Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1225 (Published 31 March 2015) Cite this as: BMJ 2015;350:h1225
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Dear Editor,
On 2015 Mar 31, Machado et al. published a systematic review and meta-analysis of the effectiveness of paracetamol (aka acetaminophen) for spinal pain and osteoarthritis [1]. Three randomized controlled trials (RCT) were included in the meta-analysis [2-4]. There are significant limitations to this analysis that undermine the manuscript and invalidate the conclusions.
Of note, the Machado et al. meta-analysis included a retracted study [2,5]. Dr. Kietaibl (formerly Kozek-Langenecker) did not consent to manuscript publication and demanded retraction after discovering deceptive practices by some co-authors that resulted in fraudulent data [5,6]. Although Machado et al. may not have been aware of the retraction at the time of manuscript preparation, in my opinion, they should have become aware later but they seem not to have notified The BMJ as evidenced by subsequent inclusion of the same retracted article in another meta-analysis despite recognizing its retracted status in the text [7]. Including a retracted study in a meta-analysis means transferring major errors from a single study into the highest level of evidence, thereby compromising and invalidating the meta-analysis results. Doing so knowingly raises larger ethical concerns.
The results of this analysis are not valid, and readers should be cautioned against applying them in clinical practice.
References
1. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and meta-analysis of randomised placebo controlled trials. Brit Med J. 2015;350.
2. Wetzel L, Zadrazil M, Paternostro-Sluga T, Authried G, Kozek-Langenecker S, Scharbert G. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study. Eur J Anaesthesiol. 2014;31(1):35-40.
3. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: A double-blind, randomised controlled trial. Lancet. 2014;384(9954):1586-1596.
4. Prior MJ, Harrison DD, Frustaci ME. A randomized, double-blind, placebo-controlled 12 week trial of acetaminophen extended release for the treatment of signs and symptoms of osteoarthritis. Curr Med Res Opin. 2014;30(11):2377-2387. https://www.ncbi.nlm.nih.gov/pubmed/25121804. doi: 10.1185/03007995.2014.949646.
5. [No Authors Listed]. Intravenous non opioid analgesic drugs in chronic low back
pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study: Retraction. Eur J Anaesthesiol. 2015;31(1):287.
6. Kietaibl S. Personal Communication: Reasons for manuscript retraction. 2018 Nov 19-21.
7. Saragiotto BT, Machado GC, Ferreira ML, Pinheiro MB, Abdel Shaheed C, Maher CG. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016(6):CD012230.
Competing interests: No competing interests
Misguided and irresponsible research in my opinion. It is siloing diseases. As if someone with osteoarthritis has just the one condition? There are usually a few chronic conditions floating around in the ONE body. So in my view Panadol Osteo is an overarching first line pain relief and it works. Your study is flawed in my view for this reason. Now it has been taken off the PBS the cost has doubled (there is no price stabilization in sight ..in fact quite the opposite....now the strike off the PBS genie is out of the bottle and costs will continue to escalate because there are no controls in place) for those who can least afford it. They are left with no other option than to go to their second line of pain relief OxyContin and Endone. Crazy world of eroding Medicare and the PBS and cost shifting to the sick and vulnerable by this government. The study did not take into account that there may be multiple conditions and just the one body and that overall Panadol may be working at a multi disease level.
Competing interests: No competing interests
Paracetamol, a grade I analgesic is recommended as the first line therapy in osteoarthritis (1-3). Despite reports of its limited efficacy in this disease (4,5), rheumatologists continue to urge general practitioners on the importance of prescribing paracetamol in first intention, this, in compliance with present guidelines (6). Discussions on the efficacy and safety of paracetamol have resurfaced in the year 2015 (7,8).
A systematic review with meta-analysis by Machado et al. showed that in the short term, paracetamol is not effective in reducing pain intensity, disability and the improvement of the quality of life of patients with low back pain. For knee and hip osteoarthritis, though paracetamol provides a significant reduction of pain intensity and disability in the short term, this efficacy is not clinically apparent (7). Machado et al. also raised some issues as concerns the safety of paracetamol. Indeed, patients taking paracetamol (3 000 mg to 3 900 mg) are more likely to have abnormal results of liver function tests in the short term. However, the relevance of these liver abnormalities remains unclear (7) thereby warranting a long-term evaluation of the consequences of this disturbance of liver function tests so as to provide answers to this question. The long term safety of paracetamol has been questioned in several reports (1,4,8), particularly in a recent systematic review conducted by Roberts et al (8). Despite methodological limitations, this review enhances the blaze by showing that paracetamol is associated with cardiovascular, gastrointestinal, and renal adverse events. Moreover, paracetamol might increase mortality (8). Association with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen has also been shown to increase the risk of mild gastrointestinal bleeding (9).
Therefore, the apparent unfavorable benefit to risk ratio of paracetamol raises a key issue: should we change our paradigm for the management of osteoarthritis and recommend as first line therapy grade II analgesics and/or NSAIDs? (10,11).
So far we have been blinded by a double game on paracetamol: its double name (acetaminophen and paracetamol) and its double AA+ (good efficacy and good tolerance). Today it seems to make room to a double CC– status (poor efficacy and poor safety). Notwithstanding, the benefit to risk ratio of any drug should also be evaluated owing to its duration in the armamentarium of prescription. Indeed, acetaminophen when prescribed at high dose on the long term, might be risky for the cardiovascular system but also for the gastrointestinal tract (9). However, we lack data on the safety profile of paracetamol when given on a short period of time. We should therefore think on this question and know what is most effective and safe in a disease such as osteoarthritis which has a limited available therapeutic arsenal. Consequently, excluding paracetamol as first line analgesic in such a situation may open the door for grade II analgesics and/or NSAIDs which have severe associated side effects, especially in osteoarthritis patients who often have multiple comorbidities (9-11).
The answer might be that in a disease like osteoarthritis it is time to consider not only the effect size of one drug but the additional effect of several non-pharmacological and pharmacological therapies among which paracetamol. Meanwhile, the approach would be to use the lowest dose of paracetamol for the shortest duration.
References
1. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669-81.
2. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465-74.
3. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363-88.
4. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;63:901-7.
5. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257.
6. Chevalier X, Marre JP, de Butler J, Hercek A. Questionnaire survey of management and prescription of general practitioners in knee osteoarthritis: a comparison with 2000 EULAR recommendations. Clin Exp Rheumatol 2004;22:205-12.
7. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015;350:h1225.
8. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis 2015 Mar 2. pii: annrheumdis-2014-206914. doi: 10.1136/annrheumdis-2014-206914.
9. Doherty M, Hawkey C, Goulder M, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011;70:1534-41.
10. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev 2006;3:CD005522.
11. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis - an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med 2015;13:55. doi: 10.1186/s12916-015-0285-8.
Competing interests: No competing interests
To criticize the efficacy and safety of paracetamol by publishing: "Objective - To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee" is not reliable when to say in the end of the abstract: "Conclusions - Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines".
Simple "low back pain" can be caused by muscular discomfort, myogelosis, and misalignments, malposition of the spinal column, scoliosis, overstraining, improper behaviour, or inadequate exercises. A "spinal pain" will be caused by an irritation of the spinal nervous system, the spinal marrow, or neuralgia of the vertebral nerves. Orthopedic experts warn to neglect "red-flag-signs" when complicated spinal pain occurs.
The German guidelines recommend paracetamol only up to 3 grams in the treatment of "low to moderate acute non-specific low back pain". Paracetamol is possible to treat sub-acute and chronic non-specific low back pain. http://www.leitlinien.de/mdb/downloads/nvl/kreuzschmerz/kreuzschmerz-1au...
The hypothesis that paracetamol 500 mg up to 3 grams a day could be n o t efficient and safe in the treatment of acute non-specific low back pain was not subject of the investigation of G. C. Machado, PhD student, et al. They are concerned about the treatment, efficacy, and safety of paracetamol for (specific or unspecific) spinal pain and osteoarthritis.
They should reconsider that most of acute non-specific low back pain will abate after 5 to 7 days by regaining normal muscular activity with or without physiotherapy. Paracetamol will be helpful but is not urgently needed. Spinal pain and osteoarthritis are different themes.
Dr. med. Thomas G. Schaetzler (MD)
Family Medicine Unit
Public GP-medical office/Fachpraxis Allgemeinmedizin
Kleppingstr. 24 D 44135 Dortmund Germany
th.g.schaetzler@gmx.de
Competing interests: No competing interests
In a recently published systematic review and meta-analysis in BMJ-Open on the efficacy of Paracetamol (PCM) in patients with low back pain, the authors conclude that their study supports “reconsidering recommending the use of paracetamol for patients suffering with low back pain in clinical practice guidelines” (1).
These rather dramatic conclusions are based upon a grand total of 2 RCT’s (2,3), of which the study by Wetzel et al., recently was retracted from the European Journal of Anaesthesiology by the authors (2). It would therefore appear to be inappropriate to use the designation “systematic review”.To undertake a meta-analysis based upon one study is also highly unusual. Notwithstanding the quality and the conclusions of the RCT in question it is most certainly premature to arrive at any conclusions as regards undertaking changes in international clinical guidelines. The authors should exclude the section on PCM and Low Back Pain in their paper until a sound conclusion can be made based on data from an appropriate number of high quality RCT`s on this subject. We feel that in the present study the title, methods, conclusions and recommendations are misleading.
Additionally, in the future International Scientific Research Fora should set minimal requirements as regards data quantity and quality required prior to meaningful systematic reviews and metaanalyses being carried out in different health care areas.
1. Machado GC, Maher CG, Ferraira PH, Pinheiro MB, Lin CC, Day RO, McLachlan AJ, Ferraira ML. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and metaanalysis of randomized placebo controlled trials. BMJ 2015; 350: h1225.
2. Wetzel L, Zadrazil M, Paternostro-Sluga T, Authried G, Kozek-Langenecker S, Scharbert G. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study: Retraction. Eur J Anaesthesiol 2015;32:287.
3. Williams CM, Maher CG, Latimer J, McLachlan AJ, Hancock MJ, Day RO, Lin CCL. Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial. The Lancet 2014; 384. 1586-1596.
Competing interests: No competing interests
What does this mean for clinical practice? I notice here and in clinical practice many reporting that these results won’t change their clinical practice. Why? Because the side effect profile of paracetamol with the “clinical experience” and “self experience” forms a belief that it is safe and significantly helps. Discussions with colleagues result in the question of if not paracetamol what else should I do? People in pain expect medication.
This is the shortfall of general public (and clinical) perception. Do people in pain actually need medication? OA is perhaps a little easier to discuss.
There is good evidence in OA to suggest 4 primary treatments (non pharmalogical) to substantially improve disability (and pain) in hip and knee OA. These are education, exercise, weightloss (where BMI is increased) and hydrotherapy. This is irrespective of disease severity, pain levels or functional status (Hochberg, 2012). However in reality, very few patients suffering OA are utilizing these treatment options. In a recent survey of 591 OA sufferers Hinmen et al (2015) demonstrated that on average, patients are utilizing only one out of four of these recommended strategies and 12% had never used any! Given that both catasrophising beliefs and fear of movement are common in OA and counter productive to participation in exercise, activity and weight-loss (Somers et al., 2009) I suspect trust in active therapy is not high in the OA population.
So are clinicians doing their best to modify this belief? We hope ……but no. A survey of UK physiotherapists highlights misperceptions about exercise in OA with many believing that exercise did not have benefit for people with more advanced disease (Holden et al 2008).
This brings me back to the point regarding colleagues continuing to recommend paracetamol: as with all placebo therapy if the relative risk is very low and the cost to the system and the consumer is minimal placebo does offer effect over doing nothing. But when there is stronger clinical evidence to support alternative treatment options we should target that first and supplement with other placebo options – not the other way round.
Thank you,
Chris Weiers
Hinman RS, Nicolson PJ, Dobson FL, & Bennell KL (2015). Use of nondrug, nonoperative interventions by community-dwelling people with hip and knee osteoarthritis. Arthritis care & research, 67 (2), 305-9
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch V, Wells G, Tugwell P, & American College of Rheumatology (2012). American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis care & research, 64 (4), 465-74
Holden MA, Nicholls EE, Hay EM, & Foster NE (2008). Physical therapists’ use of therapeutic exercise for patients with clinical knee osteoarthritis in the United kingdom: in line with current recommendations? Physical therapy, 88 (10), 1109-21
Machado, Gustavo C, Maher, Chris G, Ferreira, Paulo H, Pinheiro, Marina B, Lin, Chung-Wei Christine, Day, Richard O, . . . Ferreira, Manuela L. (2015). Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials (Vol. 350).
Competing interests: No competing interests
We can understand Dr Adam and Dr Veal’s desire to see a different result; where the status of paracetamol as an effective pain medicine could at least be preserved for the elderly or those with chronic conditions. Unfortunately their case is not consistent with the data. Older people were not excluded from these studies and the lack of effect for osteoarthritis, a chronic condition, does not lend much hope to the belief that paracetamol would be effective for chronic back pain. We also do not hold out much hope for the view that we should continue with paracetamol, because while it may not work in general it may work for some. The difficulty with this subgroup argument is that the effect of paracetamol was close to zero in the back pain trials. In order to have a subgroup where paracetamol provides appreciable pain reduction we require a subgroup where paracetamol appreciably increases pain. We think this is unlikely.
We agree with Dr Montgomery that our review had an inconvenient result. We think we all would have preferred a result that supported the endorsement of paracetamol in guidelines as a simple low cost option for back pain and osteoarthritis. But our review shows that paracetamol does not have a clinically appreciable effect on pain in these conditions and we now have to think through the other options. As Mallen and Haye noted in the accompanying editorial to our review there are non-drug options provided by physiotherapists for these two conditions but in many health care systems it may be hard to access these services. Given the burden of osteoarthritis and back pain it would make sense to try to change that situation.
Competing interests: No competing interests
Dear Sir/Madam,
Sadly, this paper demonstrates demonstrates how our profession continue to over-interpret findings from clinical studies - by definition, an artificial clinical setting. This paper unfortunately goes one step further in the case of lower back pain in that it only included data from three studies and without any comment on the quality of the selected papers. In addition, there is no information given as to the length of treatment with paracetamol included in their review apart from the comment "our results are limited to the short term efficacy of paracetamol". Lower back pain is one of the most common reasons for seeing a doctor and paracetamol has been prescribed for many decades. I would suggest that all doctors have seen patients which have benefited from paracetamol during both acute phase and chronic back pain. It is therefore both surprising and potentially misleading to suggest that paracetamol "is ineffective in reducing pain or disability in patients with low back pain" based on three studies. A much more clinically relevant review would include observational or real life data of patients with low back pain being prescribed paracetamol by their GP. In the UK, we now have access to large primary care databases which are searchable and thus could potentially provide a much more "real" picture of the benefit of paracetamol in this common clinical setting.
Competing interests: No competing interests
Machado et al [1] state that “paracetamol is ineffective in the treatment of low back pain” and base this conclusion on the analysis of three placebo controlled trials. It is important to note that one of these trials by Wetzel et al [2] has been retracted from the European Journal of Anaesthesiology.[3]
The two remaining trials [4,5] assess the efficacy of paracetamol in younger patients, principally under 55 years of age, with acute moderate to severe low back pain of less than six weeks duration. Care should be taken about generalising these findings to elderly patients and to those with chronic or persistent back pain, in whom satisfactory pain control can be particularly challenging to achieve.
1. Machado G, Maher C, Ferreira P et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015;350:h1225
2. Wetzel L, Zadrazil M, Paternostro-Sluga T, et al. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: a crossover, randomised, double-blinded, placebo-controlled study. Eur J Anaesthesiol 2014;31:35-40
3. Wetzel L, Zadrazil M, Paternostro-Sluga T, et al. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study: Retraction. Eur J Anaesthesiol 2015;32:287.
4. Williams C, MAher C, LAtimer J, et al. Efficacy of paracetamol for acute low back pain: a double-blind, randomised controlled trial. Lancet 2014;384:1586-96
5. Nadler SF, Steiner DJ, Erasala GN, et al. Continuous low-level heat wrap therapy provides more efficacy than ibuprofen and acetaminophen for acute low back pain. Spine 2002;27:1012-7
Competing interests: No competing interests
Findings of meta-analysis on the efficacy and safety of paracetamol for spinal pain and osteoarthritis are valid and consistent with current guideline recommendations
Dear Editor,
The harsh criticisms made by Professor Miller, Dr Manniche and Dr Skousgaard seem out of proportion to the single issue they raised. Our systematic review considered 13 trials, 10 for osteoarthritis and three for spinal pain [1]. The retracted Wetzel et al. trial [2] was one of the three spinal pain trials and it contributed data for only one of the four spinal pain meta-analyses. This trial had some concerns with risk of bias and if excluded the quality of evidence (GRADE criteria) increases from moderate to high for the one effect estimate it contributed to. Our new conclusion would be that there is high quality evidence that paracetamol is ineffective for improving spinal pain and disability in the immediate and short term. Our results published in 2015 are very consistent with current guidelines which independently of us have come to the same conclusion and changed recommendations of paracetamol for low back pain [3,4].
The retraction of Wetzel et al. paper was mentioned in various BMJ rapid responses soon after our publication in 2015, and this issue was notified to the Cochrane Back & Neck Group prior to manuscript submission and acknowledged in the subsequent published review [5]. The retraction notice from European Journal of Anaesthesiology states that the reason for retracting Wetzel et al. paper was because one of the authors did not consent to its submission and publication; there is no mention of fraudulent data [6]. While it is not entirely clear what happened with the Wetzel et al. trial, what is clear is that its inclusion or deletion from our meta-analysis will not change the key message we should provide to clinicians: they should reconsider the use of paracetamol for osteoarthritis and low back pain.
References
1. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
2. Wetzel L, Zadrazil M, Paternostro-Sluga T, et al. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: a crossover, randomised, double-blinded, placebo- controlled study. Eur J Anaesthesiol 2014;31:35–40.
3. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive treatments for acute, subacute, and chronic low back pain: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166:514-530.
4. National Guideline Centre. Low back pain and sciatica in over 16s: assessment and management. National Institute for Health and Care Excellence (UK); 2016:NG59.
5. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016;6:CD012230.
6. [Retraction]. Intravenous non opioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study. Eur J Anaesthesiol. 2015;31(1):287.
Gustavo C Machado (NHMRC Research Fellow, Institute for Musculoskeletal Health, Sydney)
Chris G Maher (Director, Institute for Musculoskeletal Health, Sydney)
Manuela L Ferreira (NHMRC Research Fellow, Institute of Bone and Joint Research, Sydney)
Competing interests: No competing interests