Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): randomised controlled trial
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38925.471146.4F (Published 07 September 2006) Cite this as: BMJ 2006;333:519
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
I would like to thank Dr Dawson for his comments and consideration of
the possible implications of our study findings. It is agreed that only a
small but significantly increased risk of major bleeding complications
among patients allocated to ibuprofen was demonstrated while no
significant differences were detected in use of red cell transfusions,
mean suction drainage volumes or mean post-operative haemoglobin. However
the finding that 5% of patients in the ibuprofen group experienced at
least one major bleeding event is almost identical to that demonstrated in
a recent survey of similar patients during the hospital admission period
conducted in the UK. As regards the episodes of melaena, haemorrhage (of
the surgical wound), haematuria and bleeding haemorrhoids, all were also
further formally reported as ‘serious adverse events’ most being either
considered life threatening or resulting in prolonged hospitalisation. We
did not collect data on warfarin use or prosthetic valves. It is usual
practice for patients to cease warfarin prior to admission for total hip
replacement surgery. If a patient was to remain on warfarin, it would be
considered they had a ‘bleeding disorder’ and therefore ineligible for
study participation.
It is probable that the number of serious bleeding events was
relatively small as patients with any history of a serious adverse
reaction to an NSAID, major gastrointestinal bleeds or known bleeding
disorders were ineligible for participation. However, even in this low
risk sample, the absolute difference in the percentage of patients with a
major bleeding event was 3%, equating to an additional bleeding event per
34 patients given this prophylactic treatment. Given the large numbers of
people undergoing total hip replacement surgery, this finding is not
inconsequential.
Acute pain during the hospital admission period was not monitored as
the aim of this study was to assess the effect of a routine prophylactic
strategy on long term ectopic bone related pain and disability. However,
prescribed narcotic analgesia during the admission period was recorded by
the collaborating research nurses. While there was no difference in the
number of patients receiving IV narcotics (85%), the mean dose received
per patient did appear to be slightly lower among patients allocated to
ibuprofen compared to patients allocated to placebo. Likewise, the number
of patients receiving intra-muscular or oral narcotics was slightly lower
among patients allocated to ibuprofen compared to placebo. It is planned
to analyse these important data further and report our findings. However,
again the risk of the adverse events associated with NSAIDs use in this
post operative period among patients undergoing total hip replacement
surgery would need to be weighed up against any advantages gained by a
possibly reduced short term requirement for narcotic analgesia.
The main aim of the HIPAID study was to assess the magnitude of risk
and long term benefit of introducing routine post operative NSAIDs based
prophylaxis for ectopic bone formation among all patients undergoing total
hip replacement surgery to allow more informed decision making. The main
finding of this study was that while the incidence of ectopic bone
formation was indeed reduced, there was no evidence of an overall
reduction in long term pain and disability. In addition, due to the large
number of participants randomised in this study, we were able to
demonstrate that even with a moderate dose of ibuprofen (1200mg daily)
there are real concerns regarding increased risk of major bleeding events.
However, it was not intended that the findings from this study would be
extrapolated to patients undergoing other forms of orthopaedic surgery.
1. Sharma S. Upper gastrointestinal bleeding after hip and knee
arthroplasty. Orthopedics. 2006;29:255-257.
Competing interests:
None declared
Competing interests: No competing interests
The comments made by Dr Hussein and Dr Toner-Sho regarding the dose-
response relationship for adverse events associated with NSAIDs use are
well-supported by the literature.
As regards the comments concerning the safety of participants who received
regional anaesthesia is our study, this issue was discussed by the members
of the HIPAID Management Committee at the time of developing the study
design. Spinal or epidural anaesthesia is traditionally considered contra-
indicated in patients with significant disorders of blood coagulation, due
to an increased risk of the rare event of spinal haematoma causing neural
damage. However, there is no agreement about its risk among patients
whose coagulation may be mildly altered by low to moderate doses of
NSAIDs.1 It was decided, however, that patients receiving regional
anaesthesia would be ineligible for study participation unless any spinal
catheter had been removed at least 2 hours prior to randomisation.2 It
was also concluded that any variations in the use of NSAIDs or number of
outpatient appointments and physiotherapy visits between patients during
the follow-up period would be balanced by the randomisation procedure in
this large study.
1. Royal College of Anaesthetists. Guidelines for the use of non-
steroidal anti-inflammatory drugs in the perioperative period. 1998.
2. Horlocker TT, et al. Low molecular weight heparin: biochemistry,
pharmacology, perioperative prophylaxis regimens, and guidelines for
regional anesthetic management. Anesthesia Analgesia. 1997;85:874-885.
Competing interests:
None declared
Competing interests: No competing interests
We read with great interest the article by Fransen and colleagues
(1). There are few points we would like to highlight:
Firstly, the efficacy dose-response curve for NSAIDs is flat compared with
the dose-response for adverse effects such as gastrointestinal symptoms,
dizziness, and drowsiness (3). Increasing the dose to improve analgesia is
therefore more likely to increase adverse effects than to improve
analgesia.
Optimal management requires that the correct drugs are available, and that
they are given in the correct dose by the correct route and at the correct
time. British National Formulary (BNF) recommends: initially 1.2-1.8g
daily in 3-4 divided doses; increased if necessary to max. 2.4g
daily;maintenance dose 0.6-1.2 g daily may be adequate. It is still
controversial whether the increased harm caused by COX-2 selective NSAIDs
a dose-related phenomenon or not?
Secondly, non steroidal anti-inflammatory drugs (NSAIDs) are known to
reversibly affect platelet function (2). The safety of regional
anaesthesia in these group of patients remains a crucial issue amongst
anaesthetists (62%, 8% had spinal and epidural respectively).
Thirdly, we think that the availability of ibuprofen preparation to
the public, duration of stay, number of outpatient appointments and post-
operative physiotherapy sessions; all might be very important variables.
1. Fransen M et al. Safety and efficacy of routine postoperative
ibuprofen for pain and disability related to ectopic bone formation after
hip replacement surgery (HIPAID): randomised controlled trial. BMJ 2006;
333: 519.
2. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in
patients with osteoarthritis and ischemic heart disease. Clin Pharmacol
Ther 2006; 80 (3):264-274.
3. Eisenberg E et al. Efficacy and safety of nonsteroidal
antiinflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol
1994; 12 , 2756-2765.
Dr. Hamzeh Hussein-SHO Anaesthetics
Dr. Andrew Toner- SHO Anaesthetics
Anaesthetic and Critical Care Department
Royal Surrey county Hospital
Egerton Road
Guildford, GU2 7XX
Competing interests:
None declared
Competing interests: No competing interests
The paper by Fransen and colleagues is interesting. I note in the
results that the authors identify that there was 'a significantly
increased risk of major bleeding complications among those in the
ibuprofen group' during the admission period, though there was no
difference in use of blood products (autologous or non-autologous), or in
suction drain volumes or haemoglobin between the groups. This surely
waters down their argument of ibuprofen precipitating 'major bleeding'.
There was no difference in the rates of bleeding between the two
groups at the surgical site. It would be interesting to know more about
the episodes of melaena, 'haemorrhage' (of undisclosed nature) and of the
extent of haematuria and bleeding haemorrhoids. It would also be
interesting to know the numbers of patients taking warfarin or with
prosthetic valves in the two groups.
The numbers of bleeding events are small, and by ignoring just one
bleeding event in the ibuprofen group, statistical significance of 'major
bleeding’ is abolished to a P value of 0.1 (using a Chi Sqaure).
Ibuprofen is a very useful agent as an adjunct in pain management in
many groups of patients, especially in the perioperative, as are other
NSAIDs. Interestingly the authors make no mention of acute pain scores in
the perioperative period, or of use of opiates between groups, or of the
incidence of constipation or nausea and vomiting between groups.
I would sorry to see NSAIDs banned from the orthopaedic wards based
on this study, as I observe on a daily basis that they have clear
benefits, in the short term at least.
Fransen M, Anderson C, Douglas J, Macmahon S, Neal B, Norton R, et
al. Safety and efficacy of routine postoperative ibuprofen for pain and
disability related to ectopic bone formation after hip replacement surgery
(HIPAID): randomised controlled trial. BMJ 2006; 333: 519-21.
Competing interests:
None declared
Competing interests: No competing interests
NSAIDs are very useful after hip replacement surgery
EDITOR - Fransen et al conclude that ibuprofen should not be used as
routine prophylaxis for preventing ectopic bone formation in patients
undergoing total hip replacement and stress the failure to decrease
chronic pain and discomfort following the use of this drug. [1]
While we understand the recommendation not to give non-steroidal anti-
inflammatory drugs (NSAIDs) routinely (drugs with such a well known list
of adverse effects should always be prescribed on a patient by patient
basis) we are concerned that misinterpretation of this study may
predispose some clinicians to withhold these drugs early on in the peri-
operative phase. NSAIDs are recognised to be useful adjuncts in those who
have undergone recent surgery.[2.3.] Not only do they provide profound
analgesia but they also decrease opiate usage in those without continuous
intrathecal or epidural analgesia and with appropriate patient choice and
prescription they have an acceptable side effect profile. Regular opiate
prescription in the post-operative period may lead to respiratory
depression can have other serious consequences, especially for the elderly
such as constipation.
The final paragraph of Drs Birrell and Lohmander’s excellent Editorial
stating that “on balance, this study shows that NSAIDs should not be given
routinely after hip replacement surgery” [4] may be taken out of context.
This conclusion could result in many elderly patients experiencing either
unnecessary post operative pain or unfortunate side effects of opioid
analgesia.
Oliver Seyfried SHO Anaesthesia
David Wilkinson, Consultant Anaesthetist
Homerton University Foundation NHS Trust, Homerton Row, London E9 6SR
davidwilkinson1@compuserve.com
Competing interests: None declared
References:
1. Fransen M., Anderson C., Douglas J., Macmahon S., Neal B., Norton
R., Woodward M., Cameron ID., Crawford R., Lo SK., Tregonning G., Windolf
M. Safety and efficacy of routine postoperative ibuprofen for pain and
disability related to ectopic bone formation after hip replacement surgery
(HIPAID): randomised controlled trial. British Medical Journal 2006; 333:
519-521.
2. Cashman JN., Dolin SJ. Respiratory and haemodynamic effects of
acute postoperative pain management: evidence from published data. British
Journal of Anaesthesia 2004; 93: 212-223.
3. Burns JW, Aitken HA, Bullingham RE, et al. Double-blind comparison
of the morphine sparing effect of continuous and intermittent im
administration of ketorolac. British Journal of Anaesthesia 1991;67:235-
238.
4. Birell F, Lohmander S. Non-steroidal anti-inflammatory drugs after
hip replacement. British Medical Journal 2006; 333: 507-508.
Competing interests:
None declared
Competing interests: No competing interests