is clearly needed. We agree that arthritis management needs to be individually tailored, and in some cases therapies which seem ineffective on a group level, could be of value to the individual patient. But it would have been more helpful if this editorial had offered evidence-based guidance for osteoarthritis management based on group level efficacy. As it stands the editorial adds to the chaos of life after coxibs by their (almost) “anything goes” advice. References 1. Shaughnessy AF, Gordon AE. Life without COX 2 inhibitors. Bmj 2006;332(7553):1287-8. 2. Hunter DJ, Felson DT. Osteoarthritis. Bmj 2006;332(7542):639-42. 3. Mazieres B, Schmidely N, Hauselmann HJ, Martin-Mola E, Serni U, Verbruggen AA, et al. Level of acceptability of EULAR recommendations for the management of knee osteoarthritis by practitioners in different European countries. Ann Rheum Dis 2005:ard.2003.009431. 4. Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials. Eur J Pain 2006. 5. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354(8):795-808. 6. Witte S, Lasek R, Victor N. [Meta-analysis of the efficacy of adenosylmethionine and oxaceprol in the treatment of osteoarthritis]. Orthopade 2002;31(11):1058-65. 7. Gordon A, Merenstein JH, D'Amico F, Hudgens D. The effects of therapeutic touch on patients with osteoarthritis of the knee. J Fam Pract 1998;47(4):271-7. 8. Hinman RS, Crossley KM, McConnell J, Bennell KL. Efficacy of knee tape in the management of osteoarthritis of the knee: blinded randomised controlled trial. Bmj 2003;327(7407):135. 9. Bennell KL, Hinman RS, Metcalf BR, Buchbinder R, McConnell J, McColl G, et al. Efficacy of physiotherapy management of knee joint osteoarthritis: a randomised, double blind, placebo controlled trial. Ann Rheum Dis 2005;64(6):906-12. 10. Hulme J, Robinson V, DeBie R, Wells G, Judd M, Tugwell P. Electromagnetic fields for the treatment of osteoarthritis. Cochrane Database Syst Rev 2002(1):CD003523. 11. Osiri M, Welch VV, Brosseau L, Shea B, McGowan J, Tugwell P, et al. Transcutaneous electrical nerve stimulation for knee osteoarthritis (Cochrane Review). Cochrane Database Syst Rev 2000;4. 12. Brosseau L, Robinson V, Wells G, Debie R, Gam A, Harman K, et al. Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005(4):CD002049. 13. Bjordal JM, Lopes-Martins RAB, Klovning A. Is Quality Control of Cochrane Reviews in Controversial Areas Sufficient? Journal of Alternative and Complementary Medicine 2006;12(2):181-183. 14. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10(4):287-333. Competing interests: None declared |
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Frank McKenna, Consultant Physician and Rheumatologist Trafford General Hospital Manchester
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Shaugnessy and Gardener1 are to be commended for emphasising the non- pharmacological treatment of arthritis – the daily mantra of rheumatologists. Unfortunately, they misrepresent the data from the meta –analysis of Kearney and colleagues2 that generated their leading article. Their introductory statement that COX 2 inhibitors “have been associated with an increased risk of myocardial infarction with prolonged use compared with placebo or other NSAIDs” is both misleading and inaccurate, as it is not supported by published data. The conclusions from Kearney’s meta-analysis was actually that, with the exception of naproxen, there was no difference between COX 2 inhibitors and NSAIDs in relation to vascular events. The only surprise in this study was the apparent reduction in risk from naproxen as this has not been observed in large population and case controlled studies. The results from a retrospective observational study in the Ontario population did not find any reduction in risk of a myocardial infarction from naproxen compared with COX 2 inhibitors3. A prospective large population based study conducted by the FDA in California4 found a significant association between naproxen and myocardial infarction, in addition to a number of other NSAIDs and rofecoxib, but not with celecoxib, an observation that led to a black box warning on all NSAIDs and COX 2 inhibitors in the USA. This finding was similar to that from a nested case control study from a GP data-base in the UK5. The important conclusion from all this data is that, with the exception of high dose rofecoxib, there is no greater risk of myocardial infarction from COX 2 inhibitors than non-selective NSAIDs. Whether this observation is from the drugs or the arthritis however is not clear as there is an established association between arthritis and cardio-vascular disease. Shaugnessy and Gardner also dismiss the argument for prescribing COX 2 inhibitors: “ The common assumption that COX 2 inhibitors are safer than other NSAIDs has not been borne out.” This statement is referenced with a critical review of the CLASS study yet they fail to reference a range of other studies that demonstrate increased safety from COX 2 inhibitors. It could be argued that the data from a case control study in a UK based GP register6 supports their argument as the authors concluded that there was no strong evidence for any enhanced benefit from COX 2 inhibitors. However, although the study included symptomatic ulceration in addition to serious complications, they observed that naproxen had the highest risk and did not find an association between the use of celecoxib and GI complications. The VIGOR7 and TARGET8 studies of rofecoxib and lumiracoxib respectively both found an increased rate of GI complications from non- selective NSAIDs. This potential benefit of COX 2 inhibitors was an observation also supported by the Ontario population study9. The major concern is the significant toxicity from non-selective NSAIDs. They are arguably the most toxic drugs prescribed in primary care and their toxicity is a major public health problem. Of course we need more and better outcome data to determine which group of patients should be considered for COX 2 inhibitors. Reducing the use of all these drugs is an important message, but switching patients from a COX 2 inhibitor to a non-selective NSAID confers no benefit to the patient and may increase the risk of a serious and potentially life threatening GI complication. 1.Shaugnessy AF Gordon AE Life without COX 2 inhibitors BMJ 2006;332:1287-8 (3 June) 2. Kearney PM Baigent C Godwin J Halls H Emberson JR Patrono C. Do selective cyclo-oxygenase inhibitors and traditional NSAIDs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-5(3 June) 3. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, Austin PC, Laupacis A.Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med. 2003;163:481-6 4. Graham DJ,Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non- steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365:475-81 5. Hippisley-Cox J, Coupland C Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti- inflammatory drugs: population based nested case-control analysis. BMJ. 2005;330:1366-8 6. Hippisley-Cox J, Coupland C, Logan R Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case- control analysis BMJ 2005;331:1310-1316 7. Bombardier Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8 8. Hawkey Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ; TARGET Study Group Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364(9435):665-74 9. Muhammad Mamdani, Paula A Rochon, David N Juurlink, Alex Kopp, Geoffrey M Anderson, Gary Naglie, Peter C Austin, and Andreas Laupacis Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non- steroidal anti-inflammatory drugs. BMJ 2002; 325:624-8 Competing interests: Clinical investigator COX 2 inhibitors and occasional paid lectures. |
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