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/


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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


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


at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . . . . . . 51


at least 50% pain relief over 4 to 6 hours, dental. . . . . . . . . . . . . . . . . . . . . . . 52


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


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


Participants with at least 50% pain relief over 4 to 6 hours, dental. . . . . . . . . . . . . . . . 57


Participants with at least 50% pain relief over 4 to 6 hours, other surgery. . . . . . . . . . . . . . 58

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Participants using rescue medication over 4 to 6 hours. . . . . . . . . . . . . . . . . . . . 59


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


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.


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.

1Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults (Review)

mailto:[email protected]:[email protected]


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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 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 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


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).


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


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.


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


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).


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


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).


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).


outcome: 3.1 Participants with at least 50% pain relief over 4 to 6 hours.




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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).


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.


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).


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).


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



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


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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600 to 650 mg, outcome: 4.1 Participants with at least 50% pain relief over 4 to 6 hours.


pain relief over four to six hours with 600 mg to 650 mg



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).


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


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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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.


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


(%)

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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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.


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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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


(%)

Paracetamol (%) NNTp

600-650/60 mg 7 436 50 65 6.9 (4.2 to 19)

Time to use of rescue medication


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.


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.


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.


outcome: 3.5 Participants with any adverse event.




21/91


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.




22/91


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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


http://www.medicine.ox.ac.uk/bandolierhttp://www.medicine.ox.ac.uk/bandolierhttp://www.medicine.ox.ac.uk/bandolierhttp://www.medicine.ox.ac.uk/bandolier


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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




25/91

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

References to studies included in this review

Bentley 1987 {published data only}

Bentley KC, Head TW. The additive analgesic efficacy of

acetaminophen, 1000 mg, and codeine, 60 mg, in dental

pain. Clinical Pharmacology and Therapeutics1987;42(6):

63440.

Bjune 1996 {published data only}

Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additiveanalgesic effect of codeine and paracetamol can be detected

in strong, but not moderate, pain after Caesarean section.

Baseline pain-intensity is a determinant of assay-sensitivity

in a postoperative analgesic trial. Acta Anaesthesiologica

Scandinavica1996;40(4):399407.

Bourne 2005 {published data only}

Bourne MH, Rosenthal NR, Xiang J, Jordan D, Kamin

M. Tramadol/acetaminophen tablets in the treatment of

postsurgical orthopedic pain. The American Journal of

Orthopedics2005;24(12):5927.

Breivik 1999 {published data only}

Breivik EK, Barkvoll P, Skovlund E. Combining diclofenac

with acetaminophen or acetaminophen-codeine after oral

surgery: A randomized, double-blind single-dose study.

Clinical Pharmacology and Therapeutics1999;66(6):62535.

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, randomized,

placebo- and active comparator-controlled clinical trial.

Clinical Therapeutics2001;23(9):144655.

Chang 2005 {published data only}

Chang DJ, Bird SR, Bohidar NR, King T. Analgesic efficacy

of rofecoxib compared with codeine/acetaminophen using

a model of acute dental pain. Oral Surgery Oral Medicine

Oral Pathology Oral Radiology and Endodontology2005;100

(4):e7480. [DOI: 10.1016/j.tripleo.2005.04.026]Cooper 1981 {published data only}

Cooper SA, Breen JF, Giuliani RL. The relative efficacy of

indoprofen compared with opioid analgesic combinations.

Journal of Oral Surgery1981;39(1):215.

Cooper 1988 {published data only}

Cooper SA, Firestein A, Cohn P. Double blind comparison

of meclofenamate sodium with acetaminophen,

acetaminophen with codeine and placebo for relief of

postsurgical dental pain. The Journal of Clinical Dentistry

1988;1(2):314.

Cooper 1991 {published data only}

Cooper SA, Kupperman A. The analgesic efficacy of

flurbiprofen compared to acetaminophen with codeine. The

Journal of Clinical Dentistry1991;2(3):704.

Desjardins 1986 {published data only}

Desjardins PJ, Cooper SA, Finizio T. Efficacy of low dosecombination analgesics: acetaminophen/codeine, aspirin/

butalbital/caffeine/codeine, and placebo in oral surgery

pain. Anesthesia Progress1986;33(3):1436.

Dionne 1994 {published data only}

Dionne RA, Snyder J, Hargreaves KM. Analgesic efficacy

of flurbiprofen in comparison with acetaminophen,

acetaminophen plus codeine, and placebo after impacted

third molar removal. Journal of Oral Maxillofacial Surgery

1994;52(9):91924.

Forbes 1982 {published data only}

Forbes JA, Beaver WT, White EH, White RW, Neilson GB,

Shackleford RW. Diflunisal. A new oral analgesic with

an unusually long duration of action. The Journal of the

American Medical Association1982;248(17):213942.


Forbes JA, Kolodny AL, Beaver WT, Shackleford RW,

Scarlett VR. A 12 hour evaluation of the analgesic

efficacy of diflunisal, acetaminophen, and acetaminophen

codeine combination, and placebo in postoperative pain.

Pharmacotherapy1983;3(2 Pt 2):47S54S.


Forbes JA, Jones KF, Smith WK, Gongloff CM.

Analgesic effect of an aspirin codeine butalbital caffeine

combination and an acetaminophen codeine combination

in postoperative oral surgery pain. Pharmacotherapy1986;6

(5):2407.

Forbes 1989 {published data only}Forbes JA, Butterworth GA, Burchfield WH, Yorio

CC, Selinger LR, Rosenmertz SK, et al.Evaluation of

flurbiprofen, acetaminophen, an acetaminophen-codeine

combination, and placebo in postoperative oral surgery

pain. Pharmacotherapy1989;9(5):32230.

Forbes 1990a{published data only}

Forbes JA, Butterworth GA, Burchfield WH, Beaver WT.

Evaluation of ketorolac, aspirin, and an acetaminophen-




26/91

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Pharmacotherapy1990;10(6 Pt 2):77S93S.

Forbes 1990b {published data only}

Forbes JA, Kehm CJ, Grodin CD, Beaver WT. Evaluation

of ketorolac, ibuprofen, acetaminophen, and an

acetaminophen codeine combination in postoperative oral

surgery pain. Pharmacotherapy1990;10(6 Pt 2):94S105S.


Forbes JA, Bates JA, Edquist IA, Burchfield WH, Smith

FG, Schwartz MK, et al.Evaluation of two opioid-

acetaminophen combinations and placebo in postoperative

oral surgery pain. Pharmacotherapy1994;14(2):13946.

Gertzbein 1986 {published data only}

Gertzbein SD, Tile M, McMurty RY, Kellam JF, Hunter

GA, Keith RG, et al.Analysis of the analgesic efficacy

of acetaminophen 1000 mg, codeine phosphate 60 mg,

and the combination of acetaminophen 1000 mg and

codeine phosphate 60 mg in the relief of postoperative pain.

Pharmacotherapy1986;6(3):1047.

Heidrich 1985 {published data only}Heidrich G, Slavic Svircev V, Kaiko RF. Efficacy and quality

of ibuprofen and acetaminophen plus codeine analgesia.

Pain1985;22(4):38597.

Honig 1984 {published data only}

Honig S, Murray KA. An appraisal of codeine as an

analgesic: single dose analysis. The Journal of Clinical

Pharmacology1984;24(2-3):96102.

Malmstrom 2004 {published data only}

Malmstrom K, Kotey P, Coughlin H, Desjardins PJ. A

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Pande 1996c {published data only}

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