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Single dose oral rofecoxib for postoperative pain (Review)

Barden J, Rees J, Moore RA, McQuay HJ

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2005, Issue 1

http://www.thecochranelibrary.com

Single dose oral rofecoxib for postoperative pain (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iSingle dose oral rofecoxib for postoperative pain (Review)


[Intervention Review]

Single dose oral rofecoxib for postoperative pain

Jodie Barden1, Jayne Rees2, R Andrew Moore1 , Henry J McQuay1

1Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford, UK. 2Training Team, UK Cochrane Centre,

Oxford, UK

Contact address: Sheena Derry, Pain Research and Nuffield Department of Anaesthetics, University of Oxford, West Wing (Level 6),

John Radcliffe Hospital, Oxford, Oxfordshire, OX3 9DU, UK. [email protected].

Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Publication status and date: Unchanged, published in Issue 3, 2009.

Review content assessed as up-to-date: 4 November 2004.

Citation: Barden J, Rees J, Moore RA, McQuay HJ. Single dose oral rofecoxib for postoperative pain. Cochrane Database of Systematic

Reviews 2005, Issue 1. Art. No.: CD004604. DOI: 10.1002/14651858.CD004604.pub2.


A B S T R A C T

Background

Editor’s note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004

after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. So far, other

similar anti-inflammatory drugs are unaffected. Further information is available at www.vioxx.com.

Rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor that was licensed in the UK and the US for acute pain treatment and

is associated with fewer gastrointestinal adverse events than conventional NSAIDs. Rofecoxib is believed to be at least as effective as

conventional non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative pain.

Objectives

To assess the analgesic efficacy and adverse effects of a single oral dose of rofecoxib for moderate to severe postoperative pain, and to

compare its effectiveness with other analgesics used for treating acute pain.

Search strategy

We searched The Cochrane Library (Issue 1, 2002), MEDLINE (1966 to March 2002), Biological Abstracts (1985 to Dec 2001),

CINAHL (1982 to Dec 2001), Psychinfo (1967 to Jan 2002), PubMed (March 2001) and the Oxford pain database.

Selection criteria

Randomised controlled trials (RCTs) of adult patients who received either rofecoxib or placebo for postoperative pain.

Data collection and analysis

Studies were quality scored and the data extracted by two review authors independently. Summed pain relief (TOTPAR) or pain

intensity difference (SPID) was extracted and converted into dichotomous information yielding the number of patients with at least

50% pain relief. These derived results were used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one

patient to achieve at least 50% pain relief.

1Single dose oral rofecoxib for postoperative pain (Review)


mailto:[email protected]

Main results

Seven studies met the inclusion criteria. All the studies were funded by Merck & Company, the manufacturer of rofecoxib. In total,

667 participants were treated with rofecoxib 50 mg and 315 with placebo. The NNT for rofecoxib 50 mg was 2.2 (95% CI 1.9 to

2.4), i.e., for every two participant treated with rofecoxib 50 mg, one participant experienced at least 50% pain relief that would not

have done had they received placebo. All the studies were of short duration, and reported adverse events occurred less frequently with

rofecoxib 50 mg than with placebo.

Authors’ conclusions

Rofecoxib 50 mg (a dose two to four times the standard daily dose for chronic pain) is an effective single dose oral analgesic for acute

postoperative pain.

P L A I N L A N G U A G E S U M M A R Y

Single dose oral rofecoxib for postoperative pain

The aim of this review was to assess the analgesic efficacy and adverse effects of a single oral dose of rofecoxib for moderate to severe

postoperative pain, and to compare its effectiveness with other analgesics used for treating acute pain. The management of acute

postoperative pain is not always straightforward, and can be poorly treated. A variety of analgesic options are available, including

conventional non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and diclofenac. NSAIDs have pain-

relieving, antipyretic and anti-inflammatory properties; are proven to be effective following day surgery and minor surgery; and have an

opiate-sparing effect after more major surgery. However, a major concern regarding the use of conventional NSAIDs postoperatively is

the possibility of bleeding from both the operative site (because of the inhibition of platelet aggregation) (Forrest 2002) and from the

upper gastrointestinal tract, (especially in patients stressed by surgery, the elderly, frail or dehydrated). Drug treatments that combine

the pain-relieving properties of NSAIDs without these adverse effects are likely to have a place in clinical practice. A new generation

of NSAIDs has been developed that appear to address the problem of upper gastrointestinal bleeding. These are the ’selective cyclo-

oxygenase-2 inhibitors’ or ’coxibs’. This review found that Rofecoxib 50 mg is an effective single dose oral analgesic in acute postoperative

pain but also calls for further research and an improvement in the quality of reporting, particularly with regard to aspects such as the

duration of analgesia and adverse effects, would be welcomed.

Editor’s note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004

after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. So far, other

similar anti-inflammatory drugs are unaffected. Further information is available at www.vioxx.com.

B A C K G R O U N D

The management of acute postoperative pain is not always

straightforward, and can be poorly treated. A variety of analgesic

options are available, including conventional non-steroidal anti-

inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and

diclofenac. NSAIDs have pain-relieving, antipyretic and anti-in-

flammatory properties; are proven to be effective following day

surgery and minor surgery; and have an opiate-sparing effect af-

ter more major surgery (Grahame-Smith 2002). However, a ma-

jor concern regarding the use of conventional NSAIDs postoper-

atively is the possibility of bleeding from both the operative site

(because of the inhibition of platelet aggregation) (Forrest 2002)

and from the upper gastrointestinal tract, (especially in patients

stressed by surgery, the elderly, frail or dehydrated). Drug treat-

ments that combine the pain-relieving properties of NSAIDs with-

out these adverse effects are likely to have a place in clinical prac-

tice.

Recently, a new generation of NSAIDs has been developed that

appears to address the problem of upper gastrointestinal bleed-

ing (Hawkey 2001). These are the ’selective cyclo-oxygenase-2 in-

hibitors’ or ’coxibs’. Conventional NSAIDs are thought to relieve

pain by inhibiting cyclo-oxygenases and thus the production of

prostaglandins. (Prostaglandins occur throughout body tissues and

fluids and act to stimulate pain nerve endings and promote/inhibit



the aggregation of blood platelets). Cyclo-oxygenase has at least

two isoforms, including COX-1 and COX-2. COX-1 is constitu-

tive while COX-2 is induced at sites of inflammation and produces

the prostaglandins involved in inflammatory responses and pain

mediation (Grahame-Smith 2002). Unlike conventional NSAIDs,

the new generation ’coxibs’ are highly selective inhibitors. They

act to block the action of COX-2 and thus are believed to have

fewer gastrointestinal effects (Warner 1999). In common with

other NSAIDS, however, COX-2 inhibitors can give rise to fluid

retention and renal damage (Garner 2002) so caution is needed as

regards prescribing these drugs for the elderly (Hawkey 2001). In

addition, the inhibition of COX-2 in the large bowel can worsen

inflammatory bowel disease: these drugs are therefore contraindi-

cated in ulcerative colitis and Crohn’s disease (Grahame-Smith

2002).

Nevertheless, people who suffer the chronic pain caused by os-

teoarthritis and rheumatoid arthritis have welcomed the develop-

ment of COX-2 selective inhibitors such us celecoxib, etoricoxib,

valdecoxib and rofecoxib (Garner 2002). Rofecoxib was licensed

in the UK for both symptom relief in osteoarthritis and for acute

pain treatment, and accounted for 471,000 prescription items at a

cost of £12.5 million per quarter in 2002 (PPA 2002). Rofecoxib

was also the first COX -2-specific inhibitor approved for the treat-

ment of acute pain in the US. The recommended dose for acute

pain treatment was 50 mg daily, which is two to four times the

recommended daily dose for chronic arthritis pain.

The aim of this review is to evaluate the efficacy and safety of

rofecoxib for the relief of acute postoperative pain, and to compare

its effectiveness with that of other analgesics.

O B J E C T I V E S

To assess the analgesic efficacy and adverse effects of a single oral

dose of rofecoxib for moderate to severe postoperative pain, and

to compare its effectiveness with other analgesics used for treating

acute pain.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Reports were included if they were published randomised, double

blind trials of a single oral dose of rofecoxib administered for

moderate to severe postoperative pain.

Multiple dose studies were included if the appropriate data from

the first dose were available. Postpartum pain trials were included

provided the pain investigated was due to episiotomy or Caesarean

section (with or without uterine cramp). Studies investigating pain

arising from uterine cramps alone were excluded.

Abstracts, review articles, case reports, and clinical observations

were excluded, as were reports that did not clearly state that the

interventions had been randomly allocated; were concerned with

other pain conditions; used experimental pain or volunteer par-

ticipants, or both.

Types of participants

Adult participants (aged 15 years and above) experiencing mod-

erate to severe postoperative pain.

Types of interventions

Studies were included if they contained a treatment group allocated

to a single oral dose of rofecoxib or appropriate placebo that was

administered following an operative procedure involving incision.

Types of outcome measures

The derived pain relief outcomes extracted were total pain relief

(TOTPAR) or summed pain intensity difference (SPID) over 4 to

6 hours, or sufficient data to permit their calculation.

The pain measures accepted for the calculation of TOTPAR or

SPID were:

• five-point categorical pain relief (PR) scales with

comparable wording to “none, slight, moderate, good or

complete” (scales using percentages or money as anchors were

not permitted);

• four-point categorical pain intensity (PI) scales with

comparable wording to “none, mild, moderate, severe”;

• visual analogue scales (VAS) for pain relief; VAS for pain

intensity.

Where neither TOTPAR or SPID were available, a global evalu-

ation was accepted, provided it was a five-point categorical scale,

over four to six hours, and completed by the trial participant (not

investigator, nurse, or clinician, etc). The dichotomous informa-

tion from such a measure (the number of patients reporting the

top two categories) is demonstrably comparable to the calculated

dichotomous information taken from the pain relief and pain in-

tensity measures of choice (Collins 2001).

Search methods for identification of studies

Electronic databases

The following databases were searched:

• The Cochrane Central Register of Controlled Trials

(CENTRAL) in The Cochrane Library (Issue 1, 2002)



• MEDLINE (1966 to March 2002)

• Biological Abstracts (1985 to Dec 2001)

• CINAHL (1982 to Dec 2001)

• PsycINFO (1967 to Jan 2002)

• PubMed (March 2001)

• Oxford Pain Database (Jadad 1996a)

See Appendix 1 for the search strategy used for the various

databases.

Language

No language restriction was applied.

Additional sources

The manufacturer of rofecoxib (Merck & Company) and authors

of relevant studies and reports were contacted for further published

or unpublished trials.

Data collection and analysis

Selection of studies

Electronic searches were carried out by one review author (JB).

Two review authors (JE and JB) independently reviewed the titles

and abstracts retrieved, and agreed upon the reports that would

be retrieved in full for assessment for inclusion in the review. Dis-

agreements were resolved by discussion.

Quality assessment

Each study that met the inclusion criteria was assessed indepen-

dently for quality by two review authors using the three-item Ox-

ford Quality scale (Jadad 1996b) and a consensus score out of a

maximum of five points was agreed. These scores were not used

to weight the results.

The scale used is as follows:

• Is the study randomised? If yes, add one point;

• Is the randomisation procedure reported and is it

appropriate? If yes, add one point, if no, deduct one point;

• Is the study double blind? If yes, add one point;

• Is the double blind method reported and is it appropriate?

If yes, add one point, if no, deduct one point;

• Are the reasons for patient withdrawals and dropouts

described? If yes, add one point.

The results of the quality assessment are described in the ’Method-

ological quality of included studies’ section below.

Data management

Data were extracted by two review authors (JE and JB) and

recorded on a standard data extraction form. Data suitable for

pooling were entered into RevMan 4.1 by JB.

Data analysis

For each study, the mean TOTPAR, SPID, VAS TOTPAR or VAS

SPID values for active and placebo were converted to %maxTOT-

PAR or %maxSPID by division into the calculated maximum

value (Cooper 1991). The proportion of participants in each treat-

ment group who achieved at least 50%maxTOTPAR was calcu-

lated using verified equations (Moore 1996; Moore 1997a; Moore

1997b). These proportions were then converted into the number

of participants achieving at least 50%maxTOTPAR by multiply-

ing by the total number of participants in the treatment group.

Information on the number of participants with at least 50%max-

TOTPAR for active and placebo was then used to calculate relative

benefit (RB) and number-needed-to-treat (NNT).

The number of participants who experienced at least 50% pain

relief with rofecoxib 50 mg, rofecoxib 500 mg or placebo were

entered into RevMan Analyses 1.0.1, and the relative benefit (risk)

estimates were calculated with 95% confidence intervals (CI) us-

ing a fixed-effect model (Morris 1995). Number-needed-to-treat

and number-needed-to-harm (NNT/NNH) and 95% CI were

calculated by the method of Cook and Sackett (Cook 1995). A

statistically significant difference from control was assumed when

the 95% CI of the relative benefit did not include one.

Pain measures accepted for the calculation of TOTPAR or SPID

were:

• five-point categorical pain relief (PR) scales with

comparable wording to “none, slight, moderate, good or

complete”;

• four-point categorical pain intensity (PI) scales with

comparable wording to “none, mild, moderate, severe”;

• Visual analogue scales (VAS) for pain relief;

• VAS for pain intensity;

• 5-point categorical global scale with the wording “poor, fair,

good, very good, excellent” (Collins 2001).

Heterogeneity tests were not used as they have previously been

shown to be unhelpful (Gavaghan 2000; Higgins 2002) although

homogeneity was examined visually (L’Abbe 1987). Publication

bias was not assessed using funnel plots as these tests have been

shown to be unhelpful (Sterne 2000; Tang 2000).

Adverse effects

The number of participants reporting treatment-related adverse

effects was extracted for each treatment group and the data en-

tered into RevMan Analyses 1.0.1 to enable the calculation of the

relative-risk (RR) estimates for:

• nausea,



• vomiting,

• any adverse event.

Number-needed-to-harm (NNH) estimates were also calculated.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

The searches identified over 300 hundred studies. Of these, 19

studies were identified as potential RCTs that assessed the effec-

tiveness of rofecoxib compared to placebo.

Inspection of the full publication subsequently resulted in the

exclusion of 12 studies. Of the excluded studies:

• four reports were reviews (Jeske 1999; Morrison 2000;

Stichtenoth 2001; Wynn 2000);

• one report was available as an abstract only (Mehlisch

1998);

• two studies did not indicate a baseline pain of moderate to

severe intensity (Huang 2001; Reuben 2000) required to ensure

sensitivity (Lasagna 1962);

• one study used rofecoxib in the days prior to surgery

(Reuben 2002a);

• one study did not include rofecoxib as an active comparator

(Gimbel 2001);

• one study included concurrent morphine titration (Reuben

2002);

• one study did not use postoperative pain (Morrison 1999a);

and

• one study recruited child participants (Pickering 2002).

Seven studies met the inclusion criteria and were included in the

review. All the included studies were funded by Merck & Com-

pany, the manufacturer of rofecoxib.

Six of the studies were conducted in participants who had un-

dergone surgery for the extraction of third molar teeth (Chang

2001; Chang 2002; Ehrich 1999; Fricke 2002; Malmstrom 1999;

Morrison 1999), and one study was conducted with participants

who had undergone orthopaedic surgery (Reicin 2001).

Risk of bias in included studies

Each study was read independently by two review authors, and

scored using the three item Oxford Quality scale (Jadad 1996b).

The scale used is as follows:

• Is the study randomised? If yes - one point

• Is the randomisation procedure reported and is it

appropriate? If yes add one point, if no deduct one point

• Is the study double blind? If yes then add one point

• Is the double blind method reported and is it appropriate?

If yes add one point, if no deduct one point

• Are the reasons for patient withdrawals and dropouts

described? If yes add one point

The maximum possible score is five, indicating a trial of high

methodological quality.

Quality scores were:

• five for two studies (Chang 2002; Malmstrom 1999);

• four for four studies (Ehrich 1999; Morrison 1999; Reicin

2001; Chang 2001); and

• three for one study (Fricke 2002).

and indicate that all the included studies were of good method-

ological quality.

Effects of interventions

Seven studies met the inclusion criteria and provided data for this

systematic review. One study (Ehrich 1999) assessed two doses of

rofecoxib: rofecoxib 50 mg and an experimental dose of rofecoxib

500 mg. For the studies of rofecoxib 50 mg, 667 participants re-

ceived rofecoxib and 315 received placebo. For the study of rofe-

coxib 500 mg 20 participants received rofecoxib and 35 received

placebo.

Efficacy

The pooled relative risk (RR) for rofecoxib 50 mg was 5.12 (95%

CI 3.68 to 7.14), showing that the treatment was significantly

superior to placebo for postoperative pain relief at four to six hours.

(The pooled RR estimate and NNT for rofecoxib giving at least

50% pain relief over four to six hours compared with placebo are

given in Table 1).

Data from the study by Ehrich 1999 that assessed the experimental

dose of rofecoxib 500 mg also showed a positive benefit of rofe-

coxib compared to placebo but this was a small study where only

20 participants received the active treatment.

Adverse effects

The trials of rofecoxib were of short duration and adverse events

were inconsistently reported. Those described were generally mild

and transient but one participant was withdrawn from a trial due

to a serious adverse event (Chang 2002). Overall, few adverse

events were reported: only 49 participants were nauseous and 21

participants vomited following administration of the study drug.

Data regarding the incidences of nausea and vomiting were anal-

ysed as separate sub-groups for rofecoxib 50 mg in five dental trials

with a total of 755 participants (Chang 2001; Chang 2002; Fricke

2002; Malmstrom 1999; Morrison 1999). The pooled estimates

were as follows:



• Nausea: RR 0.72 (95% CI 0.47 to 1.11).

• Vomiting: RR 0.40 (95% CI 0.22 to 0.72).

Nausea and vomiting occurred less frequently with rofecoxib 50

mg than with placebo (negative NNHs (-20 and -15 respectively),

which means that for every 20 or 15 participants treated with

rofecoxib 50 mg one fewer was nauseous or vomited than with

placebo.

Four studies reported the number of participants experiencing any

adverse event (Chang 2001; Chang 2002; Fricke 2002; Morrison

1999). The pooled estimated was RR 0.83 (95% CI 0.67 to 1.04),

and the NNH was -15.7 (i.e., for every 16 participants treated,

one fewer experienced an adverse event than with placebo).

Time to remedication

Data regarding median time to remedication was given in four

studies (Chang 2001; Chang 2002; Malmstrom 1999; Morrison

1999) which permitted the calculation of a mean across the four

studies, weighted by the number of participants included. For

placebo, the weighted mean time to remedication was 1.9 hours

(189 participants), and for rofecoxib 50 mg the weighted mean

time to remedication was 16.4 hours (443 participants).

D I S C U S S I O N

The results of this review show that rofecoxib 50 mg is an effec-

tive treatment for acute postoperative pain. When compared with

placebo, the NNT for at least 50% pain relief over six hours with

rofecoxib 50 mg was 2.2 (2.0 to 2.5). In other words, for every two

participants treated with rofecoxib 50 mg, one will achieve 50%

pain relief that would not have done had they received placebo.

When prescribed to treat chronic osteoarthritis pain, rofecoxib is

given as a 12.5 mg daily dose, increased if necessary to a maximum

of 25 mg (BNF 2001). All of the studies included in this review

of postoperative pain relief administered rofecoxib at a daily dose

of 50 mg, which is between two and four times the standard daily

dose for regular chronic pain treatment. One study (Ehrich 1999)

also included 20 participants who received rofecoxib 500 mg: this

gave an NNT of 1.5 (1.1 to 2.1); RR 12.0 (95% CI 3.06 to 47.01).

However, rofecoxib 500 mg is an experimental dose, 20 to 40

times the standard daily dose, and should not be used in a clinical

setting.

The specificity of cyclooxygenase-2 inhibition is believed to re-

sult in increased gastrointestinal safety in comparison to other

NSAIDs. The seven studies included in this review reported only

one participant withdrawing as a result of a severe adverse effect.

Otherwise, adverse events were characterised as mild and tran-

sient although reporting was inconsistent and variable in terms

of quality. The NNHs for participants experiencing either any

adverse event, nausea, or vomiting were negative, implying that

such events occurred less frequently with rofecoxib 50 mg than

with placebo. However, the number of participants included in

this analysis was small.

An important aspect of the reported efficacy of rofecoxib for

chronic pain is the extended duration of analgesia compared with

other NSAIDs (Ehrich 1999; Mehlisch 1998). This aspect cannot

be properly assessed by the four to six hour outcome data provided

by the studies included in this review. In addition, duration of

analgesic effect was inconsistently reported in the included studies,

and therefore permitted only the crudest of analyses. For rofecoxib

50 mg the weighted mean time to remedication was 16.4 hours

(443 participants) and for placebo the weighted time to remedica-

tion time was 1.9 hours (189 participants). Drawing information

from the two studies in which ibuprofen 400 mg was included

as an active comparator (Malmstrom 1999; Morrison 1999), the

weighted time to remedication for ibuprofen 400 mg was 7.4

hours (97 participants). Thus, the extended time to remedication

for rofecoxib 50 mg may represent a real clinical advantage where

the problem is not a lack of analgesic effect, but rather effective

analgesics ineffectively delivered (Bruster 1994).

When compared with other analgesics used in the postoperative

setting, the evidence from this review indicates that rofecoxib 50

mg is more effective than paracetamol 600/650 mg + codeine 60

mg which has an NNT of 4.2 (3.4 to 5.3) (Barden in press(c)).

Rofecoxib 50 mg is comparable in efficacy to standard doses of

other commonly-used analgesics such as ibuprofen 400 mg with

an NNT of 2.4 (2.3 to 2.6) (Barden in press(a)) and diclofenac

50 mg with an NNT of 2.3 (2.0 to 2.7) (Barden in press(b)).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Rofecoxib 50 mg is an effective single dose oral analgesic in acute

postoperative pain.

Implications for research

Further research and an improvement in the quality of reporting,

particularly with regard to aspects such as the duration of analgesia

and adverse effects, would be welcomed.



R E F E R E N C E S

References to studies included in this review

Chang 2001 {published data only}

Chang DJ, Fricke JR, Bird SR, Bohidar NR, Dobbins

TW, Geba GP. Rofecoxib versus codeine/acetaminophen

in postoperative dental pain: a double blind, randomised,

placebo- and active- comparartor controlled clinical trial.

Clin Ther 2001;23(9):1446–55.

Chang 2002 {published data only}

Chang DJ, Desjardins PJ, Chen E, Polis AB, et

al.Comparison of the analgesic efficacy of rofecoxib and

enteric-coated diclofenac sodium in the treatment of

postoperative dental pain: a randomized, placebo-controlled

clinical trial. Clin Ther 2002;24(4):490–502.

Ehrich 1999 {published data only}

Ehrich EW, Dallob A, De Lepeleire I, et al.Characterisation

of rofecoxib as a cyclooxygenase-2 isoform inhibitor and

demonstration of analgesia in the dental pain model.

Clinical Pharmacology and Therapeutics 1999;65:336–47.

Fricke 2002 {published data only}

Fricke J, Varkalis J, Zwillich S, Adler R, Forester E, Recker

D P, Verburg K M. Valdecoxib is more efficacious than

rofecoxib in relieving pain associated with oral surgery. Am

J Ther 2002;9:89–97.

Malmstrom 1999 {published data only}

Malmstrom K, Daniels S, Kotey P, et al.Comparison of

rofecoxib and celecoxib, two cycloocygenase-2 inhibitors,

in postoperative dental pain: a randomised placebo- and

active- comparator controlled clinical trial. Clin Ther 1999;

21(10):1653–63.

Morrison 1999 {published data only}

Morrison BW, Christensen S, YuanW, et al.Analgesic

efficacy of the cyclooxygenase-2-specific inhibitor of

rofecoxib in post-dental surgery pain: a randomised,

controlled clinical trial. Clin ther 1999;21(6):943–53.

Reicin 2001 {published data only}

Reicin A, Brown J, Jove M, deAndrade JR, Bourne M,

Krupa D, Walters D, Seidenberg B. Efficacy of single-

dose and mulitidose rofecoxib in the treatment of post-

orthopedic surgery pain. American Journal of Orthopedics

2001;30(1):40–8.

References to studies excluded from this review

Gimbel 2001 {published data only}

Gimbel JS, Brugger A, Zhao W, Verburg KM, Geis GS.

Efficacy and tolerability of celecoxib versus hydrocodone/

acetaminophen in the treatment of pain after ambulatory

orthopedic surgery in adults. Clin Ther 2001;23(2):

228–41.

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References to other published versions of this review

Barden 2002d

Barden J, Edwards JE, McQuay HJ, Moore RA. Single-

dose rofecoxib for acute postoperative apin in adults: a

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4.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Chang 2001

Methods Randomised, double blind, placebo and active control in postoperative third molar extraction. Patient

self-assessment at 30 mins, hourly up to 8 hours, at 12 hours and at 24 hrs. Medication administered

when baseline pain reached a moderate to severe intensity

Participants Third molar removal

n= 393

age = 16 yrs +

Interventions Placebo

n=31

Rofecoxib 50 mg n=182

Paracetamol 600 mg plus codeine 60 mg,

n=180

Outcomes Standard categorical pain intensity and relief scales, remedication time, adverse events. Review converts

TOTPAR to at least 50% pain relief using standard methods.

At least 50% pain relief:

Placebo 2/31

Rofecoxib 50 mg 104/182

Paracetamol 600 mg plus codeine 60 mg 49/180

Notes Median time to remedication:

1.6 hours for placebo

9.6 hours for rofecoxib 50 mg

2.3 hours for paracetamol 600 mg plus codeine 60 mg.

Patients experiencing any adverse event:

Placebo 10/31



Nausea:

Placebo 3/31



Vomiting:

Placebo 2/31

Rofecoxib 50 mg 7

QS

R = 1

DB = 2

W/D = 1

Total = 4

Risk of bias



Chang 2001 (Continued)

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Chang 2002

Methods Randomised, double blind, placebo and active control in postoperative third molar extraction. Patient self-

assessment at 30, 60 and 90 mins, hourly up to 12 hours, at 16, 20 and 24 hours. medication administered


Participants Third molar extraction

n= 305

age= 16 yrs +


n= 63

Rofecoxib 50 mg

n= 121

Diclofenac 50 mg

n= 121

Outcomes Standard categorical pain intensity and pain relief scales, remedication time, adverse events. Review con-

verts TOTPAR to at least 50% pain relief using standard methods


Placebo

?/63

Rofecoxib 50 mg ?/121

Notes Median time to remedication: > 24 hrs for rofecoxib 50 mg, 1.35 hrs for diclofenac 50 mg and placebo

Drug-related adverse events seen in 13 (10.7%) of rofecoxib patients, 27 (22.3%) of diclofenac patients

and 11 (17.5%) of placebo patients

One patient from the placebo group withdrew due to serious AE (asthma flare), no other withdrawals due

to adverse effects

R= 2

DB = 2

W = 1

QS = 5

Risk of bias





Ehrich 1999

Methods Randomised, double blind, placebo controlled in postoperative third molar extraction. Patient self-assess-

ment at 15, 30, 45, 60 and 90 mins, hourly up to 6 hours. Medication administered when baseline pain

intensity reached a moderate to severe intensity


n= 104

age = 18 to 43


n=32

Rofecoxib 50 mg

n=32

Rofecoxib 500 mg

n=20

Ibuprofen 400 mg

n=20

Outcomes Standard categorical pain intensity and pain relief scales, remedication time, adverse events. Review con-

verts TOTPAR to at least 50% pain relief using standard methods


Placebo 2/32



Ibuprofen 400 mg 14/20

Notes Remedication within 2 hours:

75% of placebo

<25% of rofecoxib 50 mg

<25% of rofecoxib 500 mg

<25% of ibuprofen 400 mg

Adverse events were reported as mild and transient with headache and nausea most frequent. No details

reported

QS

R = 1

DB = 2

WD = 1

Total = 4

Risk of bias





Fricke 2002

Methods Randomised, double-blind, placebo and active control in postoperative third molar extraction. Assessment

at 15, 30, 45 mins, 1, 1.5, hourly up to 12 hours, 16 hours and 24 hours. Medication administered when

baseline pain reached a moderate to severe intensity


n= 203

age= 18+

Interventions Rofecoxib 50 mg

n= 82

Valdecoxib 40 mg

n= 80

Placebo

n= 41

Outcomes Standard categorical pain intensity and relief scales. Review converts TOTPAR to at least 50% pain relief

using standard methods.


Rofecoxib 50 mg

31/82

Placebo

2/41

Notes No persistent or unexpected adverse events. Specific adverse events:

Nausea -

Placebo 2/41


Vomiting -

Placebo 3/41

Rofecoxib 50 mg

7/82

QS

R = 1

DB = 1

W/D = 1

Total = 3

Risk of bias





Malmstrom 1999

Methods Randomised, double-blind, placebo and active control in postoperative third molar extraction. Patient self-

assessment at 15, 30, 45, 60 and 90 mins, then hourly up to 8 hours, at 10, 12 and 24 hours. Medication

administered when baseline pain reached a moderate to severe intensity


n= 272

age= 18 yrs +


n=45


Celecoxib 200 mg

n=91

Ibuprofen 400 mg

n=46




Placebo 3/45


Celecoxib 200 mg 37/91


Notes No persistent or unexpected adverse events. Specific adverse events:

Nausea -

Placebo 9/45




Vomiting -

Placebo 6/45

Remedication within 24 hours:

91% of placebo

49% of rofecoxib 50 mg

78% of celecoxib 200 mg

76% of ibuprofen 400 mg




QS

R = 2

DB = 2

W = 1

Total = 5

Risk of bias




Malmstrom 1999 (Continued)


Morrison 1999

Methods Randomised, double blind, placebo and active control in postoperative third molar extraction. Patient self-

assessment at 30, 60 and 90 mins, hourly up to 8 hours, at 12 and at 24 hours. medication administered



n= 151

age= 16 yrs +


n=50


Ibuprofen 400 mg

n=51




Placebo 6/50



Notes Remedication within 24 hours:

92% of placebo

56% of rofecoxib 50 mg

82% of ibuprofen 400 mg

Median time to remedication:

2.4 hours for placebo

9.5 hours for rofecoxib 50.

Patients experiencing any adverse event:

Placebo 17/50



Nausea:

Placebo 9/50



Vomiting:

Placebo 7/50



QS

R = 2

DB = 1

W/D = 1



Morrison 1999 (Continued)

Total = 4

Risk of bias



Reicin 2001

Methods Randomised, double blind, placebo and active control in postoperative orthopaedic surgery. Single dose

followed by multiple doses over five days. During single dose phase, patient self-assessment at 30, 60 and

90 mins, hourly up to 8 hours and at 12 hours. Medication administered when baseline pain reached a

moderate to severe intensity

Participants Major orthopedic surgery (total hip replacement, knee replacement or femoral fracture repair)

n= 218

age= mean 64.7 yrs

Interventions Placebo, n=53

Rofecoxib 50 mg, n=110

Naproxen sodium 550 mg, n=55

Outcomes Standard categorical pain intensity and relief scales, adverse events. Review converts TOTPAR to at least

50% pain relief using standard methods

At least 50% pain relief after first dose:

Placebo 11/53


Naproxen sodium 550 mg 25/55

Notes QS

R = 2

DB = 1

W/D = 1

Total = 4

Risk of bias





Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Gimbel 2001 Did not include rofecoxib in active treatment arms

Huang 2001 Study drug administration before operation therefore insufficient baseline pain intensity

Jeske 1999 Review

Mehlisch 1998 Abstract

Morrison 1999a Not postoperative pain

Morrison 2000 Review, no identifiable unique trial data

Pickering 2002 Children, not adult participants

Reuben 2000 Immediate postoperative drug administration therefore insufficient baseline pain

Reuben 2002 Concurrent morphine administration

Reuben 2002a Not a single dose RCT, 3-day use prior to surgery

Stichtenoth 2001 Review

Wynn 2000 Review



D A T A A N D A N A L Y S E S

Comparison 1. Rofecoxib 50 mg v placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 No. patients with at least 50%

maxTOTPAR

7 982 Risk Ratio (M-H, Fixed, 95% CI) 5.12 [3.68, 7.14]

2 No. patients with nausea 5 755 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.47, 1.11]

3 No. patients with vomiting 5 755 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.22, 0.72]

4 No. patients with any adverse

event


Comparison 2. Rofecoxib 500 mg v placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 No. patients with at least 50%

pain relief


A D D I T I O N A L T A B L E S

Table 1. Results

Dose RB (95% CI) NNT (95% CI) Total number pts

50 mg 5.12 (3.68 to 7.14) 2.2 (2.0 to 2.5) 982

500 mg 12.0 (3.06 to 47.01) 1.5 (1.1 to 2.1) 52

W H A T ’ S N E W

Last assessed as up-to-date: 4 November 2004.



Date Event Description

7 November 2008 Amended Changes made to History in accordance with RevMan 5

H I S T O R Y

Protocol first published: Issue 1, 2004

Review first published: Issue 1, 2004

Date Event Description

28 May 2008 Amended Converted to new review format.

31 October 2004 Amended Editor’s note added after Rofecoxib was withdrawn from the market in September 2004

C O N T R I B U T I O N S O F A U T H O R S

All authors contributed to the writing of both the protocol and the full review.

D E C L A R A T I O N S O F I N T E R E S T

None known

S O U R C E S O F S U P P O R T

Internal sources

• Oxford Pain Relief Tust, UK.

External sources

• No sources of support supplied



N O T E S

Editor’s note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it

was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. So far other similar anti-

inflammatory drugs are unaffected. Further information is available at www.vioxx.com.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal [∗administration & dosage; adverse effects]; Cyclooxygenase Inhibitors

[∗administration & dosage; adverse effects]; Drug Approval; Lactones [∗administration & dosage; adverse effects]; Pain, Postoperative

[∗drug therapy]; Randomized Controlled Trials as Topic; Sulfones [∗administration & dosage; adverse effects]

MeSH check words

Adult; Humans



cochrane database of systematic reviews (reviews) || single dose oral rofecoxib for postoperative...

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