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Rapid Responses: Rapid Responses published:
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Combining paracetamol and ibuprofen
- Edward Purssell, 57 Waterloo Road, London SE1 8WA (3 September 2008)
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Re: Combining paracetamol and ibuprofen
- Umesh Prabhu (4 September 2008)
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conclusion?
- yogi sehgal (5 September 2008)
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A validation of Street Wisdom
- Andrew P Mimnagh (6 September 2008)
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Paracetamol plus ibuprofen for the treatment of fever in children
- Jaseem Siddiqui (6 September 2008)
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absences in IBU+Para in children
- Nicholas D Moore (10 September 2008)
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Increased risk of soft tissue infections in children who take ibuprofen and ibuprofen and paracetamol
- Carlos A Calderon Ospina, Alejandra Salcedo (11 September 2008)
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PITCH: an indication of the level of emotion in relation to childhood fevers.
- Wouter Havinga (11 September 2008)
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Paracetamol and Ibuprofen (or Dipyrone) 3 hours each
- Leonardo C M Savassi, Betim, Minas Gerais, Brazil (12 September 2008)
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Be cautious to avoid over treatment!
- Sen Devadathan (18 September 2008)
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No numbers in the abstract
- Trish Groves (23 September 2008)
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Other dangers of NSAIDs
- Marise A McQueen (24 September 2008)
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PITCH conclusions need to be retracted by the BMJ
- Wouter Havinga (29 September 2008)
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some missed points
- Gema Ponce Revilla (11 October 2008)
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A missed opportunity.
- Sharon Conroy (16 October 2008)
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Edward Purssell, Lecturer King's College London, 57 Waterloo Road, London SE1 8WA
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Fever is a common in childhood, and is one of a number of related signs and symptoms associated with conditions such as infection. Although some infections are associated with considerable morbidity and mortality, fever of itself is rarely dangerous. Whilst fever is no doubt unpleasant, it is not clear how much of the distress of the febrile child is due to the fever compared to other symptoms such as pain and reflected parental anxiety. A recent study in the BMJ sought to compare paracetamol and ibuprofen combinations with the two drugs alone1. The authors correctly note that the need to treat fever with antipyretics is not necessarily evidenced based, yet go on to test a potentially hazardous treatment that for that very purpose, when safe, perfectly acceptable treatments in the form of ibuprofen and paracetamol monotherapy are available. Although combining these drugs may seem benign, encouraging polypharmacy may lead to confusion and misdosing, and the over aggressive persuit of normothermia that many clinicians have worked hard to reduce. Even in the rarefied environment of this study, a significant number of parents were not able to dose their children correctly. It is also not clear that combining these drugs is safe2 3, something that could not be established in a study of this small size. Fever phobia among parents has been much discussed in the literature4, and it has been suggested that this extends to professionals5. This paper demonstrates that this is the case, and may, unfortunately be used by those who don’t really understand the risks and benefits of such an approach to support a treatment that is not needed, for a symptom that does not actually need treating, by people whom it is clear that even from these data, have a relatively high chance of getting the treatment wrong. With these reservations in mind, clinicians should continue to follow the recommendations contained within the NICE guidelines that parents should be advised to use one drug alone6. The author was a member of the NICE Feverish illness in children guideline development group 1. Hay AD, Costelloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst S, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. British Medical Journal 2008;337:a1409. 2. Del Vecchio MT, Sundel ER. Alternating antipyretics: is this an alternative? Pediatrics 2001;108:1236-1237. 3. Mayoral CE, Mariono RVM, Rosenfeld W, Greensher J. Alternating antipyretics: is this an alternative? Pediatrics 2000;105(5):1009-1012. 4. Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics 2001;107:1241-1246. 5. May A, Bauchner H. Fever phobia: the paediatrician's contribution. Pediatrics 1992;90(6):851-854. 6. NICE. Feverish illness in children - Assessment and initial management in children younger than 5 years. London: National Institute for Health and Clincial Excellence, 2007. Competing interests: Member of feverish illness in children NICE GDG |
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Umesh Prabhu, Consultant Paediatrician The Pennine Acute Hospitals NHS Trust
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Fever itself doesn't do any harm except producing febrile convulsion in a small percentage (5%) of children with fever. But fever can make a child uncomfortable, unwell and irritable. Hence it is important to try to bring down the fever at least to make the child comfortable. But I do agree that we should avoid polypharmacy and use either paracetamol or ibuprofen. Rarely we need to use combined therapy. My personal experience suggests that some children respond better to paracetmol and others to ibuprofen. This is just a personal observation and very unscientific and not an evidence based. I am yet to convince that giving antipyretics masks underlying meningitis or septicaemia. However, the fundamental reason for missing the diagnosis in children with serious conditions like meningitis or septicaemia is because doctors miss some important clues in the history or examination findings. These are some of the important symptoms or signs which have been missed by some doctors. 1. History of drowsiness is not taken seriously.
Hopefully the NICE guidance should help the profession to make sure that children are diagnosed and treated early. Competing interests: None declared |
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yogi sehgal, rural family physician, clinical professor, Northern Ontario School of Medicine Sioux Lookout, p8t 1a8
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Given the minimal clinical difference between acetaminophen (paracetamol) and ibuprofen, I would conclude the opposite to the authors of the paper. Acetaminophen has been around for a long time, is very inexpensive and very safe, so why would one not use it first for analgesia (not for pyrexia as there is no evidence for antipyretics preventing febrile seizures) when there are theoretical risks of ibuprofen and case reports of major (although limited and rare) renal and GI effects? Polypharmacy is perfectly reasonable as well- -we do it all the time in adults with more or less useless combinations of acetaminophen and narcotics (such as tylenol #3). There is no reason not use acetaminophen and ibuprofen together when one or the other is ineffective. This combination, in my experience, is certainly more effective than acetaminophen and codeine, which is extremely popular and overused (and abused) in North America. Every paper I've seen on analgesia in the ER suggests we are undertreating and underdosing children, so let's at least treat them with the safe drugs at good doses (acetaminophen at least 15mg/kg and ibuprofen 10mg/kg) and not discourage their use. Competing interests: None declared |
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Andrew P Mimnagh, Pricipal in General Practice Eastview Surgery L22 4QD
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It is gratifying to see a methodologically sound analysis of a "trend from the streets".Working "Out of Hours" I have seen over a decade of parents who have already firmly reached this conclusion. I welcome the opportunity to "validate" their conclusion. It does raise the issue are the other "street" conclusions without published evidence sound or not - I hope to see something on the rising "Even if its only a virus they still get better quicker with antibiotics Doc."that feels wrong to me, and ideally before widespread OTC antibiotic use emerges. Competing interests: None declared |
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Jaseem Siddiqui, General Practitioner Custom House Square Medical Centre Lower Mayor Street Dublin 1
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In my personnel experience I have found this combination far superior Competing interests: None declared |
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Nicholas D Moore, Director of Clinical Research/clinical pharmacology Bordeaux University Hospital, 33076
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Congratulations on a very interesting paper, that shows that adding paracetamol to ibuprofen may have some benefit, but only after the first four hours, when the mean temperature is already under 37. Within the first four hours, which is probably what parents look for, ibuprofen acts better and faster than paracetamol, as has already been demonstrated many times for fever in children and for pain in adults. In this period, ibu+para is marginally better than ibu alone. Maybe the best might be to use ibu+para for the first dose, then continue on ibu alone (or para alone) - this might be another interesting study, possibly avoiding the complex dosing schedule shown here. Two points that surprised me, however: - Nowhere in the abstract is the number of patients included in the study mentioned. Considering the importance of sample size in study evaluation, this is very surprising. Or I missed it, but I read the abstract through word by word 3 times (at least). In the text, there is a long paragraph on recruitment difficulties, but it is nowhere written: "in the end 156 patients were included or randomized or analyzed, 52 in each group", though of course this information can be found in tables or figures. - The authors cite an ancillary result of sam Lesko's study, concerning excess asthma in children on paracetamol, but not the main study paper, which might have been appropriate, since this study in 84000 patients established the equivalent safety of ibuprofen and paracetamol used to treat fever in children. (Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA. 1995 Mar 22-29;273(12):929-33.) Otherwise a very nice paper Competing interests: None declared |
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Carlos A Calderon Ospina, Assistant Professor Pharmacology Unit. Faculty of Medicine. Universidad del Rosario. Bogota. Colombia., Alejandra Salcedo
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Recently, the BMJ published a clinical study according to which the combination of ibuprofen and paracetamol is more effective in going temperature down in children with fever (1). In turn, ibuprofen is more effective as monotherapy than paracetanol in controlling this symptom; that is why the authors conclude that for discomfort feverish children; first it should be administrate ibuprofen and then consider adding paracetamol for 24 hours in case of do not obtain the expected recovery. However, there are a few reports that suggest an association between the intake of ibuprofen or ibuprofen and paracetamol and an increased risk to suffer from soft-tissue infections, some of them very serious such as necrotizing fasciitis (2,3,4,5,6). Some of these studies shown an increase of the risk arose from the intake of ibuprofen as monotherapy (2,3,5,6), or the combination between ibuprofen and paracetamol (3,4); but at the same time a few of them are very emphatic showing that there is not an increase in the risk associated to the intake of paracetamol alone (3,4,7). The main risk factors for suffering from necrotizing fasciitis associated to nonsteroideal anti-inflammatory drugs (NSAIDs) include age (children) and a viral disease during the treatment. In fact, a French, case (patients with soft tissue necrotizante infection)-control study, published recently (6), documented that among 38 cases that were reported to the National System of Pharmacovigilance between 2000 and 2004, 25 patients were exposed to ibuprofen and 24 patients had have chickenpox. In the same study patients had a median age of 4 years old, and the adjusted odds ratios for exposure to NSAIDs and for viral infection were 31,38 (IC 95% 6,40 – 153,84) and 17,55 (IC 95% 3,47 – 88,65) respectively. It is quite interesting that in Hay´s et. al. study (1), 57 children with viral diseases were included (36,5%), and although it says that five children were hospitalized due to adverse serious events, it is not clear how these events happened or none extra information besides the medication taken is given. To conclude, I think that is not possible to ignore the available evidence, and although the combination of ibuprofen and paracetamol could be more effective for treating fever in children, precautions have to be taken when administrating this combination in children with viral infections, especially in children with chickenpox, and in this population the administration of paracetamol should be considered as monotherapy, decreasing the risk of suffering from soft tissue infections such as necrotizing fasciitis. References 1. Hay A, Costelloe C, Redmond N, Montgomery A, Fletcher M, Hollinghurst S, Peters T. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008; 337: a1302. 2. Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE. A case- control study of necrotizing fasciitis during primary varicella. Pediatrics. 1999; 103: 783 - 790. 3. Lesko SM, O'Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella. Pediatrics. 2001; 107:1108 -1115. 4. Lesko SM. The safety of ibuprofen suspension in children. Int J Clin Pract Suppl. 2003; 135: 50 - 53. 5. Leroy S, Mosca A, Landre-Peigne C, Cosson MA, Pons G. Ibuprofen in childhood: evidence-based review of efficacy and safety. Arch Pediatr. 2007; 14: 477 - 484. 6. Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M; French Network of Pharmacovigilance Centres. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol. 2008; 33: 249 -255. 7. Mikaeloff Y, Kezouh A, Suissa S. Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease. Br J Clin Pharmacol. 2008; 65: 203 - 209. Competing interests: None declared |
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Wouter Havinga, GP locum GL6 6JL
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Competing interests: None declared |
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Leonardo C M Savassi, Coordinator Medical Residence at Family Medicine, Betim, Minas Gerais, Brazil
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Family Physicians and Pediatricians in Brazil normally prescribe Paracetamol plus Dipyrone (that has proved its safety here)or Ibuprofen only when fever comes up before 6 hours since last dose of one of them. But they're not used at the same time. We normally use only one, 3 hours each, IF fever comes up before the intervall between the doses of a single one. Fever is a normal reaction of the body and the main problem about it is febrile seizure, that has been proved not to harm (febrile seizure is a normal reaction of the body and does not impair cognition, neurological development or any other neurological condition). So, I agree with the colleagues when they use paracetamol as the first choice and associate other drugs only in cases they are needed. 1. Febrile Seizures: Clinical Practice Guideline for the Long-term Management of the Child With Simple Febrile Seizures. Pediatrics 2008;121;1281-1286. http://www.pediatrics.org/cgi/content/full/121/6/1281 2. Anthony Harnden. Editorial: Antipyretic treatment for feverish young children in primary care. BMJ 2008; 337:a1409. http://www.bmj.com/cgi/content/extract/337 3. Martin Richardson, Monica Lakhanpaul and on behalf of the Guideline. Assessment and initial management of feverish illness in children younger than 5 years:summary of NICE guidance. BMJ 2007;334;1163- 1164. http://bmj.com/cgi/content/full/334/7604/1163 4. Brazilian Cochrane Centre. Dipyrone for acute primary headaches. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004842 Competing interests: None declared |
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Sen Devadathan, Consultant Cardiologist (locum) Royal Bolton Hospital, Bolton
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Congratulations to the authors for the interesting paper. Pyrexia is a sign of healthy body's response to insult. The conventional medical wisdom is to look for the cause of pyrexia, rather than suppressing it. I agree, it is different in young children, as the febrile child becomes irritable and difficult to manage at home. Both acetaminophen and ibuprofen are effective antipyretic agents. I am sure properly administered combination is safe and more effective (as demonstrated in this study) than a single agent. But we shouldn't ignore the efficacy of sensible physical measures, in our enthusiasm for advocating pharmacologic treatments. I would use caution and restrict the combination therapy to cases where single agents have failed in controlling symptoms. We need more evidence before recommending ibuprofen- paracetamol combination to public. Competing interests: None declared |
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Trish Groves, Deputy editor BMJ
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Nicholas Moore is right, and this paper's abstract should have stated the number of participants. Our advice at http://resources.bmj.com/bmj/authors/types-of-article/research asks authors of RCTs - such as this one - to provide a CONSORT-style abstract with a "results" subheading that states the number of participants randomised to each group. For other types of study our advice asks for this subsection: participants (instead of patients or subjects) - numbers entering and completing the study, sex, and ethnic group if appropriate. Give clear definitions of how selected, entry and exclusion criteria We're sorry we didn't get the abstract right this time, and we're grateful for this important reminder. Competing interests: I'm the BMJ's senior research editor and I maintain our advice to authors |
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Marise A McQueen, Staff grade, Anaphylaxis Service, Glasgow G11 6NT
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In adults, NSAIDs and Aspirin can cause 'allergic' side effects due to intollerance of COX 1 inhibition and subsequent release of leukotreines with resultant urticaria, angioedema, rhinitis, wheeze. This intollerance may become more common in children if the NSAID Ibuprofen is used frequently over the childhood years - and presumably this is more likely to occur in 'fever phobic' parents. Admittedly, Ibuprofen is a relatively weak nsaid, but it can still cause anaphylaxis in adults. Paracetamol can also cause these COX 1 inhibitor intollerant reactions but only in highly sensitised patients since it is a very weak inhibitor of COX. I think promoting ibuprofen use in children may lead to trouble with intollerance in the long term. In addition, there is the question of Reye's syndrome which we feel may be precipitated by using Aspirin in childhood. Am I the only person who thinks Ibuprofen may have more of an Aspirin like effect, even though the molecules of aspirin and paracetamol look more alike? Could it not be that in future studies of the use of Ibuprofen in febrile children that we end up seeing more asthma developing? Marise McQueen Competing interests: None declared |
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Wouter Havinga, GP locum GL6 6JL
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Competing interests: see http://www.bmj.com/cgi/eletters/337/sep02_2/a1409#202312 |
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Gema Ponce Revilla, Internship Family Medicine centro saúde benfica, USF Rodrigues Migueis
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The authors don´t mention the range of temperatures they were treating (we don´t know the initial media temperature in each group). I think it would be adequate to mention that. In addition, they don´t mention wich were the suspected causes of fever. I consider this also important... as sometimes suspected initial viral diseases modifies and complicates with bacterian diseases and also it´s not the same treating rubella (mild fever) than flu (usually higher)for example. In my opinion the disconfort relief can be associated also to the analgesic power of both ibuprofen and paracetamol, so i think this article opens a way to investigate if the relief is associated to analgesic, or antipiretic power or both. By the way i find the article really interesting, and the discussion rich, as i can see there are lots of ways of managing fever problems that also modifies with the country we work in! Competing interests: None declared |
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Sharon Conroy, Lecturer in Paediatric Clinical Pharmacy School of Graduate Medicine and Health, University of Nottingham,
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This study by Hay et al used the maximum recommended dose of ibuprofen and a 'standard' dose of paracetamol and so was not comparing like with like - a missed opportunity funded by the HTA. Ibuprofen has already been shown by a number of other studies (some cited in Hay's paper) to be superior to paracetamol in terms of temperature reduction and duration of action, however all of these studies were either of poor methodological quality and/or used small doses of paracetamol vs maximum doses of ibuprofen. The question of 'superiority' of the two drugs therefore still unfortunately remains unanswered. I totally agree with Purssel's response and that educating healthcare professionals and parents that having a temperature is not a dangerous thing in itself and is actually part of the body’s defence system to fight infection. There is no need to treat it unless the child is very uncomfortable or distressed by it, and if so we should treat these symptoms NOT a thermometer reading. Evidence available shows that the use of anti-pyretics does not prevent febrile convulsions. Hay's study also showed that 6-13% of parents made errors in drug administration & exceeded the maximum recommended daily dose of one or both drugs when asked to give the two preparations even under these clinical trial conditions. Surely this supports NOT recommending combining the two drugs by parents at home given the lack of firm evidence that combination is superior in terms of valid outcomes i.e. patient distress/discomfort. Sharon Conroy Competing interests: I was a member of the NICE guideline development group for the management of feverish illness in children. |
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