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8/14/2019 Types of Outcome Measures
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Single dose oral paracetamol (acetaminophen) with codeine
for postoperative pain in adults (Review)
Toms L, Derry S, Moore RA, McQuay HJ
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library
2011, Issue 11
http://www.thecochranelibrary.com
Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/8/14/2019 Types of Outcome Measures
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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
19DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo, Outcome 1 Participants with
at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . 46
Analysis 1.2. Comparison 1 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo, Outcome 2 Participants with
any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Analysis 2.1. Comparison 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg, Outcome 1Participants with at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . 48
Analysis 2.2. Comparison 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg, Outcome 2
Participants using rescue medication over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . 49
Analysis 2.3. Comparison 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg, Outcome 3
Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Analysis 3.1. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 1 Participants with
at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . 51
Analysis 3.2. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 2 Participants with
at least 50% pain relief over 4 to 6 hours, dental. . . . . . . . . . . . . . . . . . . . . . . 52
Analysis 3.3. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 3 Participants with
at least 50% pain relief over 4 to 6 hours, other surgery. . . . . . . . . . . . . . . . . . . . 53
Analysis 3.4. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 4 Participants using
rescue medication over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . . . 54Analysis 3.5. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 5 Participants with
any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Analysis 4.1. Comparison 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg, Outcome 1
Participants with at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . 56
Analysis 4.2. Comparison 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg, Outcome 2
Participants with at least 50% pain relief over 4 to 6 hours, dental. . . . . . . . . . . . . . . . 57
Analysis 4.3. Comparison 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg, Outcome 3
Participants with at least 50% pain relief over 4 to 6 hours, other surgery. . . . . . . . . . . . . . 58
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Analysis 4.4. Comparison 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg, Outcome 4
Participants using rescue medication over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . 59
Analysis 4.5. Comparison 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg, Outcome 5
Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 5.1. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 1 Participants with at least
50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Analysis 5.2. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 2 Participants with at least
50% pain relief over 4 to 6 hours, dental. . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 5.3. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 3 Participants with at least
50% pain relief over 4 to 6 hours, other surgery. . . . . . . . . . . . . . . . . . . . . . . 63
Analysis 5.4. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 4 Participants using rescue
medication over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Analysis 5.5. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 5 Participants with any
adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 6.1. Comparison 6 Sensitivity analysis (paracetamol with codeine versus placebo), Outcome 1 Fewer than 40
patients in active and placebo groups, participants with at least 50% pain relief over 4 to 6 hours. . . . . . 66
Analysis 6.2. Comparison 6 Sensitivity analysis (paracetamol with codeine versus placebo), Outcome 2 More than 40
patients in active and placebo groups, participants with at least 50% pain relief over 4 to 6 hours. . . . . . 67
Analysis 7.1. Comparison 7 Sensitivity analysis (paracetamol with codeine versus paracetamol), Outcome 1 Fewer than 40patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours. . . . . . 68
Analysis 7.2. Comparison 7 Sensitivity analysis (paracetamol with codeine versus paracetamol), Outcome 2 More than 40
patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours. . . . . . 69
Analysis 8.1. Comparison 8 Paracetamol plus codeine (all doses) versus placebo, Outcome 1 Participants with any adverse
event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 9.1. Comparison 9 Paracetamol plus codeine (all doses) versus paracetamol alone, Outcome 1 Participants with
any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
71ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
88INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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[Intervention Review]
Single dose oral paracetamol (acetaminophen) with codeinefor postoperative pain in adults
Laurence Toms2, Sheena Derry1, R Andrew Moore1, Henry J McQuay1
1Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Oxford,
UK. 2 Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford, UK
Contact address: Sheena Derry, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics),
University of Oxford, Churchill Hospital, Oxford, Oxfordshire, OX3 7LJ, [email protected].
Editorial group:Cochrane Pain, Palliative and Supportive Care Group.
Publication status and date: Stable (no update expected for reasons given in Whats new), published in Issue 11, 2011.
Review content assessed as up-to-date: 14 September 2011.
Citation: Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain
in adults.Cochrane Database of Systematic Reviews2009, Issue 1. Art. No.: CD001547. DOI: 10.1002/14651858.CD001547.pub2.
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different
modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of
pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additionaladverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine
using current data, and compare findings with other analgesics evaluated similarly.
Objectives
Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component,
and associated adverse events.
Search methods
We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update.
Selection criteria
Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of parac-
etamol alone, for relief of acute postoperative pain in adults.
Data collection and analysis
Two authors assessed trial quality and extracted data. The area under the pain relief versus time curve was used to derive proportion of
participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours,
using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion
of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures
of efficacy. Information on adverse events and withdrawals were collected.
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Main results
Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response
was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000
mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300
mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two
hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four tosix hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.
Fourteenstudies, with 926 participants, were included in the comparison of paracetamol plus codeine with thesame dose of paracetamol
alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%,
increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by
about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did
not differ between groups.
Authors conclusions
This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in
about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for
remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same
dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available
for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
P L A I N L A N G U A G E S U M M A R Y
Single dose oral paracetamol (acetaminophen) plus codeine for postoperative pain relief in adults
Pain is commonly experienced after surgical procedures, and is not always well controlled. Combining analgesics from different classes
has the potential to provide adequate pain relief with reduced dose-dependent adverse events. This review assessed data from twenty-
six studies comparing paracetamol plus codeine with placebo, and fourteen studies comparing paracetamol plus codeine with the same
dose of paracetamol alone. The combination provided effective pain relief for about 40% of participants experiencing moderate to
severe pain after an operation with 600 to 650 mg paracetamol plus 60 mg codeine, the dose most commonly used in these studies, andabout 50% of participants with 800 to 1000 mg paracetamol plus 60 mg codeine, the dose most commonly used in clinical practice.
The addition of codeine provided effective pain relief to about 10% more participants than the same dose of paracetamol alone. These
single dose studies did not associate paracetamol plus codeine with any serious side effects.
B A C K G R O U N D
This is an update of a review published in The Cochrane Library
in Issue 4, 1998 on Single dose paracetamol (acetaminophen),with and without codeine, for postoperative pain (Moore 1998a).
The title now states that the review is limited to adults. The
previous review looked at three sets of comparisons: paraceta-
mol versus placebo, paracetamol with codeine versus placebo, and
paracetamol with codeine versus paracetamol. This review updates
only the paracetamol with codeine versus placebo or paracetamol
alone comparisons. A separate review looks at paracetamol versus
placebo only (Toms 2008).
Acute pain occurs as a result of tissue damage commonly acciden-
tally due to an injury or as a result of surgery. Acute postoperative
pain is a manifestation of inflammation due to tissue injury. The
management of postoperative pain and inflammation is a criticalcomponent of patient care. This is one of a series of reviews whose
aim is to present evidence for relative analgesic efficacy through
indirect comparisons with placebo, in very similar trials performed
in a standard manner, with very similar outcomes, and over the
same duration. Such relative analgesic efficacy does not in itself
determine choice of drug for any situation or patient, but guides
policy-making at the local level.
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Single dose trials in acute pain are commonly short in duration,
rarely lasting longer than 12 hours. The numbers of participants
is small, allowing no reliable conclusions to be drawn about safety.
To show that the analgesic is working it is necessary to use placebo
(McQuay 2005). There are clear ethical considerations in doing
this. These ethical considerations are answered by using acute painsituations where the pain is expected to go away, and by providing
additional analgesia, commonly called rescue analgesia, if the pain
hasnot diminished after about an hour. This is reasonable, because
not all participants given an analgesic will have significant pain
relief. Approximately 18% of participants given placebo will have
significant pain relief (Moore 2006), and up to 50% may have
inadequate analgesia with active medicines. The use of additional
or rescue analgesia is hence important for all participants in the
trials.
Clinical trials measuring the efficacy of analgesics in acute pain
have been standardised over many years. Trials have to be ran-
domised and double blind. Typically, in the first few hours or days
after an operation, patients develop pain that is moderate to severein intensity, and will then be given the test analgesic or placebo.
Pain is measured using standard pain intensity scales immediately
before the intervention, and then using pain intensity and pain
relief scales over the following four to six hours for shorter acting
drugs, and up to 12 or 24 hours for longer acting drugs. Pain relief
of half the maximum possible pain relief or better (at least 50%
pain relief) is typically regarded as a clinically useful outcome in
this setting. For patients given rescue medication it is usual for no
additional pain measurements to be made, and for all subsequent
measures to be recorded as initial pain intensity or baseline (zero)
pain relief (baseline observation carried forward). This process en-
sures that analgesia from the rescue medication is not wrongly as-
cribed to the test intervention. In some trials the last observation
is carried forward, which gives an inflated response for the test in-
tervention compared to placebo, but the effect has been shown to
be negligible over four to six hours (Moore 2005). Patients often
remain in the hospital or clinic for at least the first six hours fol-
lowing the intervention, with measurements supervised, although
they may then go home to make their own measurements in trials
of longer duration.
Paracetamol
Paracetamol (acetaminophen) was first identified as the ac-
tive metabolite of two older antipyretic drugs, acetanilide and
phenacetin in the late nineteenth century but the drug was not
added to the British Pharmacopoeia until 1963 (PIC 2008). Since
then it has become one of the most popular antipyretic and anal-
gesic drugs worldwide, and is also often used in combination with
other drugs.
The lack of significant anti-inflammatory activity for paraceta-
mol implies a mode of action distinct from that of non-steroidal
anti-inflammatory drugs (NSAIDs) yet, despite years of use and
research, the mechanisms of action of paracetamol are not fully
understood. NSAIDs act by inhibiting the activity of cyclooxyge-
nase (COX). COX (now recognised to consist of two isoforms,
COX-1 and COX-2) catalyses the production of prostaglandins
responsible for painand inflammation. Paracetamol has previouslybeen shown to have no significant effects on COX-1 or COX-2
(Schwab 2003), but is now being considered as a selective COX-
2 inhibitor (Hinz 2008). Significant paracetamol-induced inhibi-
tion of prostaglandin production has been demonstrated in tis-
sues in the brain, spleen, and lung (Flower 1972;Botting 2000).
A COX-3 hypothesis wherein the efficacy of paracetamol is at-
tributed to its specific inhibition of a third cyclooxygenase iso-
form enzyme, COX-3 (Botting 2000; Chandrasekharan 2002;
PIC 2008) now has little credibility, and a central mode action of
paracetamol is thought to be likely (Graham 2005).
Despite a lowincidence of adverse effects, paracetamol hasa recog-
nised potential for hepatotoxicity and is thought to be responsi-
ble for approximately half of all cases of liver failure in the UK(Hawton 2001). Acute paracetamol hepatotoxicity at therapeu-
tic doses is extremely unlikely despite reports of so-called ther-
apeutic misadventure (Prescott 2000). In recent years legislative
changes restricting pack sizes and the maximum number of tablets
permitted in over-the-counter sales were introduced in the UK
(CSM 1997) on the basis of evidence that poisoning is lower in
countries that restrict availability (Hawton 2001;Gunnell 1997).
The contribution of these changes to any observed reductions in
incidence of liver failure or death, which are inconvenient and
more costly (particularly to chronic pain sufferers), remains un-
certain (Hawkins 2007). There have been concerns over the safety
of paracetamol in patients with compromised hepatic function
(those with severe alcoholism, cirrhosis or hepatitis) but these havenot been substantiated (PIC 2008;Dart 2000).
Paracetamol is the analgesic of choice for adult patients in whom
salicylates or other NSAIDs are contraindicated. Such patients
include asthmatics, those with salicylate allergies, and those with
a history of peptic ulcer. Compared with available alternatives, it
is associated with few problems in all but the most compromised
of renal patients, and few drug-drug interactions. Paracetamol is
useful for children with febrile viral illnesses, in whom aspirin is
contraindicated due to the risk of Reyes syndrome (swelling of the
brain that may lead to coma and death).
Paracetamol with codeineParacetamol, NSAIDs and opioids have different mechanisms of
action and side effect profiles, and combining drugs from these
main classes may offer the opportunity to optimise efficacy and
tolerability. It is thought that reduced doses of two(or more) drugs
from different classes, given together, can provide adequate pain
relief, acting via different targets, while reducing dose dependent
adverse events (Edwards 2002). The combination of paracetamol
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and an opioid is an attractive choice, particularly for individuals
for whom NSAIDs are contraindicated. In contrast to most other
classes of analgesic, opioids do not cause direct organ damage
in long-term use, but they have limited tolerability due to their
common, troublesome side effects (constipation, somnolence, dry
mouth, nausea and dizziness), and must be used with care in theelderly, or individuals with renal impairment.
Paracetamol with codeine is an established, cheap and widely avail-
able combination. The earlier Cochrane review concluded that
the combination is effective for postoperative pain, but additional
trials have since been published. This review aims to provide more
robust estimates of both efficacy and harm, in a format which fa-
cilitates direct comparison with other analgesics.
O B J E C T I V E S
To assess the efficacy andadverse effects of single dose paracetamol
with codeine for acute postoperative pain using methods that per-
mit comparison with other analgesics evaluated in the same way,
using wider criteria of efficacy recommended by an in-depth study
at the individual patient level (Moore 2005).
M E T H O D S
Criteria for considering studies for this review
Types of studies
Studies were included if theywerefull publicationsof double blind
trialsof a single dose oral paracetamol with codeine compared with
placebo or the same dose of paracetamol alone for the treatment
of moderate to severepostoperative pain in adults, with at least ten
participants randomly allocated to each treatment group. Multiple
dose studies were included if appropriate data from the first dose
were available, and cross-over studies were included provided that
data from the first arm were presented separately.
Studies were excluded if they were:
posters or abstracts not followed up by full publication; reports of trials concerned with pain other than
postoperative pain (including experimental pain);
trials using healthy volunteers;
trials where pain relief was assessed by clinicians, nurses or
carers (i.e., not patient-reported);
trials of less than four hours duration or which failed to
present data over four to six hours post-dose.
Types of participants
Studies of adult participants (15 years and older) with postoper-
ative pain of moderate to severe intensity following day surgery
or inpatient surgery were included. For studies using a visual ana-
logue scale (VAS), pain intensity was assumed to be of at least
moderate intensity when the VAS score was greater than 30 mm(Collins 1997).Trials of patients with postpartum pain were in-
cluded provided the pain investigated resulted from episiotomy or
Caesarean section (with or without uterine cramp). Trials investi-
gating pain due to uterine cramps alone were excluded.
Types of interventions
Orally administered paracetamol with codeine and matched
placebo or the same dose of paracetamol administered for relief of
postoperative pain.
Types of outcome measures
Information extracted from the studies included:
patient characteristics;
pain model;
patient reported pain at baseline (physician, nurse, or carer
reported pain will not be included in the analysis);
patient-reported pain relief and/or pain intensity expressed
hourly over four to six hours using validated pain scales (pain
intensity and pain relief in the form of visual analogue scales or
categorical scales, or both), or reported total pain relief
(TOTPAR) or summed pain intensity difference (SPID) at four
to six hours;
patient-reported global evaluation of efficacy (PGE), using
a standard categorical rating scale;
number of participants using rescue medication, and the
time of assessment;
time to use of rescue medication;
withdrawals - all cause, adverse event;
adverse events - participants experiencing one or more, and
any serious adverse event, and the time of assessment.
Search methods for identification of studies
The following databases were searched:
Cochrane CENTRAL (November 2002 for original search
and 2002 to August 2008 for the update);
MEDLINE via Ovid (1966 to November 2002 for theoriginal review and 2002 to August 2008 for the update);
EMBASE via Ovid (1966 to November 2002 for the
original review and 2002 to August 2008 for the update);
Oxford Pain Database (Jadad 1996a).
SeeAppendix 1 for the MEDLINE search strategy,Appendix 2 for
the EMBASE search strategy, and Appendix 3for the Cochrane
CENTRAL search strategy.
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Reference lists of retrieved studies were also manually searched.
Other databases searched for the original review were not searched
for the update.
Language
No language restriction was applied.
Unpublished studies
Abstracts, conference proceedings and other grey literature were
not searched. Manufacturers were not contacted.
Data collection and analysis
Selection of studiesTwo review authors independently assessed and agreed the search
results for studies that might be included in the updated review.
Quality assessment
Two review authors independently assessed the included studies
for quality using a five-point 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 1 point, if no deduct one point;
Are the reasons for patient withdrawals and dropouts
described? If yes add one point.
The results are described under Risk of bias in included studies
and are detailed in Characteristics of included studies.
Data management
Data were extracted by two review authors and recorded on a stan-
dard data extraction form. Data suitable for pooling were entered
into RevMan 5.0.13.
Data analysis
QUOROM guidelines were followed (Moher 1999). For efficacy
analyses we used the number of participants in each treatment
group who were randomised, received medication, and provided
at least one valid post-baseline assessment. For safety analyses we
used number of participants randomised to each treatment group
who took the study medication. Analyses were planned for dif-
ferent doses (where there were at least 200 participants). Sensi-
tivity analyses were planned for pain model (dental versus other
postoperative pain), trial size (39 or fewer versus 40 or more per
treatment arm), and quality score (two versus three or more).
Primary outcome: Number of participants achieving at least
50% pain relief
For each study, mean TOTPAR (total pain relief) or SPID
(summed pain intensity difference) for active and placebo groups
were converted to %maxTOTPAR or %maxSPID by division
into the calculated maximum value (Cooper 1991). The pro-
portion of participants in each treatment group who achieved at
least 50%maxTOTPAR was calculated 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 multiplying by the total number of
participants in the treatment group. Information on the number
of participants with at least 50%maxTOTPAR for active treat-
ment and placebo was then used to calculate relative benefit (RR)
and number-needed-to-treat to benefit (NNT).
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.
If none of these measures were available, numbers of participants
reportingvery goodor excellenton a five-pointcategorical global
scale with the wording poor, fair, good, verygood, excellentwere
taken as those achieving at least 50% pain relief (Collins 2001).
Details of the scales used to measure pain and pain relief are in the
glossary (Appendix 4).
Secondary outcomes:
1.Use of rescue medication. Numbers of participants requiring
rescue medication were used to calculate numbers-needed-to-treat
to prevent (NNTp) use of rescue medication for treatment and
placebo groups. Median (or mean) time to use of rescue medica-
tion was used to calculate the weighted mean of the median (or
mean) for the outcome. Where fewer than 50% of participants
required rescue medication at the time of censorship, the median
time was taken as the time of censorship. This will give a conser-
vative estimate for time to use of rescue medication. Weighting
was by number of participants.
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2. Adverse events. Numbers of participants reporting adverse
events for each treatment group were used to calculate relative risk
(RR) and numbers needed to treat to harm (NNH) estimates for:
any adverse event;
any serious adverse event (as reported in the study);
withdrawal due to an adverse event.3.Other withdrawals.Withdrawals for reasons other than lack
of efficacy (participants using rescue medication - see above) and
adverse events were noted.
Relative benefit and risk estimates were calculated with 95% con-
fidence intervals (CI) using a fixed-effect model (Morris 1995).
NNT or NNH with 95% CI were calculated using the pooled
number of events by the method of Cook and Sackett (Cook
1995). A statistically significant difference from control was as-
sumed when the 95% CI of the relative benefit did not include
the number one.
Homogeneityof studies wasassessed visually (LAbb 1987).Thez
test (Tramr 1997) was used to determine if there was a significant
difference between NNTs for different doses of active treatment,or between groups in the sensitivity analyses.
R E S U L T S
Description of studies
See: Characteristicsof included studies; Characteristicsof excluded
studies.
Thisreview examines only trials of paracetamol pluscodeine versus
placebo or paracetamol plus codeine versus paracetamol. Trials ofparacetamol alone versus placebo are to be found in a separate
review (Toms 2008).
Included studies
Paracetamol with codeine versus placebo
Twenty-six studies with 2295 participants met our inclusion crite-
ria for the comparison of paracetamol plus codeine versus placebo
(Bentley 1987;Bjune 1996;Bourne 2005;Chang 2001;Chang
2005; Cooper 1981; Cooper 1988; Cooper 1991; Desjardins
1986; Dionne 1994; Forbes 1982; Forbes 1983; Forbes 1986;
Forbes 1989; Forbes 1990a; Forbes 1990b; Forbes 1994; Heidrich
1985;Honig 1984; Malmstrom 2004;Pande 1996c;Smith 2004;
Stubhaug 1995;Sunshine 1986;Turek 1988;Ziccardi 2000)). In
total 1357 participants were given paracetamol plus codeine and
938 placebo. The original review included 21 studies reporting 22
comparisons (1407 participants). Two of these comparisons had
group sizes of less than10 (Pande 1996a; Pande 1996b) and hence
did not meet our inclusion criteria. We found six new studies
with 908 participants (Bourne 2005;Chang 2001;Chang 2005;
Malmstrom 2004;Smith 2004;Ziccardi 2000), and excluded six
new studies (Chung 2004; De los Santos 1998;Maalaki 2002;
Macleod 2002;Peter 2001;Raeder 2001) for this update for Issue
1, 2009. Details of all studies are in the Characteristics of includedstudiesor theCharacteristics of excluded studiestables.
Paracetamol with codeine versus paracetamol
Fourteen studies with 926 participants met our inclusion crite-
ria for the comparison of paracetamol plus codeine versus parac-
etamol (Bentley 1987;Bjune 1996;Breivik 1999;Cooper 1981;
Cooper 1988;Cooper 1991;Dionne 1994;Forbes 1982;Forbes
1983;Forbes 1989;Forbes 1990b;Gertzbein 1986;Honig 1984;
Sunshine 1986). In total 462 participants were given paracetamol
with codeine and 464 paracetamol alone. Twelve studies (794 par-
ticipants) were included in the original review and two (132 par-ticipants) are new to this update (Bjune 1996andBreivik 1999)
for Issue 1, 2009. AlthoughBjune 1996did appear in the original
review, the paracetamol plus codeine arm used 800 mg of parac-
etamol with 60 mg codeine and the paracetamol only arm used
1000 mg paracetamol alone. Hence it was only analysed for its
paracetamol versus placebo comparison as the doses of paraceta-
mol are different. We considered the dose of paracetamol in the
paracetamol only armto be sufficiently similar to that in theparac-
etamol plus codeine arm, and hence we included this comparison
in our analysis. We excluded six new studies (Chung 2004;De los
Santos 1998;Maalaki 2002;Macleod 2002;Peter 2001;Raeder
2001). Details of all studies are in theCharacteristics of included
studiesor theCharacteristics of excluded studiestables.
Dose
Paracetamol with codeine versus placebo
Paracetamol 1000 mg with codeine 60 mg was used in two stud-
ies (Bentley 1987;Stubhaug 1995) and Paracetamol 800 mg with
codeine 60 mg was used in one study (Bjune 1996): for the pur-
poses of this analysis these doses will be classed as one group.
Paracetamol 600 to 650 mg with codeine 60 mg was used in 17
studies (Chang 2001;Chang 2005;Cooper 1981;Cooper 1988;
Cooper 1991;Dionne 1994;Forbes 1982;Forbes 1983;Forbes
1989;Forbes 1990a; Forbes 1990b; Honig 1984; Malmstrom
2004;Pande 1996c;Sunshine 1986;Turek 1988;Ziccardi 2000).
Paracetamol 300 mg with codeine 30 mg was used in six stud-
ies (Bourne 2005;Desjardins 1986;Forbes 1986;Forbes 1994;
Heidrich 1985;Smith 2004).
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Paracetamol with codeine versus paracetamol
Paracetamol 1000 mg with 60 mg codeine versus 1000 mg parac-
etamol alone was used in three studies (Breivik 1999; Bentley
1987;Gertzbein 1986). Paracetamol 800 mg with 60 mg codeine
versus 1000 mg paracetamol alone was used in one comparison
(Bjune 1996): for the purposes of this analysis these doses will beclassed as one group.
Paracetamol 600 mg to 650 mg plus 60 mg codeine versus parac-
etamol 600 mg to 650 mg alone was used in 10 treatment arms
(Cooper 1981; Cooper 1988; Cooper 1991; Dionne 1994; Forbes
1982; Forbes 1983; Forbes 1989; Forbes 1990b; Honig 1984;
Sunshine 1986).
Pain model
Paracetamol with codeine versus placebo
Eighteen studies enrolled patients with dental pain following ex-traction of at least oneimpactedthirdmolar (Bentley 1987; Chang
2001;Chang 2005;Cooper 1981;Cooper 1988;Cooper 1991;
Desjardins 1986; Dionne 1994; Forbes 1982; Forbes 1986; Forbes
1989; Forbes 1990a; Forbes 1990b; Forbes 1994; Malmstrom
2004;Pande 1996c;Sunshine 1986;Ziccardi 2000).
Eight studies enrolled patients with pain following other surgical
procedures. Four were mixed general surgery (Forbes 1983; Honig
1984;Smith 2004;Turek 1988), three were orthopaedic surgery
(Bourne 2005;Heidrich 1985;Stubhaug 1995) and one was Cae-
sarean section (Bjune 1996).
Paracetamol with codeine versus paracetamol
Ten studies (Bentley 1987;Breivik 1999;Cooper 1981;Cooper
1988; Cooper 1991;Dionne 1994; Forbes 1982;Forbes 1989;
Forbes 1990b;Sunshine 1986) enrolled patients with dental pain
following extraction of at least one impacted third molar.
Four studies (Forbes 1983;Bjune 1996;Gertzbein 1986;Honig
1984) enrolled patients with pain following general surgical pro-
cedures (including one study with Caesarean section).
Study duration
Paracetamol with codeine versus placebo
Study duration was four hours in five studies, five hours in one
study, six hours in 15 studies, 12 hours in three studies, and 24
hours in two studies.
Paracetamol with codeine versus paracetamol
Study duration was four hours in four studies, six hours in five
studies, eight hours in one study and 12 hours three studies.
Details of included and excluded studies are in the corresponding
Characteristics of studies tables.
Risk of bias in included studies
Paracetamol with codeine versus placebo
Ten studies were given a quality score of five (Bourne 2005; Forbes
1983;Forbes 1986;Forbes 1989;Forbes 1990a; Forbes 1990b;
Forbes 1994; Malmstrom 2004; Smith 2004; Sunshine 1986), ten
a score of four (Bjune 1996;Chang 2001;Chang 2005;Cooper
1981; Cooper 1988; Desjardins 1986; Forbes 1982; Pande 1996c;
Stubhaug 1995; Ziccardi2000),fiveascoreofthree(Bentley1987;
Cooper 1991;Dionne 1994;Honig 1984;Turek 1988), and onea score of two (Heidrich 1985).
Paracetamol with codeine versus paracetamol
Five studies were given a quality score of five (Breivik 1999; Forbes
1983; Forbes 1989; Forbes 1990b; Sunshine 1986), four a score of
four (Bjune 1996; Cooper 1981; Cooper 1988; Forbes 1982), and
five a score of three (Bentley 1987;Cooper 1991;Dionne 1994;
Gertzbein 1986;Honig 1984).
Further details are in Characteristics of included studies.
Effects of interventions
Number of participants achieving at least 50% pain
relief
Paracetamol with codeine versus placebo
800 to 1000 mg paracetamol with 60 mg codeine versus
placebo
Three studies provided data: 121 participants were treated
with paracetamol plus codeine and 71 with placebo (Table 1;
Figure 1; Summary of results A).
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Figure 1. Forest plot of comparison: 3 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo,
outcome: 1.1 Participants with at least 50% pain relief over 4 to 6 hours.
The proportion of participants experiencing at least 50%
pain relief over four to six hours with 800 mg to 1000 mg of
paracetamol plus 60 mg codeine was 53% (64/121).
The proportion of participants experiencing at least 50%
pain relief over 4 to 6 hours with placebo was 7% (5/71).
The relative benefit of treatment compared with placebowas 6.3 (2.9 to 14).
The NNT for at least 50% pain relief over four to six hours
was 2.2 (1.8 to 2.9). For every two participants treated with
paracetamol plus codeine, one would experience at least 50%
pain relief who would not have done so with placebo.
600 to 650 mg paracetamol with 60 mg codeine versus
placebo Seventeen studies provided data: 857 participants were
treated with 600/650 mg paracetamol plus 60 mg codeine and
556 with placebo (Table 1;Figure 2; Summary of results A).
Figure 2. Forest plot of comparison: 5 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo,
outcome: 3.1 Participants with at least 50% pain relief over 4 to 6 hours.
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The proportion of participants experiencing at least 50%
pain relief over four to six hours with 600/650 mg paracetamol
plus 60 mg codeine was 43% (370/857).
The proportion of patients experiencing at least 50% pain
relief over four to six hours with placebo was 17% (96/556).
The relative benefit of treatment compared with placebowas 2.6 (2.2 to 3.2).
The NNT for at least 50% pain relief over four to six hours
was 3.9 (3.3 to 4.7). For every four participants treated with
600/650 mg paracetamol plus 60 mg codeine, one would
experience at least 50% pain relief who would not have done so
with placebo.
300 mg paracetamol with 30 mg codeine versus placebo
Six studies provided data: 379 participants were treated
with 300 paracetamol plus 30 mg codeine and 311 with placebo
(Table 1;Figure 3; Summary of results A).
Figure 3. Forest plot of comparison: 7 Paracetamol 300 mg plus codeine 30 mg versus placebo, outcome:
5.1 Participants with at least 50% pain relief over 4 to 6 hours.
The proportion of participants experiencing at least 50%
pain relief over four to six hours with 300 mg paracetamol plus
30 mg codeine was 32% (123/379). The proportion of patients experiencing at least 50% pain
relief over four to six hours with placebo was 18% (56/311).
The relative benefit of treatment compared with placebo
was 1.9 (1.4 to 2.5).
The NNT for at least 50% pain relief over four to six hours
was 6.9 (4.8 to 12). For every seven participants treated with 300
mg paracetamol plus 30 mg codeine, one would experience at
least 50% pain relief who would not have done so with placebo.
Summary of results A: participants achieving at least 50% pain relief over 4 to 6 hours: paracetamol plus codeine versus
placebo
Dose (mg) Studies Participants Paracetamol + codeine
(%)
Placebo (%) NNT (95%CI)50% PR
800-1000/60 mg 3 192 53 7 2.2 (1.8 to 2.9)
600-650/60 mg 17 1413 43 17 3.9 (3.3 to 4.7)
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(Continued)
300/30 mg 6 690 32 18 6.9 (4.8 to 12)
The 800 mg to 1000 mg paracetamol plus 60 mg codeine dose
was significantly superior to 600 mg to 650 mg paracetamol plus
60 mg codeine (z = 3.42, P < 0.0067), and to 300 mg paracetamol
plus 30 mg codeine (z = 4.94, P < 0.0006). Since the total number
of participants in the highest dose group is relatively small, the
extent of the difference between the groups is not robust. There
was borderline significance between 600 to 650 mg paracetamol
plus 60 mg codeine and 300 mg paracetamol plus 30 mg codeine
(z = 2.78, P < 0.0056).
Paracetamol with codeine versus paracetamol
800 to 1000 mg paracetamol plus 60 mg codeine versus same
dose paracetamol alone
Four studies provided data: 109 participants were treated
with 1000 mg paracetamol plus 60 mg codeine, 44 with 800 mg
paracetamol plus 60 mg codeine, and 151 with 1000 mg
paracetamol alone (Table 1;Figure 4; Summary of results B).
Figure 4. Forest plot of comparison: 4 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol
1000 mg, outcome: 2.1 Participants with at least 50% pain relief over 4 to 6 hours.
The proportion of patients experiencing at least 50% pain
relief over four to six hours with 800 mg to 1000 mg
paracetamol plus 60 mg codeine was 59% (90/153).
The proportion of participants experiencing at least 50%
pain relief over four to six hours with 1000 mg paracetamol
alone was 42% (68/151).
The relative benefit of combination treatment compared
with paracetamol alone was 1.3 (1.1 to 1.6). The NNT for at least 50% pain relief over four to six hours
was 6.1 (3.6 to 19). For every six participants treated with 800
mg to 1000 mg paracetamol plus 60 mg codeine, one would
experience at least 50% pain relief who would not have done so
with the same dose of paracetamol alone.
Omitting the study that compared 800 mg paracetamol plus 60
mg codeine with 1000 mg paracetamol alone, gave a slightly lower
(better) NNT, but did not significantly change the result.
600 to 650 mg paracetamol plus 60 mg codeine versus same
dose paracetamol alone Ten studies provided data: 309 participants were treated
with 600 mg to 650 mg paracetamol plus 60 mg codeine and
313 with 600-650 mg paracetamol alone (Table 1;Figure 5;
Summary of results B).
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Figure 5. Forest plot of comparison: 6 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol
600 to 650 mg, outcome: 4.1 Participants with at least 50% pain relief over 4 to 6 hours.
The proportion of participants experiencing at least 50%
pain relief over four to six hours with 600 mg to 650 mg
paracetamol plus 60 mg codeine was 53% (165/309).
The proportion of participants experiencing at least 50%
pain relief over four to six hours with 600/650 mg paracetamol
alone was 41% (129/313).
The relative benefit of combination treatment compared
with paracetamol alone was 1.3 (1.1 to 1.5).
The NNT for at least 50% pain relief over four to six hours
was 8.2 (5.0 to 23). For every eight participants treated with 600
mg to 650 mg paracetamol plus 60 mg codeine, one would
experience at least 50% pain relief who would not have done so
with the same dose of paracetamol alone.
Summary of results B: participants achieving at least 50% pain relief over 4 to 6 hours: paracetamol plus codeine versus the
same dose of paracetamol alone
Dose (mg) Studies Participants Paracetamol + codeine
(%)
Paracetamol (%) NNT (95%CI)50% PR
800-1000/60 4 304 59 42 6.1 (3.6 to 19)
1000/60 3 217 68 48 5.1 (3.1 to 15)
600-650/60 10 622 53 41 8.2 (5.0 to 23)
The addition of 60 mg codeine to effective doses of paracetamol
increases the number of participants achieving effective pain relief
by 10 to 15%. There was no clear dose response.
Sensitivity analysis
Sensitivity analyses were carried out on the primary outcome of
number of participants achieving at least 50% pain relief.
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Paracetamol with codeine versus placebo
Study quality
Only one study (Heidrich 1985) had a quality score of two. A
formal sensitivity analysis by quality was therefore not performed.Removing this single study from the analysis for paracetamol 300
mg plus codeine 30 mg versus placebo did not change the results
for relative benefit or NNT.
Pain model
For 600 mg to 650 mg paracetamol plus 60 mg codeine in
dental studies only, the relative benefit of treatment compared
with placebo was 2.7 (2.2 to 3.4), and the NNT for at least 50%
pain relief over four to six hours was 3.9 (3.3 to 4.8). For other
surgical trials only, the relative benefit of treatment compared
with placebo was 2.4 (1.5 to 3.7), and the NNT for at least 50%
pain relief over four to six hours was 3.7 (2.5 to 7.2).
For 300 mg paracetamol plus 30 mg codeine in dental trials
only, the relative benefit of treatment compared with placebo was
3.3 (1.8 to 6.2), and the NNT for at least 50% pain relief overfour to six hours was 5.4 (3.7 to 9.7). For other surgical trials
only, the relative benefit of treatment compared with placebo was
1.5 (1.1 to 2.1), and the NNT for at least 50% pain relief over
four to six hours was 7.9 (4.6 to 27).
There were insufficient data to analyse the 1000 mg paracetamol
plus 60 mg codeine dose separately. For both comparisons, the
95% CIs were overlapping, indicating no statistically significant
differences between studies in dental and other surgery for this
outcome.
Sensitivity analysis - effect of pain model: paracetamol plus codeine versus placebo
Study characteris-
tics
Studies Participants Paracetamol + codeine
(%)
Placebo (%) NNT (95%CI)50% PR
600-650/60 mg
dental
14 1221 43 17 3.9 (3.3 to 4.8)
600-650/60 mg
other surgical
3 192 46 20 3.7 (2.5 to 7.2)
300/60 mg dental 3 299 27 9 5.4 (3.7 to 9.7)
300/60 mg other
surgical
3 391 37 24 7.9 (4.6 to 27)
Study size
Five studies, with 629 participants, had more than 40
patients in both the paracetamol plus codeine and placebo arms.
The NNT for at least 50% pain relief over 4 to 6 hours was 6.7
(4.6 to 12). Four of these five studies used 300 mg paracetamol
plus 30 mg codeine.
Ten studies with 572 participants had fewer than 40
patients in both the paracetamol with codeine and placebo arms.
The NNT for at least 50% pain relief over four to six hours was3.0 (2.4 to 3.8). All of these studies used 600 mg paracetamol
plus 60 mg codeine or more.
There was no overlap in the 95% CIs for the larger and smaller
studies, indicating a statistically significant difference between
these two groups of studies. However, the comparison is con-
founded by dose, since for the larger group size, four of these five
studies used 300 mg paracetamol plus 30 mg codeine in contrast
to the smaller group size, where all of the studies used a dose of
600 mg paracetamol plus 60 mg codeine or more.
Paracetamol with codeine versus paracetamol
Study quality
All trials scored three or more on the Oxford pain score, hence a
sensitivity analysis was not possible.
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Pain model
The primary outcome of at least 50% pain relief was compared in
dental versus other surgical pain models. There were insufficient
data to compare the results of different pain models separately for
each dose.
Study size
Three studies, with 259 participants, had more than 40
patients in both the paracetamol with codeine and paracetamol
alone arms. All three studies used 800 mg to 1000 mg
paracetamol plus 60 mg codeine versus 1000 mg paracetamol.
The NNT for at least 50% pain relief over four to six hours was
7.1 (4.1 to 150).
Ten studies, with 588 participants, had fewer than 40
patients in both the paracetamol with codeine and paracetamol
only arms. Nine of these studies used 600 mg to 650 mg
paracetamol plus 60 mg codeine versus the same dose ofparacetamol, and one used 1000 mg paracetamol plus 60 mg
codeine versus the same dose of paracetamol. The NNT for at
least 50% pain relief over four to six hours was 6.4 (4.3 to 13).
No significant effect of size on the primary outcome was demon-
strated using 40 participants per treatment arm as the threshold.
Sensitivity analysis - effect of study size: paracetamol plus codeine versus the same dose of paracetamol alone
Study characteris-
tics
Studies Participants Paracetamol + codeine
(%)
Paracetamol alone (%) NNT (95%CI) 50% PR
40 participants in
active and compara-
tor groups
3 259 56 43 7.1 (4.1 to 150)
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Figure 6. Forest plot of comparison: 5 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo,
outcome: 3.4 Participants using rescue medication over 4 to 6 hours.
Figure 7. Forest plot of comparison: 7 Paracetamol 300 mg plus codeine 30 mg versus placebo, outcome:
5.4 Participants using rescue medication over 4 to 6 hours.
Five peoplewould need to betreated with 600 to 650 mgparaceta-
mol plus 60 mg codeine to prevent one needing rescue medication
over four to six hours, who would have needed it with placebo.
Paracetamol with codeine versus paracetamol
Nine studies, with 563 participants, reported the proportion tak-
ing rescue medication over four to six hours ( Table 1). For 600
mg to 650 mg paracetamol plus 60 mg codeine, seven studieswith 436 participants reported this outcome. The weighted mean
proportion was 50% (108/216) in the combination group versus
65% (142/220) in the paracetamol alone group, giving a NNTp
of 6.9 (4.2 to 19) (Figure 8; Summary of results C). There was
insufficient data to analyse the 1000 mg paracetamol plus 60 mg
codeine dose separately.
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Figure 8. Forest plot of comparison: 6 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol
600 to 650 mg, outcome: 4.4 Participants using rescue medication over 4 to 6 hours.
Adding 60 mg codeine to 600 mg to 650 mg paracetamol reduced
the number of participants requiring rescue medication over four
to six hours by 15%. Seven people would need to be treated with
the combination to prevent one requiring rescue medication overfour to six hours, who would have needed it with 600 mg to 650
mg paracetamol alone.
Summary of results C: number of participants using rescue medication in 4 to 6 hours
Dose Studies Participants Paracetamol + codeine
(%)
Placebo (%) NNTp
600-650/60 mg 10 657 62 80 5.6 (4.0 to 9.0)
300/30 mg 4 529 48 57 not calculated
Studies Participants Paracetamol + codeine
(%)
Paracetamol (%) NNTp
600-650/60 mg 7 436 50 65 6.9 (4.2 to 19)
Time to use of rescue medication
Paracetamol with codeine versus placebo
Eighteen studies reported time to use of rescue medication (all of
those reporting the number remedicating) (Table 1). Eight studies
reported the median time, eight studies the mean time, and two
studies reported both median and mean times to use of rescue
medication. Therewere insufficient datato analyse eitherthe mean
or median time to use of rescue medication by dose.
The range of values for median time was 2.3 to 6.5 hours for
combination treatment and 1.0 to 3.2 hours for placebo, and for
mean time was 3.1 to 7.0 hours for combination treatment and
2.2 to 3.5 hours for placebo. The weighted mean of the median
time to use of rescue medication was 4.3 hours for paracetamolplus codeine (all doses) versus 2.0 hours for placebo. The weighted
mean of the mean time to use of rescue medication was 4.1 hours
for paracetamol (all doses) versus 2.4 hours for placebo (Summary
of results D).
Half of the participants required rescue medication by 4.3 hours
when treated with paracetamol plus codeine, compared to 2.0
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hours when treated with placebo.
Paracetamol with codeine versus paracetamol
Eight studies reported time to use of rescue medication, five of
which reported the median, and three the mean time (Table 1).
There were insufficient data to analyse either the mean or median
time to use of rescue medication by dose.
The range of values for median time was 4.1 to more than eight
hours for combination treatment and 2.8 to 8.0 hours for parac-
etamol alone, and the range for mean time was 3.1 to 3.8 hours
for combination treatment and 3.2 to 3.6 hours for paracetamol
alone. The weighted mean of the median time to remedication
was 5.4 hours for paracetamol plus codeine (all doses) versus 4.1
hours for paracetamol alone. The weighted mean of the mean time
to remedication was 3.5 hours for paracetamol plus codeine (all
doses) versus 3.4 hours for paracetamol alone (Summary of resultsD).
Half of the participants required rescue medication by 5.4 hours
when treated with paracetamol plus codeine, compared to 4.1
hours when treated with the same dose of paracetamol alone.
Summary of results D - weighted mean time to use of rescue medication
Weighted mean Paracetamol + codeine Placebo
Median (hr) 4.3 2.0
Mean (hr) 4.1 2.4
Paracetamol + codeine Paracetamol
Median (hr) 5.4 4.1
Mean (hr) 3.5 3.4
Adverse events
Thetime over which adverse eventswere collected variedfrom four
hours to seven days. It was unclear in some reports whether the
adverse event reports covered the duration of the trial, or whether
they included any adverse events occurring between the end of the
trial and a follow-up visit some days later. Few studies reported
whether adverse event data continued to be collected after rescue
medication had been taken. Reported adverse events were mainly
mild and transient, and there were no serious adverse events re-
ported.
Paracetamol with codeine versus placebo
Twenty studies reported numbers of participants with one or more
adverse events (Table 2). For all doses together, the NNH for any
adverse event for paracetamol plus codeine compared to placebo
was 8.9 (6.6 to 14) (Figure 9), and for 600 mg to 650 mg parac-
etamol plus 60 mg codeine compared to placebo the NNH was
6.0 (4.6 to 8.3) (Figure 10). For the higher and lower doses the
relative risk was not significant.
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Figure 9. Forest plot of comparison: 8 Paracetamol plus codeine (all doses) versus placebo, outcome: 8.1
Participants with at least one adverse event.
Figure 10. Forest plot of comparison: 5 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo,
outcome: 3.5 Participants with any adverse event.
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Paracetamol with codeine versus paracetamol
Eleven studies reported numbers of participants with one or more
adverse events (Table 2). There were no significant differences in
relative risk and NNH for any adverse event between paracetamol
plus codeine and paracetamol alone at any dose, or for all dosescombined (Figure 11).
Figure 11. Forest plot of comparison: 9 Paracetamol plus codeine (all doses) versus paracetamol alone,
outcome: 9.1 Participants with any adverse event.
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thisdegreeofvariationiscommoninpainstudies(McQuay 1996),
and occurs because of the random play of chance (Moore 1998b).
Paracetamol plus codeine was significantly better than placebo,
with a clear dose response for the primary outcome of at least 50%
pain relief over four to six hours. At doses of 300 mg paraceta-
mol plus 30 mg codeine about 30% of participants achieved thislevel of pain relief, rising to about 40% with 600 mg to 650 mg
paracetamol plus 60 mg codeine, and 50% with 800 to 1000 mg
paracetamol plus 60 mg codeine. Corresponding NNTs were 6.9
(4.8 to 12), 3.9 (3.3 to 4.7) and 2.2 (1.8 to 2.9). These results
are consistent with those found in the earlier review, but should
be more robust because of the increased number of participants.
Seven people would need to be treated with 600 mg paracetamol
plus 60 mg codeine, and two with 1000 mg paracetamol plus 60
mg codeine, for one more to experience at least 50% pain relief,
who would not have done so with placebo.
Because thesame methods of analyses have been used, it is possible
to compare the NNT for a single dose of oral paracetamol plus
codeine with that of a single dose of other analgesics.
Analgesics with comparable efficacy to 1000 mg
paracetamol plus 60 mg codeine include celecoxib 400 mg
(NNT 2.5 (2.2 to 2.9)) (Derry 2008), diclofenac 100 mg (NNT
1.8 (1.5 to 2.1)) (Collins 1999), and ibuprofen 400 mg (NNT
2.7 (2.5 to 3.0)) (Collins 1999).
Paracetamol combination analgesics with comparable
efficacy to 1000 mg paracetamol plus 60 mg codeine include 650
mg paracetamol plus 10 mg oxycodone (NNT 2.6 (2.0 to 3.5)),
and 650 mg paracetamol plus 75 mg tramadol (NNT 2.6 (2.3 to
3.0)).
Analgesics with comparable efficacy to 600 mg to 650 mg
paracetamol plus 60 mg codeine include celecoxib 200 mg
(NNT 4.2 (3.4 to 5.6)) (Derry 2008), paracetamol 1000 mg
(NNT 3.6 (3.2 to 4.1)) (Toms 2008), and aspirin 600 mg to 650
mg (NNT 4.4 (4.0 to 4.9) (Oldman 1999).
Paracetamol combination analgesics with comparable
efficacy to 600 mg to 650 mg paracetamol plus 60 mg codeine
include 650 mg paracetamol plus 65 mg dextropropoxyphene
HCl (NNT 4.4 (3.5 to 5.6)).
Analgesics with lower efficacy in single dose studies include
codeine 60 mg alone (NNT 17 (11 to 48)) and tramadol 50 mg
(NNT 8.3 (6.0 to 13)). Analgesics with superior efficacy include etoricoxib 180/
240 mg (NNT 1.5 (1.3 to 1.7) and etoricoxib 120 mg (NNT
1.9 (1.7 to 2.1)) (Clarke in press).
A current listing of reviews of analgesics in the single dose post-
operative pain model can be found at www.medicine.ox.ac.uk/
bandolier.
The comparison of combination therapy with the same dose of
paracetamol alone demonstrated that the addition of codeine in-
creased the number of participants with at least 50% pain relief by
over 10%. No statistically significant difference was demonstrated
between 800 mg to 1000 mg paracetamol plus 60 mg codeine and
600 mg to 650 mg paracetamol plus 60 mg codeine, although thehigher dose did give a lower (better) NNT of 6.1 (3.6 to 19) com-
pared to 8.2 (5.0 to 23). Six people would need to be treated with
1000 mg paracetamol plus 60 mg codeine for one more to expe-
rience at least 50% pain relief, who would not have done so with
the same dose of paracetamol alone. One of the four studies con-
tributing to the higher dose analysis compared 800 mg paraceta-
mol plus 60 mg codeine with 1000 mg paracetamol alone, rather
than 800 mg (exactly the same dose). Omitting this study from
the analysis gave a lower (better) NNT of 5.1 (3.1 to 15), but did
not significantly change the result. The higherdose of paracetamol
in the comparator arm would be expected, if anything, to reduce
the estimate of efficacy for the combination therapy arm.
We have effective analgesics, but clinical practice finds it difficult
to use effective analgesics effectively. More immediately relevant
outcomes are needed than relative benefit and even NNTs. One
such outcome is the time before participants with adequate pain
relief require additional analgesic because the pain has returned.
This can be measured in terms of the mean or median time to
remedication, or the percentage of participants needing moreanal-
gesic over a particular time. This update includes both these out-
comes. The previous review did not report data on participants
using rescue medication, and not all studies (17/28) provided this
information, which restricted analysis, particularly by dose.
The median time to use of rescue medication varied greatly be-
tween trials, particularly for the active treatment arms, but wasgenerally longer for paracetamol plus codeine than for placebo or
paracetamol alone. The weighted mean of the median time to use
of rescue medication (all doses of paracetamol plus codeine) at 4.3
hours is equal to or shorter than most non-selective NSAIDs (di-
clofenac 50 mg 3.8 hours, ibuprofen 400 mg 5.3 hours, naproxen
9.8 hours) and much shorter than etoricoxib 120 mg and rofe-
coxib 50 mg (20 hours or more). The addition ofcodeine toparac-
etamol extended the duration of action by about one hour. There
were insufficient data to analyse this by dose, as not all studies
reporting number of patients remedicating also reported this out-
come. Most of the data was for the 600 mg to 650 mg paraceta-
mol plus 60 mg codeine dose, for which about 60% of partici-
pants receiving the combination therapy used rescue medication
over four to six hours, compared to about 80% of those receiving
placebo. Five participants would need to be treated with this dose
of the combination to prevent one using rescue medication over
four to six hours, who would have done so if treated with placebo.
The addition of 60 mg codeine to 600 mg to 650 mg paracetamol
decreased the number of participants using rescue medication by
about 15%; seven people would need to be treated with 600 mg
20Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults (Review)
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to 650 mg paracetamol plus 60 mg codeine for one fewer to need
rescue medication over four to six hours, who would have done so
if treated with the same dose of paracetamol alone.
Longer duration of action is desirable in an analgesic, particularly
in a postoperative setting where the patient may experience post-
operative nausea, or be dependent on a third party to respond to arequest for rescue medication. Duration of pain relief and require-
ment of rescue medication information have only recently been
recognisedas importantoutcomes (Moore 2005),and a fuller eval-
uation of the importance of these outcomes will depend on more
data being collected from other, ongoing, systematic reviews.
Assessment of adverse events is limited in single dose studies as
the size and duration of the trials permits only the simplest analy-
sis, as has been emphasised previously (Edwards 1999). Combin-
ing results was potentially hampered by the different periods over
which the data was collected. There was also an uncertainty about
whether adverse event data continued to be collected after rescue
medication had been taken. This could disproportionately inflateadverse events in the placebo groups, which tended to use more
rescue medication. Most adverse events were reported as mild to
moderate in intensity, and were most likely to be related to the
anaesthetic or surgical procedure (e.g. nausea, vomiting and som-
nolence). Although the original review compared individual ad-
verse events, we deemed there to be insufficient data in for this
analysis to be valid.
There was a significant difference between paracetamol plus
codeine and placebo for numbers of participants experiencing any
adverse event in the hours immediately following a single dose
of the study medication for all doses together and for 600 mg to
650 mg paracetamol plus 60 mg codeine. Analyses for higher and
lower doses did not show a significant difference, but numbers ofparticipants in these groups were small. There was no significant
difference between paracetamol plus codeine and the same dose
of paracetamol alone.
No serious adverse events or withdrawals due to adverse events
were reported. It is important to recognise that adverse event anal-
ysis after single dose oral administration will not reflect possible
adverse events occurring with use of drugs for longer periods of
time. In addition, the relatively small numbers of participants,
even when allthe trialswere combined,and short duration of stud-
ies is insufficient to detect rare but serious adverse events, which
typically occur with longer use, and usually less frequently than
one in 1000.
All studies were of adequate or good methodological quality. The
sensitivity analyses did not demonstrate an effect of dental model
onNNT for50% pain reliefin thecomparison of paracetamol plus
codeine andplacebo, where there were sufficient data to analyse by
dose. For the comparison of combination therapy with placebo,
studies with fewer than 40 participants in each treatment arm
had a higher active response rate and lower (better) NNT than
those with more than 40 per treatment arm, but this comparison
was confounded by dose, with the smaller treatment arms using
600 mg paracetamol plus 60 mg codeine (nine studies) or 1000
mg paracetamol plus 60 mg codeine (one study), and the larger
treatment arms using 300 mg paracetamol plus 30 mg codeine
(four studies) or 600 mg paracetamol plus 60 mg codeine (onestudy). The comparison of combination therapy with paracetamol
alone was also confounded by dose, but did not demonstrate a
difference between smaller and larger studies.
The main limitation is that these were single-dose studies, and they
could be criticised because pain relief, even in the acute setting,
usually requires multiple dosing. That is true, but, in very general
terms, pain is pain, and these single dose studies have been used for
over 60 years to establish that a drug is actually an analgesic. The
relative effectiveness of drugsand otherinterventions in this setting
translates well to other settings like migraine, or musculoskeletal
pain. It is unfortunate that so little data were available for the
1000 mg paracetamol plus 60 mg codeine dose. This is the most
commonly used dose in clinical practice insome parts of theworld,including the UK, but is under-represented in these studies. The
information that is available indicates that this dose is superior to
the lower doses.
A U T H O R S C O N C L U S I O N SImplications for practice
The data found in this update for Issue 1, 2009 further supports
previous findings although more research is still required. The
combination of paracetamol and codeine is an effective analgesic
in postoperative pain with a low incidence of adverse events. At
a dose of 1000 mg paracetamol plus 60 mg codeine it provideseffective analgesia for over half of patients with moderate to severe
postoperative pain following various types of surgery. The addi-
tion of codeine increases the proportion of patients with effective
pain relief by over 10%, but increases the number of patients ex-
periencing adverse events. Associated adverse events were of mild
or moderate intensity, and did not lead to withdrawal.
Implications for research
Additional data for the higher dose is needed to confirm the dose
response demonstrated in this review, and provide a more robust
estimate of efficacy. More consistent data on use of rescue medica-
tion would provide betterestimates of duration of analgesia, which
in turn may help to decide which analgesics are most effective inthe clinical setting. While more recent studies were generally of
good quality, and efficacy data, where collected, was well reported,
the quality of adverse event reporting remains problematical.
A C K N O W L E D G E M E N T S
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Sally Collins, Dawn Carroll and Jayne Rees were authors on the
original review; Martin Tramr, Marie Bisercic and Anna Old-
man translated reports, and Clare Abbott helped with obtaining
a mountain of papers. Sources of support for the original review
were: Anglia and Oxford RHA, UK, NHS Research and Develop-
ment Health Technology Evaluation Programmes, UK, and Eu-ropean Union Biomed 2 Grant no. BMH4 CT95 0172, UK.
R E F E R E N C E S
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