Types of Outcome Measures

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 in The 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.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA 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. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo, Outcome 2 Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg, Outcome 1 Participants with at least 50% pain relief over 4 to 6 hours. . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.5. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 5 Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . .
1 1 2 2 4 4 6 8 8 9 10 11 14 14 15 17 17 18 19 21 21 22 26 43 46 47 48 49 50 51 52 53 54 55 56 57 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. . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 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. . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.5. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 5 Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . 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. . . . . . Analysis 7.1. Comparison 7 Sensitivity analysis (paracetamol with codeine versus paracetamol), Outcome 1 Fewer than 40 patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours. . . . . . 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. . . . . . Analysis 8.1. Comparison 8 Paracetamol plus codeine (all doses) versus placebo, Outcome 1 Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 9.1. Comparison 9 Paracetamol plus codeine (all doses) versus paracetamol alone, Outcome 1 Participants with any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59 60 61 62 63 64 65 66 67 68 69 70 71 71 83 86 86 87 87 87 87 88
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[Intervention Review]
Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults
Laurence Toms2 , Sheena Derry1 , R Andrew Moore1 , Henry J McQuay1
1 Pain
Research and Nufeld Department of Clinical Neurosciences (Nufeld Division of Anaesthetics), University of Oxford, Oxford, UK. 2 Pain Research and Nufeld Department of Anaesthetics, University of Oxford, Oxford, UK Contact address: Sheena Derry, Pain Research and Nufeld Department of Clinical Neurosciences (Nufeld Division of Anaesthetics), University of Oxford, Churchill Hospital, Oxford, Oxfordshire, OX3 7LJ, UK. sheena.derry@pru.ox.ac.uk.
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 Reviews 2009, Issue 1. Art. No.: CD001547. DOI: 10.1002/14651858.CD001547.pub2. Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT 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 efcacy 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 additional adverse events. New studies have been published since. This review sought to evaluate efcacy and safety of paracetamol plus codeine using current data, and compare ndings with other analgesics evaluated similarly. Objectives Assess efcacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efcacy 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 paracetamol 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-benet (NNT) was calculated using 95% condence intervals (CIs). Proportion of participants using rescue analgesia over a specied time period, and time to use of rescue analgesia, were sought as additional measures of efcacy. Information on adverse events and withdrawals were collected.
Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
Main results Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Signicant 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 to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo. Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same 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 conrms previous ndings 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.
PLAIN LANGUAGE SUMMARY 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 twentysix 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, and about 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.
BACKGROUND
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: paracetamol 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 accidentally due to an injury or as a result of surgery. Acute postoperative pain is a manifestation of inammation due to tissue injury. The management of postoperative pain and inammation is a critical component of patient care. This is one of a series of reviews whose aim is to present evidence for relative analgesic efcacy 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 efcacy 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 pain situations where the pain is expected to go away, and by providing additional analgesia, commonly called rescue analgesia, if the pain has not diminished after about an hour. This is reasonable, because not all participants given an analgesic will have signicant pain relief. Approximately 18% of participants given placebo will have signicant 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 efcacy of analgesics in acute pain have been standardised over many years. Trials have to be randomised and double blind. Typically, in the rst few hours or days after an operation, patients develop pain that is moderate to severe in 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 ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention. In some trials the last observation is carried forward, which gives an inated response for the test intervention 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 rst six hours following the intervention, with measurements supervised, although they may then go home to make their own measurements in trials of longer duration.
anti-inammatory 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 cyclooxygenase (COX). COX (now recognised to consist of two isoforms, COX-1 and COX-2) catalyses the production of prostaglandins responsible for pain and inammation. Paracetamol has previously been shown to have no signicant effects on COX-1 or COX-2 (Schwab 2003), but is now being considered as a selective COX2 inhibitor (Hinz 2008). Signicant paracetamol-induced inhibition of prostaglandin production has been demonstrated in tissues in the brain, spleen, and lung (Flower 1972; Botting 2000). A COX-3 hypothesis wherein the efcacy of paracetamol is attributed to its specic inhibition of a third cyclooxygenase isoform 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 low incidence of adverse effects, paracetamol has a recognised potential for hepatotoxicity and is thought to be responsible for approximately half of all cases of liver failure in the UK (Hawton 2001). Acute paracetamol hepatotoxicity at therapeutic doses is extremely unlikely despite reports of so-called therapeutic 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 uncertain (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 have not 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
Paracetamol (acetaminophen) was rst identied as the active 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 analgesic drugs worldwide, and is also often used in combination with other drugs. The lack of signicant anti-inammatory activity for paracetamol implies a mode of action distinct from that of non-steroidal
Paracetamol with codeine

Paracetamol, NSAIDs and opioids have different mechanisms of action and side effect proles, and combining drugs from these main classes may offer the opportunity to optimise efcacy 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 the elderly, or individuals with renal impairment. Paracetamol with codeine is an established, cheap and widely available 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 efcacy and harm, in a format which facilitates direct comparison with other analgesics.
Types of participants Studies of adult participants (15 years and older) with postoperative pain of moderate to severe intensity following day surgery or inpatient surgery were included. For studies using a visual analogue 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 included provided the pain investigated resulted from episiotomy or Caesarean section (with or without uterine cramp). Trials investigating 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.
OBJECTIVES
To assess the efcacy and adverse effects of single dose paracetamol with codeine for acute postoperative pain using methods that permit comparison with other analgesics evaluated in the same way, using wider criteria of efcacy recommended by an in-depth study at the individual patient level (Moore 2005).
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 efcacy (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.
METHODS
Criteria for considering studies for this review
Types of studies Studies were included if they were full publications of double blind trials of a single dose oral paracetamol with codeine compared with placebo or the same dose of paracetamol alone for the treatment of moderate to severe postoperative pain in adults, with at least ten participants randomly allocated to each treatment group. Multiple dose studies were included if appropriate data from the rst dose were available, and cross-over studies were included provided that data from the rst 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.
Search methods for identication 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 the original 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). See Appendix 1 for the MEDLINE search strategy, Appendix 2 for the EMBASE search strategy, and Appendix 3 for 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.
who took the study medication. Analyses were planned for different doses (where there were at least 200 participants). Sensitivity 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).
Language No language restriction was applied.

Primary outcome: Number of participants achieving at least 50% pain relief
Unpublished studies Abstracts, conference proceedings and other grey literature were not searched. Manufacturers were not contacted.
Data collection and analysis
Selection of studies Two 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 ve-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.
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 proportion of participants in each treatment group who achieved at least 50%maxTOTPAR was calculated using veried 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 treatment and placebo was then used to calculate relative benet (RR) and number-needed-to-treat to benet (NNT). Pain measures accepted for the calculation of TOTPAR or SPID were: ve-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 reporting very good or excellent on a ve-point categorical global scale with the wording poor, fair, good, very good, excellent were 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).
Data management Data were extracted by two review authors and recorded on a standard data extraction form. Data suitable for pooling were entered into RevMan 5.0.13.
Secondary outcomes:
Data analysis QUOROM guidelines were followed (Moher 1999). For efcacy 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
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 medication 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 conservative 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 efcacy (participants using rescue medication - see above) and adverse events were noted. Relative benet and risk estimates were calculated with 95% condence intervals (CI) using a xed-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 signicant difference from control was assumed when the 95% CI of the relative benet did not include the number one. Homogeneity of studies was assessed visually (LAbb 1987). The z test (Tramr 1997) was used to determine if there was a signicant difference between NNTs for different doses of active treatment, or between groups in the sensitivity analyses.
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 included studies or the Characteristics of excluded studies tables.
Paracetamol with codeine versus paracetamol
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. This review examines only trials of paracetamol plus codeine versus placebo or paracetamol plus codeine versus paracetamol. Trials of paracetamol alone versus placebo are to be found in a separate review (Toms 2008).
Fourteen studies with 926 participants met our inclusion criteria for the comparison of paracetamol plus codeine versus paracetamol (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 participants) were included in the original review and two (132 participants) are new to this update (Bjune 1996 and Breivik 1999) for Issue 1, 2009. Although Bjune 1996 did appear in the original review, the paracetamol plus codeine arm used 800 mg of paracetamol 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 paracetamol are different. We considered the dose of paracetamol in the paracetamol only arm to be sufciently similar to that in the paracetamol 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 the Characteristics of included studies or the Characteristics of excluded studies tables.
Dose Included studies
Paracetamol with codeine versus placebo
Twenty-six studies with 2295 participants met our inclusion criteria 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 than 10 (Pande 1996a; Pande 1996b) and hence
Paracetamol 1000 mg with codeine 60 mg was used in two studies (Bentley 1987; Stubhaug 1995) and Paracetamol 800 mg with codeine 60 mg was used in one study (Bjune 1996): for the purposes 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 studies (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 paracetamol 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 be classed as one group. Paracetamol 600 mg to 650 mg plus 60 mg codeine versus paracetamol 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
Study duration was four hours in four studies, six hours in ve 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
Eighteen studies enrolled patients with dental pain following extraction of at least one impacted third molar (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 Caesarean section (Bjune 1996).
Ten studies were given a quality score of ve (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; Ziccardi 2000), ve a score of three (Bentley 1987; Cooper 1991; Dionne 1994; Honig 1984; Turek 1988), and one a score of two (Heidrich 1985).
Five studies were given a quality score of ve (Breivik 1999; Forbes 1983; Forbes 1989; Forbes 1990b; Sunshine 1986), four a score of four (Bjune 1996; Cooper 1981; Cooper 1988; Forbes 1982), and ve a score of three (Bentley 1987; Cooper 1991; Dionne 1994; Gertzbein 1986; Honig 1984). Further details are in Characteristics of included studies.
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 procedures (including one study with Caesarean section). Study duration
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).
Study duration was four hours in ve studies, ve hours in one study, six hours in 15 studies, 12 hours in three studies, and 24 hours in two studies.
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 benet of treatment compared with placebo was 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.
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 benet of treatment compared with placebo was 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 benet 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 (%) (%) 53 43 7 17 NNT (95%CI) 50% PR
800-1000/60 mg 600-650/60 mg
3 17
192 1413
2.2 (1.8 to 2.9) 3.9 (3.3 to 4.7)

9
(Continued)
300/30 mg
690
32
18
6.9 (4.8 to 12)
The 800 mg to 1000 mg paracetamol plus 60 mg codeine dose was signicantly 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 signicance 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 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 benet 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 signicantly 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 benet 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 (%) (%) 59 68 53 42 48 41 NNT (95%CI) 50% PR
800-1000/60 1000/60 600-650/60
4 3 10
304 217 622
6.1 (3.6 to 19) 5.1 (3.1 to 15) 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 benet or NNT. Pain model For 600 mg to 650 mg paracetamol plus 60 mg codeine in dental studies only, the relative benet 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 benet 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 benet of treatment compared with placebo was 3.3 (1.8 to 6.2), and the NNT for at least 50% pain relief over four to six hours was 5.4 (3.7 to 9.7). For other surgical trials only, the relative benet 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 insufcient data to analyse the 1000 mg paracetamol plus 60 mg codeine dose separately. For both comparisons, the 95% CIs were overlapping, indicating no statistically signicant differences between studies in dental and other surgery for this outcome.
Sensitivity analysis - effect of pain model: paracetamol plus codeine versus placebo Study characteris- Studies tics 600-650/60 dental 600-650/60 other surgical mg 14 Participants Paracetamol + codeine Placebo (%) (%) 43 17 NNT (95%CI) 50% PR
1221
3.9 (3.3 to 4.8)
mg 3
192
46
20
3.7 (2.5 to 7.2)
300/60 mg dental
299 391
27 37
9 24
5.4 (3.7 to 9.7) 7.9 (4.6 to 27)
300/60 mg other 3 surgical
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 ve 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 was 3.0 (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 signicant difference between these two groups of studies. However, the comparison is con-
founded by dose, since for the larger group size, four of these ve 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 insufcient 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 of paracetamol, 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 signicant effect of size on the primary outcome was demonstrated 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- Studies tics 40 participants in 3 active and comparator groups <40 participants in 10 active and comprator groups Participants Paracetamol + codeine Paracetamol alone (%) (%) 56 43 NNT (95%CI) 50% PR
259
7.1 (4.1 to 150)
588
54
39
6.4 (4.3 to 13)
Use of rescue medication
Number of participants using rescue medication over 4 to 6 hours
In total 16 studies, with 1313 participants, reported the number of participants taking rescue medication over four to six hours (Table
1). For 600 mg to 650 mg paracetamol plus 60 mg codeine, 10 studies with 657 participants reported this outcome. The weighted mean proportion was 59% (198/320) in the combination group versus 80% (270/337) in the placebo group, giving a NNTp of 4.8 (3.6 to 7.2) (Figure 6). For 300 mg paracetamol with 30 mg codeine, four studies with 529 participants reported this outcome. The weighted mean proportion was 48% (143/297) in the combination group versus 57% (132/232) in the placebo group. The NNTp was not calculated (Figure 7; Summary of results C). There were insufcient data to analyse the 1000 mg paracetamol plus 60 mg codeine dose separately.
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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 people would need to be treated with 600 to 650 mg paracetamol 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 taking rescue medication over four to six hours (Table 1). For 600 mg to 650 mg paracetamol plus 60 mg codeine, seven studies with 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 insufcient 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 over four 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 (%) (%) 62 48 80 57 NNTp
600-650/60 mg 300/30 mg
10 4 Studies
657 529 Participants
5.6 (4.0 to 9.0) not calculated NNTp
Paracetamol + codeine Paracetamol (%) (%) 50 65
600-650/60 mg
436
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. There were insufcient data to analyse either the 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 paracetamol plus 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, ve of which reported the median, and three the mean time (Table 1). There were insufcient 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 paracetamol 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 results D). 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 Median (hr) Mean (hr) Paracetamol + codeine 4.3 4.1 Paracetamol + codeine Median (hr) Mean (hr) 5.4 3.5 Placebo 2.0 2.4 Paracetamol 4.1 3.4
ported. Adverse events The time over which adverse events were collected varied from 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 reParacetamol 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 paracetamol 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 signicant.
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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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Eleven studies reported numbers of participants with one or more adverse events (Table 2). There were no signicant differences in relative risk and NNH for any adverse event between paracetamol plus codeine and paracetamol alone at any dose, or for all doses combined (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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Summary of results E - participants with one or more adverse events Dose (mg) Studies Participants Paracetamol + codeine Placebo (%) (%) 31 27 35 15 19 31 18 14 NNH (95%CI) any AE
All doses 800-1000/60 mg 600-650/60 mg 300/30 mg
20 3 14 3
1811 209 1187 344
8.6 (6.4 to 13) not calculated 6.0 (4.6 to 8.3) not calculated
Paracetamol + codeine Paracetamol (%) (%) All doses 800-1000/60 mg 600-650/60 mg 11 4 7 767 324 443 27 31 23 24 29 20 not calculated not calculated not calculated
Withdrawals Table 2 Participants who took rescue medication were classied as withdrawals due to lack of efcacy, and are reported under use of rescue medication above. Data on other withdrawals were generally poorly reported, probably because these were single dose studies where withdrawals for reasons other than lack of efcacy are uncommon. Some studies reported participants who had invalid data due to inadequate baseline pain, who violated a protocol, or took rescue medication within the rst hour, as withdrawals or exclusions. Whether these should be included in the intention to treat population is arguable. Attrition due to invalid data is unlikely to affect results. No study reported any withdrawals due to adverse events.
added 459 participants treated with 600 mg paracetamol plus 60 mg codeine, and 109 treated with 300 mg paracetamol plus 30 mg codeine. This more than doubles the number of participants for the 600 plus 60 mg dose analysis, and adds 75% more to the 300 plus 30 mg analysis. No new trials compared 1000 mg paracetamol plus 60 mg codeine with placebo. For the comparison with paracetamol alone, only 74 new participants treated with 800 or 1000 mg paracetamol plus 60 mg codeine were added, but even this almost doubled the number available for analysis at this dose (Moore 1998a). The primary measure of efcacy was the proportion of patients achieving at least 50% pain relief over four to six hours. This is now generally regarded as a useful level of pain relief in acute pain, and also in chronic pain conditions such as arthritis (Moore 2008) and neuropathic pain (Straube 2008). It has the advantage that it also highlights that not all of those given an analgesic have useful pain relief, and that interventions do not work in everyone. Participants not having a useful level of pain relief are important because therapeutic failure is to be avoided. Figures and tables therefore provide percentages of patients with outcomes, as well as statistical comparisons. The variation in placebo and active response rates was large, but
DISCUSSION
Since the previous review of paracetamol with codeine in acute pain a number of new studies of good methodological quality have been published. For the comparison with placebo, new studies
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this degree of variation is common in pain studies (McQuay 1996), and occurs because of the random play of chance (Moore 1998b). Paracetamol plus codeine was signicantly 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 paracetamol plus 30 mg codeine about 30% of participants achieved this level 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 the same 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 efcacy 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 efcacy 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 efcacy 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 efcacy 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 efcacy 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 efcacy 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 postoperative 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 increased the number of participants with at least 50% pain relief by over 10%. No statistically signicant 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 the higher dose did give a lower (better) NNT of 6.1 (3.6 to 19) compared 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 experience at least 50% pain relief, who would not have done so with the same dose of paracetamol alone. One of the four studies contributing to the higher dose analysis compared 800 mg paracetamol 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 signicantly change the result. The higher dose of paracetamol in the comparator arm would be expected, if anything, to reduce the estimate of efcacy for the combination therapy arm. We have effective analgesics, but clinical practice nds it difcult to use effective analgesics effectively. More immediately relevant outcomes are needed than relative benet 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 more analgesic over a particular time. This update includes both these outcomes. 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 between trials, particularly for the active treatment arms, but was generally 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 (diclofenac 50 mg 3.8 hours, ibuprofen 400 mg 5.3 hours, naproxen 9.8 hours) and much shorter than etoricoxib 120 mg and rofecoxib 50 mg (20 hours or more). The addition of codeine to paracetamol extended the duration of action by about one hour. There were insufcient data to analyse this by dose, as not all studies reporting number of patients remedicating also reported this outcome. Most of the data was for the 600 mg to 650 mg paracetamol plus 60 mg codeine dose, for which about 60% of participants 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
20
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 postoperative nausea, or be dependent on a third party to respond to a request for rescue medication. Duration of pain relief and requirement of rescue medication information have only recently been recognised as important outcomes (Moore 2005), and a fuller evaluation 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 analysis, as has been emphasised previously (Edwards 1999). Combining 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 inate adverse 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 somnolence). Although the original review compared individual adverse events, we deemed there to be insufcient data in for this analysis to be valid. There was a signicant 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 signicant difference, but numbers of participants in these groups were small. There was no signicant 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 analysis after single dose oral administration will not reect possible adverse events occurring with use of drugs for longer periods of time. In addition, the relatively small numbers of participants, even when all the trials were combined, and short duration of studies is insufcient 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 on NNT for 50% pain relief in the comparison of paracetamol plus codeine and placebo, where there were sufcient 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 (one study). 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 drugs and other interventions 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 in some parts of the world, 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.
AUTHORS CONCLUSIONS Implications for practice

The data found in this update for Issue 1, 2009 further supports previous ndings 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 provides effective analgesia for over half of patients with moderate to severe postoperative pain following various types of surgery. The addition of codeine increases the proportion of patients with effective pain relief by over 10%, but increases the number of patients experiencing 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 conrm the dose response demonstrated in this review, and provide a more robust estimate of efcacy. More consistent data on use of rescue medication would provide better estimates of duration of analgesia, which in turn may help to decide which analgesics are most effective in the clinical setting. While more recent studies were generally of good quality, and efcacy data, where collected, was well reported, the quality of adverse event reporting remains problematical.
ACKNOWLEDGEMENTS
21
Sally Collins, Dawn Carroll and Jayne Rees were authors on the original review; Martin Tramr, Marie Bisercic and Anna Oldman 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 Development Health Technology Evaluation Programmes, UK, and European Union Biomed 2 Grant no. BMH4 CT95 0172, UK.
REFERENCES
References to studies included in this review

Bentley 1987 {published data only} Bentley KC, Head TW. The additive analgesic efcacy of acetaminophen, 1000 mg, and codeine, 60 mg, in dental pain. Clinical Pharmacology and Therapeutics 1987;42(6): 63440. Bjune 1996 {published data only} Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additive analgesic 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 Scandinavica 1996;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 Orthopedics 2005;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 Therapeutics 1999;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 Therapeutics 2001;23(9):144655. Chang 2005 {published data only} Chang DJ, Bird SR, Bohidar NR, King T. Analgesic efcacy of rofecoxib compared with codeine/acetaminophen using a model of acute dental pain. Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology 2005;100 (4):e7480. [DOI: 10.1016/j.tripleo.2005.04.026] Cooper 1981 {published data only} Cooper SA, Breen JF, Giuliani RL. The relative efcacy of indoprofen compared with opioid analgesic combinations. Journal of Oral Surgery 1981;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 efcacy of urbiprofen compared to acetaminophen with codeine. The Journal of Clinical Dentistry 1991;2(3):704. Desjardins 1986 {published data only} Desjardins PJ, Cooper SA, Finizio T. Efcacy of low dose combination analgesics: acetaminophen/codeine, aspirin/ butalbital/caffeine/codeine, and placebo in oral surgery pain. Anesthesia Progress 1986;33(3):1436. Dionne 1994 {published data only} Dionne RA, Snyder J, Hargreaves KM. Analgesic efcacy of urbiprofen 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. Diunisal. A new oral analgesic with an unusually long duration of action. The Journal of the American Medical Association 1982;248(17):213942. Forbes 1983 {published data only} Forbes JA, Kolodny AL, Beaver WT, Shackleford RW, Scarlett VR. A 12 hour evaluation of the analgesic efcacy of diunisal, acetaminophen, and acetaminophen codeine combination, and placebo in postoperative pain. Pharmacotherapy 1983;3(2 Pt 2):47S54S. Forbes 1986 {published data only} 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. Pharmacotherapy 1986;6 (5):2407. Forbes 1989 {published data only} Forbes JA, Butterworth GA, Burcheld WH, Yorio CC, Selinger LR, Rosenmertz SK, et al.Evaluation of urbiprofen, acetaminophen, an acetaminophen-codeine combination, and placebo in postoperative oral surgery pain. Pharmacotherapy 1989;9(5):32230. Forbes 1990a {published data only} Forbes JA, Butterworth GA, Burcheld WH, Beaver WT. Evaluation of ketorolac, aspirin, and an acetaminophen22
codeine combination in postoperative oral surgery pain. Pharmacotherapy 1990;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. Pharmacotherapy 1990;10(6 Pt 2):94S105S. Forbes 1994 {published data only} Forbes JA, Bates JA, Edquist IA, Burcheld WH, Smith FG, Schwartz MK, et al.Evaluation of two opioidacetaminophen combinations and placebo in postoperative oral surgery pain. Pharmacotherapy 1994;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 efcacy 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. Pharmacotherapy 1986;6(3):1047. Heidrich 1985 {published data only} Heidrich G, Slavic Svircev V, Kaiko RF. Efcacy and quality of ibuprofen and acetaminophen plus codeine analgesia. Pain 1985;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 Pharmacology 1984;24(2-3):96102. Malmstrom 2004 {published data only} Malmstrom K, Kotey P, Coughlin H, Desjardins PJ. A randomized, double-blind, parallel-group study comparing the analgesic effect of etoricoxib to placebo, naproxen sodium, and acetaminophen with codeine using the dental impaction pain model. The Clinical Journal of Pain 2004; 20(3):14755. Pande 1996c {published data only} Pande AC, Pyke RE, Greiner M, Cooper SA, Benjamin R, Pierce MW. Analgesic efcacy of the K-receptor agonist, Enadoline, in dental surgery pain. Clinical Neuropharmacology 1996;19(1):927. Smith 2004 {published data only} Smith AB, Ravikumar TS, Kamin M, Jordan D, Xiang J, Capss- Study Group, et al.Combination tramadol plus acetaminophen for postsurgical pain. American Journal of Surgery 2004;187(4):5217. Stubhaug 1995 {published data only} Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effect of 50 mg and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison. Pain 1995;62(1):1118. Sunshine 1986 {published data only} Sunshine A, Marrero I, Olson N, McCormick N, Laska EM. Comparative study of urbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain. The American Journal of Medicine 1986;80(3A):504.
Turek 1988 {published data only} Turek MD, Baird WM. Double blind parallel comparison of ketoprofen (Orudis), acetaminophen plus codeine, and placebo in postoperative pain. The Journal of Clinical Pharmacology 1988;28(12 Suppl):S238. Ziccardi 2000 {published data only} Ziccardi VB, Desjardins PJ, Daly-DeJoy E, Seng GF. Single-dose vicoprofen compared with acetaminophen with codeine and placebo in patients with acute postoperative pain after third molar extractions. Journal of Oral and Maxillofacial Surgery : ofcial journal of the American Association of Oral and Maxillofacial Surgeons 2000;58(6): 6228.
References to studies excluded from this review

Becker 1990 {published data only} Becker J, Beckmann J, Bertelt C, Gundert-Remy U, Rohmel J, Ohlendorf D. Double blind biometric study on postoperative effects of analgesics [Doppelblindstudie uber postoperative analgetikawirkungen]. Deutsche Zahnarztliche Zeitschrift 1990;45(1):368. Behotas 1992 {published data only} Behotas S, Chauvin A, Castiel J, Martin A, Boureau F, Barrat J, Lienhart A. Analgesic efcacy of ibuprofen for post-episiotomy pain [Effets antalgiques de Libuprofene dans les doulers apres episiotomie]. Annales Franaises dAnesthsie et de Ranimation 1992;11(1):226. Chung 2004 {published data only} Chung F, Tong D, Miceli PC, Reiz J, Harsanyi Z, Darke AC, Payne LW. Controlled-release codeine is equivalent to acetaminophen plus codeine for post-cholecystectomy analgesia. Canadian Journal of Anaesthesia 2004;51(3): 21621. Cooper 1984 {published data only} Cooper SA. Five studies on ibuprofen for postsurgical dental pain. The American Journal of Medicine 1984;Suppl:707. De los Santos 1998 {published data only} De los Santos AR, Mart MI, Espinosa D, Di Girolamo G, Vinacur JC, Casadei A. Lysine clonixinate vs. paracetamol/ codeine in postepisiotomy pain. Acta Physiologica, Pharmacologica et Therapeutica Latinoamericana 1998;48 (1):528. Forbes 1981 {published data only} Forbes JA, Bowser MW, Calderazzo JP, Foor VM. An evaluation of the analgesic efcacy of three opioid-analgesic combinations in postoperative oral surgery pain. Journal of Oral Surgery 1981;39:10812. Fulkerson 1986 {published data only} Fulkerson JP, Folcik MA. Analgesia following arthroscopic surgery: comparison of Diunisal and acetaminophen with codeine. Arthroscopy 1986;2(2):10810. Jacobson 1987 {published data only} Jacobson J, Bertilson SO. Analgesic efcacy of paracetamol/ codeine and paracetamol/dextropropoxyphene in pain after episiotomy and ruptures in connection with childbirth. The Journal of International Medical Research 1987;15(2):8995.
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Levin 1974 {published data only} Levin HM, Bare WW, Berry FN, Miller JM. Acetaminophen with codeine for the relief of severe pain in postpartum patients. Current Therapeutic Research 1974;16(9):9217. Maalaki 2002 {published data only} Maaliki H, Church L. Which is better for the management of postpartum perineal pain: Ibuprofen or acetaminophen with codeine?. The Journal of Family Practice 2002;51(3): 207. Macleod 2002 {published data only} Macleod AG, Ashford B, Voltz M, Williams B, Cramond T, Gorta L, et al.Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain: a randomized, double-blind, prospective trial. Australian Dental Journal 2002;47(2):14751. Matthews 1984 {published data only} Matthews RW, Scully CM, Levers BG. The efcacy of diclofenac sodium (Voltarol) with and without paracetamol in the control of post surgical dental pain. British Dental Journal 1984;157(10):3579. Ottinger 1990 {published data only} Ottinger ML, Kinney KW, Black JR, Wittenberg M. Comparison of urbiprofen and acetaminophen with codeine in postoperative foot pain. Journal of the American Podiatry Association 1990;80(5):26670. Oullette 1986 {published data only} Ouellette RD, Feinberg A, Laraja R, et al.Naproxen sodium vs acetaminophen plus codeine in postsurgical pain. Current Therapeutic Research, Clinical and Experimental 1986;39(5): 83945. Pande 1996a {published data only} Pande AC, Pyke RE, Greiner M, Cooper SA, Benjamin R, Pierce MW. Analgesic efcacy of the kappa-receptor agonist, enadoline, in dental surgery pain. Clinical Neuropharmacology 1996;19(1):927. Pande 1996b {published data only} Pande AC, Pyke RE, Greiner M, Wideman GL, Benjamin R, Pierce MW. Analgesic efcacy of enadoline versus placebo or morphine in postsurgical pain. Clinical Neuropharmacology 1996;19(5):4516. Peter 2001 {published data only} Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomized controlled trial. Canadian Medical Association Journal 2001;165(9):12039. Petti 1985 {published data only} Petti A. Postoperative pain relief with pentazocine and acetaminophen: comparison with other analgesic combinations and placebo. Clinical Therapeutics 1985;8(1): 12633. Quiding 1982a {published data only} Quiding H, Persson G, Ahlstrom U, Bangens S, Hellem S, Johansson G, et al.Paracetamol plus supplementary doses of codeine. An analgesic study of repeated doses. The Journal of Clinical Pharmacology 1982;23(4):3159.
Quiding 1983 {published data only} Quiding H, Haggquist SO. Visual analogue scale and the analysis of analgesic action. The Journal of Clinical Pharmacology 1983;24(4):4758. Quiding 1984 {published data only} Quiding H, Oikarinen V, Sane J, Sjoblad AM. Analgesic efcacy after single and repeated doses of codeine and acetaminophen. The Journal of Clinical Pharmacology 1984 Jan;24(1):2734. Raeder 2001 {published data only} Raeder JC, Steine S, Vatsgar TT. Oral ibuprofen versus paracetamol plus codeine for analgesia after ambulatory surgery. Anesthesia and Analgesia 2001;92(6):14702. Scoren 1987 {published data only} Scoren RD, Corn H, Rhodes P, Schwarz M, Segal PL, Marks MH. Pain following periodontal surgery treatment with a nonnarcotic analgesic compared with two codeine combinations. Current Therapeutic Research, Clinical and Experimental 1987;42(3):46371. Skjelbred 1977 {published data only} Skjelbred P, Album B, Lokken P. Acetylsalicylic acid vs paracetamol: effects on postoperative course. European Journal of Clinical Pharmacology 1977;12(4):25764. Sunshine 1988 {published data only} Sunshine A, Olson NZ. Analgesic efcacy of ketoprofen in postpartum, general surgery, and chronic cancer pain. The Journal of Clinical Pharmacology 1988;28:S47S54. Sveen 1975 {published data only} Sveen K, Gilhuus MoeO. Paracetamol/codeine in relieving pain following removal of impacted mandibular third molars. International Journal of Oral Surgery 1975;4(6): 25866. Torabinejad 1994 {published data only} Torabinejad M, Dorn SO, Eleazer PD, Frankson M, Jouhari B, Mullin RK, et al.Effectiveness of various medications on postoperative pain following root canal obturation. Journal of Endodontics 1994;20(9):42731. Vangen 1988 {published data only} Vangen O, Doessland S, Lindbaek E. Comparative study of ketorolac and paracetamol/codeine in alleviating pain following gynaecological surgery. The Journal of International Medical Research 1988;16(6):44351. Wittenberg 1984 {published data only} Wittenberg M, Kinney KW, Black JR. Comparison of ibuprofen and acetaminophen codeine in postoperative foot pain. Journal of the American Podiatry Association 1984;74 (5):2337.
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Flower 1972 RJ Flower, JR Vane. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4acetamidophenol). Nature 1972;240:410411. Graham 2005 Graham GG, Scott KF. Mechanism of action of paracetamol. American Journal of Therapeutics 2005;12(1):4655. Gunnell 1997 D Gunnell, K Hawton, V Garnier, C Bismuth, J Fagg. Use of paracetamol for suicide and non-fatal poisoning in the UK and France: are restrictions on availability justied? . Journal of Epidemiology and Community Health 1997;51: 1759. Hawkins 2007 Hawkins LC, Edwards JN, Dargan PI. Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature. Drug Safety 2007;30(6):46579. Hawton 2001 K Hawton, E Townsend, J Deeks, L Appleby, D Gunnell, O Bennewith, J Cooper. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. BMJ 2001;322: 17. Hinz 2008 Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J 2008;22(2):38390. Jadad 1996a Jadad AR, Carroll D, Moore A, McQuay H. Developing a database of published reports of randomised clinical trials in pain research. Pain 1996;66:23946. Jadad 1996b Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al.Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17:112. LAbb 1987 LAbb KA, Detsky AS, ORourke K. Meta-analysis in clinical research. Annals of Internal Medicine 1987;107: 22433. McQuay 1996 McQuay H, Carroll D, Moore A. Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain 1996;64(2):3315. [DOI: 10.1016/ 0304-3959(95)00116-6] McQuay 2005 McQuay HJ, Moore RA. Placebo. Postgraduate Medical Journal 2005;81:15560. Moher 1999 Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;27 (354):1896900.
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Moore 1996 Moore A, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics. Pain 1996;66(2-3):22937. Moore 1997a Moore A, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics: Verication from independent data. Pain 1997;69(1-2):12730. Moore 1997b Moore A, Moore O, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics: Use of pain intensity and visual analogue scales. Pain 1997;69(3): 3115. Moore 1998b Moore RA, Gavaghan D, Tramr MR, Collins SL, McQuay HJ. Size is everything--large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Pain 1998;78(3): 20916. [DOI: 10.1016/S0304-3959(98)00140-7] Moore 2003 Moore RA, Edwards J, Barden J, McQuay HJ. Bandoliers Little Book of Pain. Oxford: Oxford University Press, 2003. [ISBN: 0192632477] Moore 2005 Moore RA, Edwards JE, McQuay HJ. Acute pain: individual patient meta-analysis shows the impact of different ways of analysing and presenting results. Pain 2005;116(3):32231. Moore 2006 Moore A, McQuay H. Bandoliers Little Book of Making Sense of the Medical Evidence. Oxford: Oxford University Press, 2006. [ISBN: 0198566042] Moore 2008 Moore RA, Moore OA, Derry S, McQuay HJ. Numbers needed to treat calculated from responder rates give a better indication of efcacy in osteoarthritis trials than mean pain scores. Arthritis Research and Therapy 2008;10(2):R39. [DOI: 10.1186/ar2394] Morris 1995 Morris JA, Gardner MJ. Calculating condence intervals for relative risk, odds ratio and standardised ratios and rates. In: Gardner MJ, Altman DG editor(s). Statistics with condence - condence intervals and statistical guidelines. London: British Medical Journal, 1995:5063.
Oldman 1999 Oldman A, Smith LA, Collins S, Carroll D, Wiffen PJ, McQuay HJ, Rees J, Moore A. Single dose oral aspirin for acute pain. Cochrane Database of Systematic Reviews 1999, Issue 4. [DOI: 10.1002/14651858.CD002067] PIC 2008 Paracetamol Information Centre. www.pharmweb.net Accessed 3 July 2008. Prescott 2000 LF Prescott. Therapeutic misadventure with paracetamol: Fact or ction?. American Journal of Therapeutics 2000;7(2): 99114. Schwab 2003 JM Schwab, HJ Schluesener, S Laufer. COX-3: just anothet COX or the solitary elusive target of paracetamol?. The Lancet 2003;361:981982. Straube 2008 Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrolment: denition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. British Journal of Clinical Pharmacology 2008;66:26675. [DOI: 10.1111/ j.1365-2125.2008.03200.x] Toms 2008 Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD004602.pub2] Tramr 1997 Tramr MR, Reynolds DJM, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. BMJ 1997;315:63540.
References to other published versions of this review

Moore 1997 Moore A, Collins S, Carroll D, McQuay H. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain 1997;70:193201. Moore 1998a Moore A, Collins S, Carroll D, McQuay H, Edwards J. Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain. Cochrane Database of Systematic Reviews 1998, Issue 4. [DOI: 10.1002/ 14651858.CD001547] Indicates the major publication for the study
26
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Bentley 1987 Methods RCT, single oral dose, 4 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline the hourly to 4 hours Impacted third molar extraction Mean age mid 20s N = 128 Paracetamol+codeine 1000/60 mg, n = 41 Paracetamol 1000 mg, n = 41 Codeine 60 mg, n = 21 Placebo, n = 17 PI: non std 10 point scale PR: std 5 point scale Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event Oxford Quality Score: R1, DB1, W1
Participants
Interventions
Outcomes
Notes
Bjune 1996 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate (more than 40 mm on 100 mm VAS) to severe (greater than 60 mm on a std 100 mm VAS) intensity Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Caesarean section Age: 27 - 37 years N = 125 Paracetamol+codeine 800/60 mg, n = 50 Paracetamol 1000 mg, n = 50 Placebo, n = 25 PI: std 4 point scale and std 100 mm VAS (no pain to unbearable pain) PR: std 5 point scale Number of patients reporting any adverse event and serious adverse events Oxford Quality Score: R1, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
27
Bourne 2005 Methods RCT, DB single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes the hourly to 4 hours. Multiple dose phase continued after initial 4 hours Orthopaedic surgery Mean age 46 years N = 153 M = 83, F = 70 Paracetamol+codeine 300/30 mg, n = 55 Paracetamol+tramadol 325/37.5 mg, n = 49 Placebo, n = 49 PI: std 4 point scale PR: non std 6 point scale Number of patients using rescue medication Number of patients withdrawing due to adverse event Oxford Quality Score: R2, DB2, W1
Participants
Interventions
Outcomes
Notes
Breivik 1999 Methods RCT, DB single oral dose, dummy, 5 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline the every 30 minutes to 8 hours Impacted third molar extraction Mean age 25 years N = 120 M = 44, F = 76 Paracetamol+codeine 1000/60 mg, n = 24 Paracetamol 1000 mg, n = 22 Diclofenac 100 mg, n = 22 Paracetamol+diclofenac 1000/100 mg, n = 24 Paracetamol+diclofenac+codeine 1000/100/60 mg, n = 24 PI: std 100 mm VAS PR: std 5 point scale PGE: non std 4 point scale Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R2, DB2, W1
Participants
Interventions
Outcomes
Notes
28
Chang 2001 Methods RCT, DB single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Impacted third molar extraction Mean age 21 years N = 292 M = 122, F = 371 Paracetamol+codeine 600/60 mg, n = 180 Rofecoxib 50mg, n = 182 Placebo, n = 31 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R1, DB2, W1
Participants
Interventions
Outcomes
Notes
Chang 2005 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at: 0, 0.5, 1, 2, 3, 4, 5, 6, 24 hours Impacted third molar extraction Mean age 19 years N = 390 Paracetamol+codeine 600/60 mg, n = 180 Rofecoxib 50 mg, n = 180 Placebo, n = 30 PI: std 4 point scale PR: std 5 point scale PGE: std 5 pt scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R1, DB2, W1 Patients asked to refrain from rescue medication for 1.5 hours
Participants
Interventions
Outcomes
Notes
29
Cooper 1981 Methods RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 4 hours Impacted third molar extraction Mean age early 20s N = 248 Paracetamol 650 mg, n = 37 Paracetamol+codeine 650/60 mg, n = 42 Paracetamol+d-propoxyphene 650/100 mg, n = 42 Ibuprofen 200 mg, n = 42 Placebo, n = 37 PI: std 4 point scale PR: std 5 point scale PGE: std 5 pt scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R1, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Cooper 1988 Methods RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 4 hours Impacted third molar extraction Age 18-57 years N =165 Paracetamol 600 mg, n = 36 Paracetamol+codeine 600/60 mg, n = 31 Placebo, n = 40 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Number of patients using rescue medication Number of patients withdrawing due to adverse event Oxford Quality Score R1, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
30
Cooper 1991 Methods RCT, DB, single oral dose, 6 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Impacted tooth removal Age young adults n=247 Paracetamol 650 mg, n = 37 Paracetamol+codeine 650/60 mg, n = 39 Zomepirac 100 mg, n = 23 Flurbiprofen 50 mg, n = 42 Flurbiprofen 100 mg, n = 41 Placebo, n = 44 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R1, DB1, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Desjardins 1986 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes, then hourly to 6 hours Oral Surgery Age 18+ years N = 137 Paracetamol+codeine 300/30 mg, n = 39 Aspirin+butalbital+caffeine+codeine 325/50/40/30 mg, n = 43 Placebo, n = 41 PI: std 4 point scale PR: std 5 point scale Time to use of rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R1, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
31
Dionne 1994 Methods RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain reached moderate to severe intensity Pain assessed at baseline then hourly to 6 hours Impacted third molar removal Age 16+ years N = 135 Paracetamol 500 mg, n = 72 Piroxicam 20 mg, n = 76 Piroxicam cyclodextrin =20 mg, n = 74 Placebo, n = 76 PI: std 4 point scale PR: std 5 point scale Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R1, DB1, W1
Participants
Interventions
Outcomes
Notes
Forbes 1982 Methods RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 12 hours Impacted third molar removal Age 15+ years N = 177 Paracetamol 600 mg, n = 34 Paracetamol+codeine 600/60 mg, n = 31 Diusinal 500 mg, n = 32 Diusinal 1000 mg, n = 32 Placebo, n = 30 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R1, DB2, W1 Patients asked to refrain from rescue medication for 2 hours
Participants
Interventions
Outcomes
Notes
32
Forbes 1983 Methods RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 ,90, 120 mins then hourly to 12 hours General, gynaecological or orthopaedic surgery Age 19+ years N = 132 Paracetamol+codeine 600/60 mg, n = 26 Paracetamol 600 mg, n = 26 Diusinal 500 mg, n = 26 Diusinal 1000 mg, n = 28 Placebo, n = 26 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R2, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Forbes 1986 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline the hourly to 6 hours Removal of impacted 3rd molar Age 15+ years N = 146 Paracetamol+codeine 300/30 mg, n = 43 Aspirin+butalbital+caffeine+codeine 325/50/40/15 mg, n = 41 Placebo, n = 38 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R2, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
33
Forbes 1989 Methods RCT, DB, single oral dose, 4 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 12 hours Impacted third molar removal Age 15+ years N = 107 Paracetamol 600 mg, n = 22 Paracetamol+codeine 600/60 mg, n = 17 Flurbiprofen 100 mg, n = 26 Placebo, n = 23 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R2, DB2, W1 Patients asked to refrain from rescue medication for 2 hours
Participants
Interventions
Outcomes
Notes
Forbes 1990a Methods RCT, DB, single oral dose, 6 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 6 hours Removal of impacted 3rd molar (1 or more) Age 15+ years N = 162 Paracetamol+codeine 600/60 mg, n = 27 Aspirin 650 mg, n = 32 Ketorolac 10 mg, n = 37 Placebo, n = 32 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score R2, DB2, W1 Patients asked to refrain from rescue medication for 2 hours
34
Participants
Interventions
Outcomes
Notes
Forbes 1990b Methods RCT, DB, single oral dose, 6 parallel groups. Followed by multiple dose phase Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at baseline then hourly to 6 hours Removal of impacted 3rd molar (1 or more) Age 15+ years N = 206 Paracetamol+codeine 600/60 mg, n = 38 Paracetamol 600 mg, n = 36 Ketorolac 10 mg, n = 31 Ketorolac 20 mg, n = 35 ibuprofen 400 mg, n = 32 Placebo, n = 34 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R2, DB2, W1 Patients asked to refrain from rescue medication for 2 hours
Participants
Interventions
Outcomes
Notes
Forbes 1994 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes the hourly to 6 hours Removal of impacted 3rd molar Age 15+ years N = 324 Paracetamol+codeine 300/30 mg, n = 93 Paracetamol+hydrocodone bitartrate 500/7.5 mg, n = 94 Placebo, n = 45 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event
Participants
Interventions
Outcomes
35
Forbes 1994
(Continued)
Notes
Oxford Quality Score: R2, DB2, W1 Patients asked to refrain from rescue medication for 2 hours
Gertzbein 1986 Methods RCT, DB, single oral dose, 2 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 5 hours Elective orthopaedic or general surgery Age 16 - 65 years N = 116 Paracetamol+codeine 1000/60 mg, n = 45 Paracetamol 1000 mg, n = 45 PI: std 4 point scale and std 100mm VAS PR: std 5 point scale PGE: non std 4 point scale Time to use of rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R1, DB1, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Heidrich 1985 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Orthopaedic surgery Age 18-65 years N = 120 Paracetamol+codeine 300/30 mg, n = 40 Ibuprofen 400 mg, n = 40 Placebo, n = 40 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event
Participants
Interventions
Outcomes
36
Heidrich 1985
(Continued)
Notes
Oxford Quality Score: R1, DB1, W0
Honig 1984 Methods RCT, DB, single oral dose, 4 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 mins then hourly to 6 hours Elective abdominal, orthopaedic, rectal, thoracic and vascular surgery Age 19-87 years N = 116 Paracetamol 600 mg, n = 28 Paracetamol+codeine 600/60 mg, n = 28 Codeine 60 mg, n = 28 Placebo, n = 25 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Number of patients using rescue medication Number of serious adverse events Oxford Quality Score R1, DB2, W0
Participants
Interventions
Outcomes
Notes
Malmstrom 2004 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60, 90, 120 minutes, then hourly to 8 hours, then at 10, 12, 20 and 24 hours Impacted third molar removal Mean age 23 years N = 201 M = 97, F = 104 Paracetamol+codeine 600/60 mg, n = 50 Naproxen sodium 550mg, n = 50 Etoricoxib 120mg, n = 50 Placebo, n = 50 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events
37
Participants
Interventions
Outcomes
Malmstrom 2004
(Continued)
Number of patients withdrawing due to adverse event Notes Oxford Quality Score:R2, DB2, W1
Pande 1996c Methods RCT, DB, single oral dose, 4 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes, the hourly to 6 hours Removal of impacted third molar N = 100 Paracetamol+codeine 600/60 mg, n = 23 Placebo, n = 26 PI: std 4 point scale PR: std 5 point scale Oxford Quality Score: R1, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Smith 2004 Methods RCT, DB single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 4 hours Orthopaedic surgery Mean age 47 years N = 305 M = 215, F = 90 Paracetamol+codeine 300/30 mg, n = 109 Paracetamol+tramadol 325/37.5 mg, n = 98 Placebo, n = 98 PI: std 4 point scale PR: non std 6 point scale Number of patients using rescue medication Oxford Quality Score: R2, DB2, W1
Participants
Interventions
Outcomes
Notes
38
Stubhaug 1995 Methods RCT, DB, single oral dose, 4 parallel groups Baseline pain was >60 mm on VAS scale (severe) Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Orthopaedic surgery Age: Adults N = 144 Paracetamol+codeine 1000/60 mg, n = 36 Tramadol 50 mg, n = 33 Tramadol 100 mg, n = 35 Placebo, n = 33 PI: std 100 mm VAS Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Oxford Quality score: R1, DB2, W1
Participants
Interventions
Outcomes
Notes
Sunshine 1986 Methods RCT, DB, single oral dose, 6 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes, then hourly to 6 hours Removal of impacted third molar Age 16+ years N =182 Paracetamol 650 mg, n = 30 Paracetamol+codeine 650/60 mg, n = 31 Flurbiprofen 50 mg, n = 31 Flurbiprofen 100 mg, n = 29 Zomepirac 100 mg, n = 31 Placebo, n = 30 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Overall improvement: non std 7 point scale Oxford Quality Score R2, DB2, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
39
Turek 1988 Methods RCT, DB, single oral dose, 4 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60 minutes then hourly to 6 hours Elective surgery - mainly orthopaedic, abdominal, gynaecological and urological Age 18+ years N = 161 Paracetamol+codeine 650/60 mg, n = 39 Ketoprofen 50 mg, n = 41 Ketoprofen 150 mg, n = 39 Placebo, n = 41 PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale (patients reporting very good or excellent) Time to use of rescue medication Number of patients using rescue medication Number of patients reporting any adverse event and serious adverse events Number of patients withdrawing due to adverse event Oxford Quality Score: R1, DB1, W1 Patients asked to refrain from rescue medication for 1 hour
Participants
Interventions
Outcomes
Notes
Ziccardi 2000 Methods RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain reached a moderate to severe intensity Pain assessed at 0, 30, 60, 90 and 120 minutes then hourly to 8 hours Impacted third molar extraction Mean age 25 years N = 125 M = 50, F = 75 Paracetamol+codeine 600/60 mg, n = 49 Ibuprofen+hydrocodone 400/150 mg, n = 49 Placebo, n = 27 PI: std 4 point scale PR: std 5 point scale PGE: non std 5 point scale Time to use of rescue medication Number of patients reporting any adverse event and serious adverse events Oxford Quality Score: R2, DB2, W0
Participants
Interventions
Outcomes
Notes
40
DB: double blind; F: female; M: male; N: total number of participants in study; n: number of participants in treatment arm; R: randomisation RCT: randomised controlled trial; PI: pain intensity; PR: pain relief; PGR: patient global response; std: standard; W: withdrawals
Characteristics of excluded studies [ordered by study ID]
Study Becker 1990 Behotas 1992
Reason for exclusion Pain only assessed for 2 hours after administration of the interventions Interventions were given when pain was of sufcient intensity that analgesia would normally be given and data was only presented for pain relief over the rst hour No appropriate control (Paracetamol with codeine vs codeine CR) Inadequate description of method. Excluded as did not state whether allocation was randomised or if the studies (summary of ve trials) were double blind No appropriate control (Lysine Clonixinate (LC) vs Paracetamol with codeine) Inadequate description of method. Excluded as did not state whether allocation was randomised No appropriate control (Diunisal v paracetamol plus codeine) No appropriate control (paracetamol plus codeine v paracetamol plus dextropropoxyphene) PI scale was 5 point and therefore not validated for the data extraction method. No results for pain relief which would allow the calculation of TOTPAR were presented. Global evaluation was in the opinion of the investigator and not the patient No appropriate control (Paracetamol with codeine vs. ibuprofen) Insufcient baseline pain (not of moderate or severe intensity, less than 30 mm on 100 mm VAS). No placebo group Intervention administered immediately after surgery before anaesthetic wore off. Therefore inadequate baseline pain No appropriate control (paracetamol plus codeine v urbiprofen) No appropriate control (paracetamol plus codeine v naproxen) Fewer than 10 patients in the treatment arm Fewer than 10 patients in the treatment arm No appropriate control (ibuprofen vs. paracetamol with codeine)
41
Chung 2004 Cooper 1984
De los Santos 1998 Forbes 1981 Fulkerson 1986 Jacobson 1987 Levin 1974
Maalaki 2002 Macleod 2002
Matthews 1984
Ottinger 1990 Oullette 1986 Pande 1996a Pande 1996b Peter 2001
(Continued)
Petti 1985 Quiding 1982a
Single blind study Patients instructed to take tablets when pain relief was needed. Mean baseline pain minus 2 standard deviations was less than 30 mm for all interventions (>30 mm equates to at least moderate pain), therefore it is probable that patients with mild pain were included Patients instructed to take tablets when pain relief was needed. Mean baseline pain minus 2 standard deviations was less than 30 mm for all interventions (>30 mm equates to at least moderate pain), therefore it is probable that patients with mild pain were included No appropriate control (paracetamol v codeine) No appropriate control (ibuprofen vs paracetamol with codeine) No appropriate control (paracetamol plus codeine v APC v naproxen) No appropriate control (paracetamol v aspirin) Outline of 5 studies. Study 3 and 4 compare paracetamol plus codeine to placebo. Study 4 is a duplicate of an included RCT. Study 3 cannot be included as the report fails to state whether the allocation to each intervention was randomised Intervention administered immediately after surgery before anaesthetic wore off. Therefore inadequate baseline pain Intervention administered immediately after surgery before anaesthetic wore off. Therefore inadequate baseline pain No appropriate control (paracetamol plus codeine v ketorolac) No appropriate control (paracetamol plus codeine v ibuprofen)
Quiding 1983
Quiding 1984 Raeder 2001 Scoren 1987 Skjelbred 1977 Sunshine 1988
Sveen 1975
Torabinejad 1994
Vangen 1988 Wittenberg 1984
42
DATA AND ANALYSES
Comparison 1. Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo
Outcome or subgroup title 1 Participants with at least 50% pain relief over 4 to 6 hours 2 Participants with any adverse event
No. of studies 3 3
No. of participants 192 209
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 6.34 [2.93, 13.73] 0.89 [0.58, 1.39]
Comparison 2. Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg
Outcome or subgroup title 1 Participants with at least 50% pain relief over 4 to 6 hours 2 Participants using rescue medication over 4 to 6 hours 3 Participants with any adverse event
No. of studies 4 2 4
No. of participants 304 127 324
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)
Effect size 1.31 [1.06, 1.62] 0.61 [0.41, 0.89] 1.13 [0.70, 1.81]
Comparison 3. Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo
Outcome or subgroup title 1 Participants with at least 50% pain relief over 4 to 6 hours 2 Participants with at least 50% pain relief over 4 to 6 hours, dental 3 Participants with at least 50% pain relief over 4 to 6 hours, other surgery 4 Participants using rescue medication over 4 to 6 hours 5 Participants with any adverse event
No. of studies 17 14
Effect size 2.64 [2.17, 3.21] 2.70 [2.18, 3.35]
192
Risk Ratio (M-H, Fixed, 95% CI)
2.36 [1.49, 3.73]
10 14
657 1258
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.75 [0.68, 0.82] 1.57 [1.27, 1.93]
43
Comparison 4. Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg
No. of studies 10 8
Effect size 1.30 [1.11, 1.52] 1.32 [1.11, 1.57]
110
1.21 [0.83, 1.77]
7 7
436 443
0.75 [0.64, 0.88] 1.11 [0.79, 1.57]
Comparison 5. Paracetamol 300 mg plus codeine 30 mg versus placebo
No. of studies 6 3
Effect size 1.87 [1.42, 2.47] 3.31 [1.76, 6.23]
391
1.51 [1.11, 2.05]
4 3
529 344
0.79 [0.68, 0.91] 0.85 [0.50, 1.45]
Comparison 6. Sensitivity analysis (paracetamol with codeine versus placebo)
Outcome or subgroup title 1 Fewer than 40 patients in active and placebo groups, participants with at least 50% pain relief over 4 to 6 hours
No. of studies 10
No. of participants 572
Statistical method Risk Ratio (M-H, Fixed, 95% CI)
Effect size 3.01 [2.31, 3.92]
44
2 More than 40 patients in active and placebo groups, participants with at least 50% pain relief over 4 to 6 hours
629
1.57 [1.21, 2.03]
Comparison 7. Sensitivity analysis (paracetamol with codeine versus paracetamol)
Outcome or subgroup title 1 Fewer than 40 patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours 2 More than 40 patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours
No. of studies 10
Effect size 1.36 [1.15, 1.60]
259
1.30 [1.02, 1.65]
Comparison 8. Paracetamol plus codeine (all doses) versus placebo
Outcome or subgroup title 1 Participants with any adverse event
No. of studies 20
Effect size 1.37 [1.15, 1.63]
Comparison 9. Paracetamol plus codeine (all doses) versus paracetamol alone
Outcome or subgroup title 1 Participants with any adverse event
No. of studies 11
Effect size 1.10 [0.87, 1.40]
45
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.
Review: Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 4/17 0/21 1/33
Risk Ratio M-H,Fixed,95% CI
Weight
Bentley 1987 Bjune 1996 Stubhaug 1995
27/41 16/44 21/36
76.7 % 9.1 % 14.2 %
2.80 [ 1.16, 6.78 ] 16.13 [ 1.01, 256.67 ] 19.25 [ 2.74, 135.26 ]
Total (95% CI)
121
71
100.0 %
6.34 [ 2.93, 13.73 ]
Total events: 64 (Paracet+codeine), 5 (Placebo) Heterogeneity: Chi2 = 4.97, df = 2 (P = 0.08); I2 =60% Test for overall effect: Z = 4.69 (P < 0.00001) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours placebo
Favours paracet+codeine
46
Analysis 1.2. Comparison 1 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo, Outcome 2 Participants with any adverse event.
Comparison: 1 Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo Outcome: 2 Participants with any adverse event
Study or subgroup
Paracet+codeine n/N
Placebo n/N 9/19 1/25 15/36
Weight
Bentley 1987 Bjune 1996 Stubhaug 1995
15/42 10/50 10/37
42.8 % 4.6 % 52.6 %
0.75 [ 0.40, 1.41 ] 5.00 [ 0.68, 36.90 ] 0.65 [ 0.34, 1.25 ]
Total (95% CI)
129
80
100.0 %
0.89 [ 0.58, 1.39 ]
Total events: 35 (Paracet+codeine), 25 (Placebo) Heterogeneity: Chi2 = 4.06, df = 2 (P = 0.13); I2 =51% Test for overall effect: Z = 0.50 (P = 0.62) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours placebo
47
Analysis 2.1. Comparison 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg, Outcome 1 Participants with at least 50% pain relief over 4 to 6 hours.
Comparison: 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg Outcome: 1 Participants with at least 50% pain relief over 4 to 6 hours
Study or subgroup
Paracet+codeine n/N
Paracet n/N 19/41 12/43 12/22 25/45
Weight
Bentley 1987 Bjune 1996 Breivik 1999 Gertzbein 1986
27/41 16/44 17/23 30/45
27.8 % 17.7 % 17.9 % 36.5 %
1.42 [ 0.96, 2.11 ] 1.30 [ 0.70, 2.42 ] 1.36 [ 0.86, 2.13 ] 1.20 [ 0.86, 1.67 ]
Total (95% CI)
153
151
100.0 %
1.31 [ 1.06, 1.62 ]
Total events: 90 (Paracet+codeine), 68 (Paracet) Heterogeneity: Chi2 = 0.45, df = 3 (P = 0.93); I2 =0.0% Test for overall effect: Z = 2.46 (P = 0.014) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours paracet
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.
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
Study or subgroup
Paracet+codeine n/N
Paracet n/N 28/41 8/22
Weight
Bentley 1987 Breivik 1999
18/41 4/23
77.4 % 22.6 %
0.64 [ 0.43, 0.96 ] 0.48 [ 0.17, 1.36 ]
Total (95% CI)
64
63
100.0 %
0.61 [ 0.41, 0.89 ]
0.02
0.1
10
50
Favours paracet
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.
Comparison: 2 Paracetamol 800 to 1000 mg plus codeine 60 mg versus paracetamol 1000 mg Outcome: 3 Participants with any adverse event
Study or subgroup
Paracet+codeine n/N
Paracet n/N 21/42 10/50 3/24 13/46
Odds Ratio M-H,Fixed,95% CI
Weight
Odds Ratio M-H,Fixed,95% CI
Bentley 1987 Bjune 1996 Breivik 1999 Gertzbein 1986
15/42 10/50 13/23 13/47
41.8 % 24.8 % 4.0 % 29.4 %
0.56 [ 0.23, 1.33 ] 1.00 [ 0.38, 2.66 ] 9.10 [ 2.11, 39.34 ] 0.97 [ 0.39, 2.40 ]
Total (95% CI)
162
162
100.0 %
1.13 [ 0.70, 1.81 ]
Total events: 51 (Paracet+codeine), 47 (Paracet) Heterogeneity: Chi2 = 10.49, df = 3 (P = 0.01); I2 =71% Test for overall effect: Z = 0.49 (P = 0.62) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours paracet
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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 2/31 8/30 6/37 9/40 9/44 18/25 6/30 5/26 0/23 1/32 0/34 6/30 6/50 0/26 10/30 8/41 2/27
Weight
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
49/180 86/180 24/42 17/31 17/39 20/24 21/31 16/26 8/17 9/27 9/38 14/30 20/50 6/23 19/31 14/39 21/49
3.3 % 13.3 % 6.2 % 7.6 % 8.2 % 17.0 % 5.9 % 4.8 % 0.4 % 0.9 % 0.5 % 5.8 % 5.8 % 0.5 % 9.8 % 7.5 % 2.5 %
4.22 [ 1.08, 16.47 ] 1.79 [ 0.97, 3.31 ] 3.52 [ 1.62, 7.67 ] 2.44 [ 1.26, 4.71 ] 2.13 [ 1.08, 4.22 ] 1.16 [ 0.85, 1.57 ] 3.39 [ 1.59, 7.21 ] 3.20 [ 1.38, 7.44 ] 22.67 [ 1.40, 367.54 ] 10.67 [ 1.44, 78.93 ] 17.05 [ 1.03, 282.36 ] 2.33 [ 1.04, 5.25 ] 3.33 [ 1.46, 7.60 ] 14.63 [ 0.87, 246.20 ] 1.84 [ 1.03, 3.28 ] 1.84 [ 0.87, 3.89 ] 5.79 [ 1.47, 22.82 ]
Total (95% CI)
857
556
100.0 %
2.64 [ 2.17, 3.21 ]
0.02
0.1
10
50
Favours placebo
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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 2/31 8/30 6/37 9/40 9/44 18/25 6/30 0/23 1/32 0/34 6/50 0/26 10/30 2/27
Weight
Chang 2001 Chang 2005 Cooper 1981 Cooper 1988 Cooper 1991 Dionne 1994 Forbes 1982 Forbes 1989 Forbes 1990a Forbes 1990b Malmstrom 2004 Pande 1996c Sunshine 1986 Ziccardi 2000
49/180 86/180 24/42 17/31 17/39 20/24 21/31 8/17 9/27 9/38 20/50 6/23 19/31 21/49
4.0 % 16.2 % 7.5 % 9.3 % 10.0 % 20.8 % 7.2 % 0.5 % 1.1 % 0.6 % 7.1 % 0.6 % 12.0 % 3.0 %
4.22 [ 1.08, 16.47 ] 1.79 [ 0.97, 3.31 ] 3.52 [ 1.62, 7.67 ] 2.44 [ 1.26, 4.71 ] 2.13 [ 1.08, 4.22 ] 1.16 [ 0.85, 1.57 ] 3.39 [ 1.59, 7.21 ] 22.67 [ 1.40, 367.54 ] 10.67 [ 1.44, 78.93 ] 17.05 [ 1.03, 282.36 ] 3.33 [ 1.46, 7.60 ] 14.63 [ 0.87, 246.20 ] 1.84 [ 1.03, 3.28 ] 5.79 [ 1.47, 22.82 ]
Total (95% CI)
762
459
100.0 %
2.70 [ 2.18, 3.35 ]
0.02
0.1
10
50
Favours placebo
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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 5/26 6/30 8/41
Weight
Forbes 1983 Honig 1984 Turek 1988
16/26 14/30 14/39
26.6 % 31.9 % 41.5 %
3.20 [ 1.38, 7.44 ] 2.33 [ 1.04, 5.25 ] 1.84 [ 0.87, 3.89 ]
Total (95% CI)
95
97
100.0 %
2.36 [ 1.49, 3.73 ]
Total events: 44 (Paracet+codeine), 19 (Placebo) Heterogeneity: Chi2 = 0.92, df = 2 (P = 0.63); I2 =0.0% Test for overall effect: Z = 3.67 (P = 0.00024) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours placebo
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.
Comparison: 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo Outcome: 4 Participants using rescue medication over 4 to 6 hours
Study or subgroup
Paracet+codeine n/N
Placebo n/N 20/37 33/40 37/44 26/30 22/26 21/23 27/32 33/34 16/30 34/41
Weight
Cooper 1981 Cooper 1988 Cooper 1991 Forbes 1982 Forbes 1983 Forbes 1989 Forbes 1990a Forbes 1990b Honig 1984 Turek 1988
5/42 18/31 31/39 17/31 16/26 11/17 23/27 31/38 10/30 26/39
8.2 % 11.1 % 13.4 % 10.2 % 8.5 % 6.9 % 9.5 % 13.4 % 6.2 % 12.8 %
0.22 [ 0.09, 0.53 ] 0.70 [ 0.51, 0.98 ] 0.95 [ 0.77, 1.16 ] 0.63 [ 0.45, 0.90 ] 0.73 [ 0.51, 1.03 ] 0.71 [ 0.49, 1.03 ] 1.01 [ 0.81, 1.25 ] 0.84 [ 0.71, 0.99 ] 0.63 [ 0.34, 1.15 ] 0.80 [ 0.62, 1.04 ]
Total (95% CI)
320
337
100.0 %
0.75 [ 0.68, 0.82 ]
0.1 0.2
0.5
10
Favours placebo
54
Analysis 3.5. Comparison 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo, Outcome 5 Participants with any adverse event.
Comparison: 3 Paracetamol 600 to 650 mg plus codeine 60 mg versus placebo Outcome: 5 Participants with any adverse event
Study or subgroup
Paracet+codeine n/N
Placebo n/N 10/31 14/30 4/37 3/40 7/44 5/25 4/26 2/26 5/34 0/38 18/50 1/30 4/41 6/27
Weight
Chang 2001 Chang 2005 Cooper 1981 Cooper 1988 Cooper 1991 Dionne 1994 Forbes 1983 Forbes 1989 Forbes 1990a Forbes 1990b Malmstrom 2004 Sunshine 1986 Turek 1988 Ziccardi 2000
83/180 63/180 10/42 4/31 8/39 9/24 11/26 1/17 9/31 8/40 25/50 3/31 11/39 21/49
16.9 % 23.8 % 4.2 % 2.6 % 6.5 % 4.9 % 4.0 % 1.6 % 4.7 % 0.5 % 17.8 % 1.0 % 3.9 % 7.7 %
1.43 [ 0.84, 2.44 ] 0.75 [ 0.49, 1.15 ] 2.20 [ 0.75, 6.43 ] 1.72 [ 0.42, 7.13 ] 1.29 [ 0.51, 3.23 ] 1.88 [ 0.73, 4.79 ] 2.75 [ 1.00, 7.53 ] 0.76 [ 0.08, 7.79 ] 1.97 [ 0.74, 5.25 ] 16.17 [ 0.97, 270.83 ] 1.39 [ 0.88, 2.20 ] 2.90 [ 0.32, 26.38 ] 2.89 [ 1.00, 8.32 ] 1.93 [ 0.89, 4.19 ]
Total (95% CI)
779
479
100.0 %
1.57 [ 1.27, 1.93 ]
0.02
0.1
10
50
Favours placebo
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.
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
Study or subgroup
Paracet+codeine n/N
Paracet n/N 21/37 12/36 10/37 24/27 15/34 13/26 1/22 7/36 11/28 15/30
Weight
Cooper 1981 Cooper 1988 Cooper 1991 Dionne 1994 Forbes 1982 Forbes 1983 Forbes 1989 Forbes 1990b Honig 1984 Sunshine 1986
24/42 17/31 17/39 20/24 21/31 16/26 8/17 9/38 14/30 19/31
17.4 % 8.7 % 8.0 % 17.6 % 11.2 % 10.1 % 0.7 % 5.6 % 8.9 % 11.9 %
1.01 [ 0.69, 1.48 ] 1.65 [ 0.94, 2.88 ] 1.61 [ 0.85, 3.05 ] 0.94 [ 0.75, 1.17 ] 1.54 [ 0.98, 2.41 ] 1.23 [ 0.75, 2.01 ] 10.35 [ 1.43, 75.00 ] 1.22 [ 0.51, 2.93 ] 1.19 [ 0.65, 2.16 ] 1.23 [ 0.78, 1.93 ]
Total (95% CI)
309
313
100.0 %
1.30 [ 1.11, 1.52 ]
0.02
0.1
10
50
Favours paracet
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.
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
Study or subgroup
Paracet+codeine n/N
Paracet n/N 21/37 12/36 10/37 24/27 15/34 1/22 7/36 15/30
Weight
Cooper 1981 Cooper 1988 Cooper 1991 Dionne 1994 Forbes 1982 Forbes 1989 Forbes 1990b Sunshine 1986
24/42 17/31 17/39 20/24 21/31 8/17 9/38 19/31
21.5 % 10.7 % 9.9 % 21.7 % 13.8 % 0.8 % 6.9 % 14.7 %
1.01 [ 0.69, 1.48 ] 1.65 [ 0.94, 2.88 ] 1.61 [ 0.85, 3.05 ] 0.94 [ 0.75, 1.17 ] 1.54 [ 0.98, 2.41 ] 10.35 [ 1.43, 75.00 ] 1.22 [ 0.51, 2.93 ] 1.23 [ 0.78, 1.93 ]
Total (95% CI)
253
259
100.0 %
1.32 [ 1.11, 1.57 ]
0.02
0.1
10
50
Favours paracet
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.
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
Study or subgroup
Paracet+codeine n/N
Paracet n/N 13/26 11/28
Weight
Forbes 1983 Honig 1984
16/26 14/30
53.3 % 46.7 %
1.23 [ 0.75, 2.01 ] 1.19 [ 0.65, 2.16 ]
Total (95% CI)
56
54
100.0 %
1.21 [ 0.83, 1.77 ]
0.02
0.1
10
50
Favours paracet
58
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.
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
Study or subgroup
Paracet+codeine n/N
Paracet n/N 2/37 28/36 35/37 24/34 19/26 18/22 12/28
Weight
Cooper 1981 Cooper 1988 Cooper 1991 Forbes 1982 Forbes 1983 Forbes 1989 Honig 1984
5/42 18/31 21/39 17/31 16/26 11/17 10/30
1.6 % 19.3 % 26.8 % 17.1 % 14.2 % 11.7 % 9.3 %
2.20 [ 0.45, 10.68 ] 0.75 [ 0.53, 1.06 ] 0.57 [ 0.42, 0.77 ] 0.78 [ 0.53, 1.14 ] 0.84 [ 0.57, 1.24 ] 0.79 [ 0.53, 1.18 ] 0.78 [ 0.40, 1.51 ]
Total (95% CI)
216
220
100.0 %
0.75 [ 0.64, 0.88 ]
0.1 0.2
0.5
10
Favours paracet
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.
Comparison: 4 Paracetamol 600 to 650 mg plus codeine 60 mg versus paracetamol 600-650 mg Outcome: 5 Participants with any adverse event
Study or subgroup
Paracet+codeine n/N
Paracet n/N 12/37 6/37 7/27 11/26 3/26 5/41 1/30
Weight
Cooper 1981 Cooper 1991 Dionne 1994 Forbes 1983 Forbes 1989 Forbes 1990b Sunshine 1986
10/42 8/39 9/24 11/26 1/17 8/40 3/31
28.5 % 13.7 % 14.7 % 24.5 % 5.3 % 11.0 % 2.3 %
0.73 [ 0.36, 1.50 ] 1.26 [ 0.49, 3.30 ] 1.45 [ 0.64, 3.29 ] 1.00 [ 0.53, 1.89 ] 0.51 [ 0.06, 4.51 ] 1.64 [ 0.59, 4.59 ] 2.90 [ 0.32, 26.38 ]
Total (95% CI)
219
224
100.0 %
1.11 [ 0.79, 1.57 ]
0.02
0.1
10
50
Favours paracet
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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 15/49 7/41 1/38 3/45 3/40 27/98
Weight
Bourne 2005 Desjardins 1986 Forbes 1986 Forbes 1994 Heidrich 1985 Smith 2004
24/55 12/39 13/43 23/93 8/40 43/109
26.8 % 11.5 % 1.8 % 6.8 % 5.1 % 48.0 %
1.43 [ 0.85, 2.39 ] 1.80 [ 0.79, 4.10 ] 11.49 [ 1.58, 83.76 ] 3.71 [ 1.18, 11.71 ] 2.67 [ 0.76, 9.33 ] 1.43 [ 0.96, 2.13 ]
Total (95% CI)
379
311
100.0 %
1.87 [ 1.42, 2.47 ]
0.02
0.1
10
50
Favours placebo
61
Analysis 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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 7/41 1/38 3/45
Weight
Desjardins 1986 Forbes 1986 Forbes 1994
12/39 13/43 23/93
57.2 % 8.9 % 33.9 %
1.80 [ 0.79, 4.10 ] 11.49 [ 1.58, 83.76 ] 3.71 [ 1.18, 11.71 ]
Total (95% CI)
175
124
100.0 %
3.31 [ 1.76, 6.23 ]
0.02
0.1
10
50
Favours placebo
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.
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
Study or subgroup
Paracet+codeine n/N
Placebo n/N 15/49 3/40 27/98
Weight
Bourne 2005 Heidrich 1985 Smith 2004
24/55 8/40 43/109
33.5 % 6.3 % 60.1 %
1.43 [ 0.85, 2.39 ] 2.67 [ 0.76, 9.33 ] 1.43 [ 0.96, 2.13 ]
Total (95% CI)
204
187
100.0 %
1.51 [ 1.11, 2.05 ]
0.02
0.1
10
50
Favours placebo
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.
Comparison: 5 Paracetamol 300 mg plus codeine 30 mg versus placebo Outcome: 4 Participants using rescue medication over 4 to 6 hours
Study or subgroup
Paracet+codeine n/N
Placebo n/N 18/49 39/45 36/40 39/98
Weight
Bourne 2005 Forbes 1994 Heidrich 1985 Smith 2004
10/55 72/93 34/40 28/109
12.8 % 35.4 % 24.2 % 27.6 %
0.49 [ 0.25, 0.97 ] 0.89 [ 0.76, 1.05 ] 0.94 [ 0.80, 1.12 ] 0.65 [ 0.43, 0.96 ]
Total (95% CI)
297
232
100.0 %
0.79 [ 0.68, 0.91 ]
0.1 0.2
0.5
10
Favours placebo
64
Analysis 5.5. Comparison 5 Paracetamol 300 mg plus codeine 30 mg versus placebo, Outcome 5 Participants with any adverse event.
Comparison: 5 Paracetamol 300 mg plus codeine 30 mg versus placebo Outcome: 5 Participants with any adverse event
Study or subgroup
Paracet+codeine n/N
Placebo n/N 4/41 9/46 10/65
Weight
Desjardins 1986 Forbes 1986 Forbes 1994
2/39 6/46 18/107
15.4 % 35.5 % 49.1 %
0.53 [ 0.10, 2.71 ] 0.67 [ 0.26, 1.72 ] 1.09 [ 0.54, 2.22 ]
Total (95% CI)
192
152
100.0 %
0.85 [ 0.50, 1.45 ]
0.02
0.1
10
50
Favours paracet+placebo
Favours placebo
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.
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
Study or subgroup
Paracetamol with codeine n/N
Paracetamol n/N 18/25 6/30 5/26 0/23 1/32 0/34 6/30 0/26 1/33 10/30
Weight
Dionne 1994 Forbes 1982 Forbes 1983 Forbes 1989 Forbes 1990a Forbes 1990b Honig 1984 Pande 1996c Stubhaug 1995 Sunshine 1986
20/24 21/31 16/26 8/17 9/27 9/38 14/30 6/23 21/36 19/31
36.5 % 12.6 % 10.4 % 0.9 % 1.9 % 1.1 % 12.4 % 1.0 % 2.2 % 21.1 %
1.16 [ 0.85, 1.57 ] 3.39 [ 1.59, 7.21 ] 3.20 [ 1.38, 7.44 ] 22.67 [ 1.40, 367.54 ] 10.67 [ 1.44, 78.93 ] 17.05 [ 1.03, 282.36 ] 2.33 [ 1.04, 5.25 ] 14.63 [ 0.87, 246.20 ] 19.25 [ 2.74, 135.26 ] 1.84 [ 1.03, 3.28 ]
Total (95% CI)
283
289
100.0 %
3.01 [ 2.31, 3.92 ]
Total events: 143 (Paracetamol with codeine), 47 (Paracetamol) Heterogeneity: Chi2 = 51.15, df = 9 (P<0.00001); I2 =82% Test for overall effect: Z = 8.15 (P < 0.00001) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours paracetamol
Favours placebo
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.
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
Study or subgroup
Paracetamol n/N 15/49 3/45 3/40 6/50 37/98
Weight
Bourne 2005 Forbes 1994 Heidrich 1985 Malmstrom 2004 Smith 2004
24/55 23/93 8/40 20/50 43/109
23.4 % 6.0 % 4.4 % 8.8 % 57.4 %
1.43 [ 0.85, 2.39 ] 3.71 [ 1.18, 11.71 ] 2.67 [ 0.76, 9.33 ] 3.33 [ 1.46, 7.60 ] 1.04 [ 0.74, 1.47 ]
Total (95% CI)
347
282
100.0 %
1.57 [ 1.21, 2.03 ]
Total events: 118 (Paracetamol with codeine), 64 (Paracetamol) Heterogeneity: Chi2 = 11.52, df = 4 (P = 0.02); I2 =65% Test for overall effect: Z = 3.40 (P = 0.00068) Test for subgroup differences: Not applicable
0.01
0.1
10
100
Favours paracetamol
Favours placebo
67
Analysis 7.1. Comparison 7 Sensitivity analysis (paracetamol with codeine versus paracetamol), Outcome 1 Fewer than 40 patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours.
Comparison: 7 Sensitivity analysis (paracetamol with codeine versus paracetamol) Outcome: 1 Fewer than 40 patients in active and control groups, Participants with at least 50% pain relief over 4 to 6 hours
Study or subgroup
Paracetamol n/N 12/22 12/36 10/37 24/27 15/34 13/26 1/22 7/36 11/28 15/30
Weight
Breivik 1999 Cooper 1988 Cooper 1991 Dionne 1994 Forbes 1982 Forbes 1983 Forbes 1989 Forbes 1990b Honig 1984 Sunshine 1986
17/23 17/31 17/39 20/24 21/31 16/26 8/17 9/38 14/30 19/31
10.4 % 9.4 % 8.7 % 19.1 % 12.1 % 11.0 % 0.7 % 6.1 % 9.6 % 12.9 %
1.36 [ 0.86, 2.13 ] 1.65 [ 0.94, 2.88 ] 1.61 [ 0.85, 3.05 ] 0.94 [ 0.75, 1.17 ] 1.54 [ 0.98, 2.41 ] 1.23 [ 0.75, 2.01 ] 10.35 [ 1.43, 75.00 ] 1.22 [ 0.51, 2.93 ] 1.19 [ 0.65, 2.16 ] 1.23 [ 0.78, 1.93 ]
Total (95% CI)
290
298
100.0 %
1.36 [ 1.15, 1.60 ]
Total events: 158 (Paracetamol with codeine), 120 (Paracetamol) Heterogeneity: Chi2 = 16.26, df = 9 (P = 0.06); I2 =45% Test for overall effect: Z = 3.68 (P = 0.00023) Test for subgroup differences: Not applicable
0.01
0.1
10
100
Favours paracetamol
Favours placebo
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.
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
Study or subgroup
Paracetamol n/N 19/41 12/43 25/45
Weight
Bentley 1987 Bjune 1996 Gertzbein 1986
27/41 16/44 30/45
33.8 % 21.6 % 44.5 %
1.42 [ 0.96, 2.11 ] 1.30 [ 0.70, 2.42 ] 1.20 [ 0.86, 1.67 ]
Total (95% CI)
130
129
100.0 %
1.30 [ 1.02, 1.65 ]
Total events: 73 (Paracetamol with codeine), 56 (Paracetamol) Heterogeneity: Chi2 = 0.41, df = 2 (P = 0.81); I2 =0.0% Test for overall effect: Z = 2.12 (P = 0.034) Test for subgroup differences: Not applicable
0.01
0.1
10
100
Favours paracetamol
Favours placebo
69
Analysis 8.1. Comparison 8 Paracetamol plus codeine (all doses) versus placebo, Outcome 1 Participants with any adverse event.
Comparison: 8 Paracetamol plus codeine (all doses) versus placebo Outcome: 1 Participants with any adverse event
Study or subgroup
Paracetamol n/N
Placebo n/N 9/19 1/25 10/31 14/30 4/37 9/40 7/44 4/41 5/25 4/26 9/46 2/26 5/34 0/38 10/65 18/50 15/36 1/30 4/41 6/27
Weight
Bentley 1987 Bjune 1996 Chang 2001 Chang 2005 Cooper 1981 Cooper 1988 Cooper 1991 Desjardins 1986 Dionne 1994 Forbes 1983 Forbes 1986 Forbes 1989 Forbes 1990a Forbes 1990b Forbes 1994 Malmstrom 2004 Stubhaug 1995 Sunshine 1986 Turek 1988 Ziccardi 2000
15/42 10/50 83/180 63/180 10/42 17/31 8/39 2/39 9/24 11/26 6/46 1/17 9/31 8/40 18/107 25/50 10/37 3/31 11/39 21/49
7.7 % 0.8 % 10.6 % 15.0 % 2.7 % 4.9 % 4.1 % 2.4 % 3.1 % 2.5 % 5.6 % 1.0 % 3.0 % 0.3 % 7.8 % 11.2 % 9.5 % 0.6 % 2.4 % 4.8 %
0.75 [ 0.40, 1.41 ] 5.00 [ 0.68, 36.90 ] 1.43 [ 0.84, 2.44 ] 0.75 [ 0.49, 1.15 ] 2.20 [ 0.75, 6.43 ] 2.44 [ 1.26, 4.71 ] 1.29 [ 0.51, 3.23 ] 0.53 [ 0.10, 2.71 ] 1.88 [ 0.73, 4.79 ] 2.75 [ 1.00, 7.53 ] 0.67 [ 0.26, 1.72 ] 0.76 [ 0.08, 7.79 ] 1.97 [ 0.74, 5.25 ] 16.17 [ 0.97, 270.83 ] 1.09 [ 0.54, 2.22 ] 1.39 [ 0.88, 2.20 ] 0.65 [ 0.34, 1.25 ] 2.90 [ 0.32, 26.38 ] 2.89 [ 1.00, 8.32 ] 1.93 [ 0.89, 4.19 ]
Total (95% CI)
1100
711
100.0 %
1.37 [ 1.15, 1.63 ]
Total events: 340 (Paracetamol), 137 (Placebo) Heterogeneity: Chi2 = 34.42, df = 19 (P = 0.02); I2 =45% Test for overall effect: Z = 3.58 (P = 0.00034) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours placebo
70
Analysis 9.1. Comparison 9 Paracetamol plus codeine (all doses) versus paracetamol alone, Outcome 1 Participants with any adverse event.
Comparison: 9 Paracetamol plus codeine (all doses) versus paracetamol alone Outcome: 1 Participants with any adverse event
Study or subgroup
Paracetamol+Codeine Paracetamol n/N n/N 21/42 10/50 3/24 12/37 6/37 7/27 11/26 3/26 5/41 13/46 1/30
Weight
Bentley 1987 Bjune 1996 Breivik 1999 Cooper 1981 Cooper 1991 Dionne 1994 Forbes 1983 Forbes 1989 Forbes 1990b Gertzbein 1986 Sunshine 1986
15/42 10/50 13/23 10/42 8/39 9/24 11/26 1/17 8/40 13/47 3/31
22.8 % 10.9 % 3.2 % 13.9 % 6.7 % 7.2 % 12.0 % 2.6 % 5.4 % 14.3 % 1.1 %
0.71 [ 0.43, 1.18 ] 1.00 [ 0.46, 2.19 ] 4.52 [ 1.48, 13.82 ] 0.73 [ 0.36, 1.50 ] 1.26 [ 0.49, 3.30 ] 1.45 [ 0.64, 3.29 ] 1.00 [ 0.53, 1.89 ] 0.51 [ 0.06, 4.51 ] 1.64 [ 0.59, 4.59 ] 0.98 [ 0.51, 1.88 ] 2.90 [ 0.32, 26.38 ]
Total (95% CI)
381
386
100.0 %
1.10 [ 0.87, 1.40 ]
Total events: 101 (Paracetamol+Codeine), 92 (Paracetamol) Heterogeneity: Chi2 = 12.75, df = 10 (P = 0.24); I2 =22% Test for overall effect: Z = 0.78 (P = 0.43) Test for subgroup differences: Not applicable
0.02
0.1
10
50
Favours paracet
ADDITIONAL TABLES
Table 1. Summary of outcomes - analgesia and use of rescue medication
Analgesia Study ID Treatment PI or PR Number 50% PR (1) 27/41 (2) 19/41
Rescue medication with PGE: v good or Median time to Number using excellent use (hr) No data (1) 4.1 (2) 3.3 at 4 hr: (1) 44
Bentley 1987
(1) Paraceta- TOTPAR 5: mol+codeine (1) 11.5 1000/60 mg, n=
71
(Continued)
41 (2) 8.7 (2) Paracetamol (4) 4.9 1000 mg, n=41 (3) Codeine 60 mg, n=21 (4) Placebo, n= 17 Bjune 1996 (1) Paracetamol+codeine 800/60 mg, n= 50 (2) Paracetamol 1000 mg, n=50 (3) Placebo, n= 25 TOTPAR 6: severe pain (1) 10.5 (2) 6.4 (3) 0 moderate pain (1) 6.5 (2) 8.0 (3) 1.5 SPID 4: (1) 2.8 (3) 2.1 Baseline PI: (1) 2.1 (2) 2.2
(4) 4/17
(4) 1.4
(2) 68 (4) 81
(1) 16/44 (2) 12/43 (3) 0/21
No usable data
No data
No data
Bourne 2005
(1) Paracetamol+codeine 300/30 mg, n= 55 (2) Paracetamol+tramadol 325/37.5 mg, n= 49 (3) Placebo, n= 49
(1) 24/55 (3) 15/49
No usable data
No data
at 4 hr: (1) 18 (3) 37
Breivik 1999
(1) Paraceta- TOTPAR 6: mol+codeine (1) 15.5 1000/60 mg n= (2) 12.1 24 (2) Paracetamol 1000 mg, n=22 (3) Diclofenac 100 mg, n=22 (4) Paracetamol+diclofenac 1000/100 mg, n=24 (5) Paracetamol+diclofenac+codeine 1000/100/60 mg, n=24 (1) Paraceta- TOTPAR 6: mol+codeine (1) 7.0 600/60 mg n= (3) 3.4
(1) 17/23 (2) 12/22
No data
No data
at 6 hr: (1) 17 (2) 38
Chang 2001
(1) 49/180 (3) 2/31
(1) 27/180 (3) 0/31
(1) 2.3 (3) 1.6
No data
72
(Continued)
180 (2) Rofecoxib 50mg n=182 (3) Placebo n=31 Chang 2005 (1) Paraceta- TOTPAR 6: mol+codeine (1) 10.7 600/60 mg n= (3) 6.7 180 (2) Rofecoxib 50 mg n=180 (3) Placebo n=30 (1) Paracetamol+codeine 650/60 mg, n= 42 (2) Paracetamol 650 mg, n=37 (3) Paracetamol+dpropoxyphene 650/100 mg, n= 42 (4) Ibuprofen 200 mg, n=42 (5) Placebo, n= 37 (1) Paracetamol+codeine 600/60 mg, n= 31 (2) Paracetamol 600 mg, n=36 (3) Meclofenamate Na 100 mg, n=36 (2) Placebo, n= 40 (1) Paracetamol+codeine 650/60 mg, n= 39 (2) Paracetamol 650 mg, n=37 (3) Zomepirac 100 mg, n=23 (4) Flurbiprofen TOTPAR 4: (1) 8.4 (2) 8.2 (5) 3.4 (1) 86/180 (3) 8/30 (1) 123/180 (3) 3/30 (1) 6.5 (3) 3.2 at 24 hr: (1) 86 (3) 73
Cooper 1981
(1) 24/42 (2) 21/37 (5) 6/37
No usable data
Mean: (1) 3.1 (2) 3.5 (5) 2.9
at 4 hr: (1) 12 (2) 5 (5) 54
Cooper 1988
TOTPAR 6: (1) 12.0 (2) 8.0 (4) 6.3
(1) 17/31 (2) 12/36 (4) 9/40
(1) 15/31 (2) 12/36 (4) 8/40
No data
at 6 hr: (1) 58 (2) 78 (4) 82
Cooper 1991
TOTPAR 6: (1) 10.1 (2) 6.8 (6) 5.7
(1) 17/39 (2) 10/37 (6) 9/44
(1) 14/39 (2) 3/37 (6) 2/44
Mean: (1) 3.5 (2) 3.2 (6) 3.1
at 6 hr: (1) 80 (2) 95 (6) 84
73
(Continued)
50 mg, n=42 (5) Flurbiprofen 100 mg, n=41 (6) Placebo, n= 44 Desjardins 1986 (1) Paraceta- TOTPAR 6: mol+codeine (1) 7.8 300/30 mg, n= (3) 5.1 39 (2) Aspirin+butalbital+caffeine+codeine 325/50/40/30 mg, n=43 (3) Placebo, n= 41 (1) Paracetamol+codeine 650/60 mg, n= 24 (2) Paracetamol 650 mg, n=27 (3) Flurbiprofen 50 mg, n=25 (4) Flurbiprofen 100 mg, n=22 (5) Placebo, n= 25 (1) Paracetamol+codeine 600/60 mg, n= 31 (2) Paracetamol 600 mg, n=34 (3) Diusinal 500 mg, n=32 (4) Diusinal 1000 mg, n=32 (5) Placebo, n= 30 (1) Paracetamol+codeine 600/60 mg, n= 26 (2) Paracetamol 600 mg, n=26 (3) Diusinal TOTPAR 6: (1) 16.9 (2) 18.4 (5) 14.9 (1) 12/39 (3) 7/41 No usable data Mean: (1) 3.4 (3) 3.0 No data
Dionne 1994
(1) 20/24 (2) 24/27 (5) 18/25
No usable data
No data
No data
Forbes 1982
TOTPAR 4: (1) 9.7 (2) 8.9 (5) 3.8
(1) 21/31 (2) 15/34 (5) 6/30
No usable data
(1) 5.3 (2) 3.5 (5) 2.4
at 6 hr: (1) 56 (2) 70 (5) 82
Forbes 1983
TOTPAR 6: (1) 13.5 (2) 11.2 (5) 5.4
(1) 16/26 (2) 13/26 (5) 5/26
No usable data
(1) 5.3 (2) 4.0 (5) 2.4
at 6 hr: (1) 63 (2) 73 (5) 86
74
(Continued)
500 mg, n=26 (4) Diusinal 1000 mg, n=28 (5) Placebo, n= 26 Forbes 1986 (1) Paraceta- TOTPAR 6: mol+codeine (1) 7.4 300/30 mg, n= (3) 2.4 43 (2) Aspirin+butalbital+caffeine+codeine 325/50/40/15 mg, n=41 (3) Placebo, n= 38 (1) Paracetamol+codeine 600/60 mg, n= 17 (2) Paracetamol 600 mg, n=22 (3) Flurbiprofen 100 mg, n=26 (4) Placebo, n= 23 TOTPAR 6: (1) 10.5 (2) 4.5 (3) 2.0 (1) 13/43 (2) 1/38 No usable data Mean: (1) 4.5 (2) 3.0 No data
Forbes 1989
(1) 8/17 (2) 1/22 (4) 0/23
No usable data
(1) 5.1 (2) 2.8 (4) 1.7
at 6 hr: (1) 64 (2) 82 (4) 91
Forbes 1990a
(1) Paraceta- TOTPAR 6: mol+codeine (1) 8.6 600/60 mg, n= (4) 2.9 27 (2) Aspirin 650 mg, n=32 (3) Ketorolac 10 mg, n=37 (4) Placebo, n= 32 (1) Paracetamol+codeine 600/60 mg, n= 38 (2) Paracetamol 600 mg, n=36 (3) Ketorolac 10 mg, n=31 (4) Ketorolac 20 mg, n=35 (5) ibuprofen TOTPAR 6: (1) 6.2 (2) 5.8 (6) 1.9
(1) 9/27 (4) 1/32
No usable data
Mean: (1) 4.3 (4) 3.1
at 6 hr: (1) 85 (4) 84
Forbes 1990b
(1) 9/38 (2) 7/36 (6) 0/34
No usable data
(1) 2.6 (2) 3.0 (6) 1.8
at 6 hr: (1) 82 (2) 81 (6) 97
75
(Continued)
400 mg, n=32 (6) Placebo, n= 34 Forbes 1994 (1) Paraceta- TOTPAR 6: mol+codeine (1) 6.6 300/30 mg, n= (3) 3.4 93 (2) Paracetamol+hydrocodone bitartrate 500/7. 5 mg, n=94 (3) Placebo, n= 45 (1) Paraceta- TOTPAR 5: mol+codeine (1) 11.5 1000/60 mg, n= (2) 10.2 45 (2) Paracetamol 1000 mg, n=45 (1) Paraceta- TOTPAR 6: mol+codeine (1) 5.5 300/30 mg, n= (3) 3.3 40 (2) Ibuprofen 400 mg, n=40 (3) Placebo, n= 40 (1) Paracetamol+codeine 600/60 mg, n= 30 (2) Paracet 600 mg, n=28 (3) Codeine 60 mg, n=28 (4) Placebo, n= 30 TOTPAR 6: (1) 10.6 (2) 8.9 (4) 5.9 (1) 23/93 (3) 3/45 No usable data Mean: (1) 3.9 (3) 3.4 at 6 hr: (1) 77 (3) 87
Gertzbein 1986
(1) 30/45 (2) 25/45
No usable data
Mean: (1) 3.8 (2) 3.6
No data
Heidrich 1985
(1) 8/40 (3) 3/40
No data
Mean: (1) 4.7 (3) 3.5
(1) 85 (3) 90
Honig 1984
(1) 14/30 (2) 11/28 (4) 6/30
(1) 12/30 (2) 8/28 (4) 4/30
No data
at 6 hr: (1) 33 (2) 43 (4) 53
Malmstrom 2004
(1) Paraceta- TOTPAR 6: mol+codeine (1) 9.2 600/60 mg, n= (4) 4.2 50 (2) Etoricoxib 120 mg, n=50 (3) Naproxen sodium 550 mg,
(1) 20/50 (4) 6/50
at 8 hr: (1) 24/50 (4) 7/50
(1) 3.6 (4) 1.6
at 24 hr: (1) 76 (4) 99
76
(Continued)
n=50 (4) Placebo, n= 50 Pande 1996a (1) Paracetamol+codeine 600/60 mg, n= 23 (2) Placebo, n= 26 SPID 6: (1) 3.1 (2) 0 Baseline PI: 2.5 (1) 6/23 (2) 0/26 No usable data No data No data
Smith 2004
1)ParacetaSPID 4: mol+codeine (1) 2.7 300/30 mg, n= (3) 2.0 109 2) Paracetamol+tramadol 325/37.5 mg, n= 98 3) Placebo n=98 (1) Paracetamol+codeine 1000/60 mg, n= 36 (2) Tramadol 50 mg, n=33 (3) Tramadol 100 mg, n=35 (4) Placebo, n= 33 (1) Paracetamol+codeine 650/60 mg, n= 31 (2) Paracetamol 650 mg, n=30 (3) Flurbiprofen 50 mg, n=31 (4) Flurbiprofen 100 mg, n=29 (5) Zomepirac 100 mg, n=31 (6) Placebo, n= 30 VAS SPID 6: (1) 204 (4) 17 Baseline PI: (1) 67 (4) 66
(1) 43/109 (3) 27/98
No usable data
No data
at 4 hr: (1) 26 (3) 40
Stubhaug 1995
(1) 21/36 (4) 1/33
No usable data
(1) >6 (4) 2.8
at 6 hr: (1) 36 (4) 82
Sunshine 1986
TOTPAR 6: (1) 13.4 (2) 11.1 (6) 8.3
(1) 19/31 (2) 15/30 (6) 10/30
No usable data
No data
at 6 hr: (1) 30 (2) 47 (6) 43
Turek 1988
(1) Paraceta- TOTPAR 6: mol+codeine (1) 8.1 650/60 mg, n= (4) 4.6
(1) 14/39 (4) 8/41
No usable data
Mean: (1) 3.5
at 6 hr: (1) 67
77
(Continued)
39 (2) Ketoprofen 50 mg, n=41 (3) Ketoprofen 150 mg, n=39 (4) Placebo, n= 41 Ziccardi 2000 (1) Paraceta- TOTPAR 6: mol+codeine (1) 9.8 300/30 mg, n= (3) 3.5 49 (2) Ibuprofen+hydrocodone 200/75 mg, n= 49 (3) Placebo, n= 27 (1) 21/49 (3) 2/27 No usable data
(4) 2.2
(4) 83
(1) 3.0 (3) 1.0
No data
Table 2. Summary of outcomes - adverse events and withdrawals
Adverse events Study ID Bentley 1987 Treatment Any Serious No data
Withdrawals Adverse event None reported Other 1 pt lost to follow up, 4 had invalid data
(1) Paraceta- (1) 15/42 mol+codeine 1000/ (2) 21/42 60 mg, n=41 (4) 9/19 (2) Paracetamol 1000 mg, n=41 (3) Codeine 60 mg, n=21 (4) Placebo, n=17 (1) Paraceta- (1) 10/50 mol+codeine 800/ (2) 10/50 60 mg, n=50 (3) 1/25 (2) Paracetamol 1000 mg, n=50 (3) Placebo, n=25 (1) Paraceta- No single dose data mol+codeine 300/ 30 mg, n = 55 (2) Paracetamol+tramadol 325/ 37.5 mg, n = 49 (3) Placebo, n = 49
Bjune 1996
None
None reported
6 paracetamol+codeine pts, 7 paracetamol pts, 4 placebo pts had invalid data
Bourne 2005
No single dose data
No single dose data
None
78
(Continued)
Breivik 1999
(1) Paraceta- (1) 13/23 mol+codeine 1000/ (2) 3/24 60 mg n=24 (2) Paracetamol 1000mg, n=22 (3) Diclofenac 100 mg, n=22 (4) Paracetamol+diclofenac 1000/100 mg, n=24 (5) Paracetamol+diclofenac+codeine 1000/100/60 mg, n=24 (1) Paraceta- At 24 hr: mol+codeine 600/ (1) 83/180 60 mg n=180 (2) 10/31 (2) Rofecoxib 50 mg n=182 (3) Placebo n=31 (1) Paraceta- At 24 hr: mol+codeine 600/ (1) 63/180 60 mg n=180 (3) 14/30 (2) Rofecoxib 50 mg n=180 (3) Placebo n=30 (1) Paracet+codeine (1) 10/42 650/60 mg, n=42 (2) 12/37 (2) Paracetamol 650 (5) 4/37 mg, n=37 (3) Paracetamol+dpropoxyphene 650/ 100 mg, n=42 (4) Ibuprofen 200 mg, n=42 (5) Placebo, n=37
None
None
1 pt in paracetamol+codeine group lost to follow up, 4 pts (2 paracetamol, 2 diclofenac) had invalid data
Chang 2001
None
None
6 pts lost to follow up, 1 para/codeine group vomited medication
Chang 2005
None
None
1 rofecoxib pt lost to follow up
Cooper 1981
None
None
31 pts had invalid data
Cooper 1988
(1) Paraceta- 15 None mol+codeine 600/ pts in total reported 60 mg, n=31 adverse events (2) Paracetamol 600 mg, n=36 (3) Meclofenamate Na 100 mg, n=36 (4) Placebo, n=40
None
11 pts lost to follow up, 3 had invalid data
79
(Continued)
Cooper 1991
(1) Paraceta- (1) 8/39 mol+codeine 650/ (2) 6/37 60 mg, n=39 (6) 7/44 (2) Paracetamol 650 mg, n=37 (3) Zomepirac 100 mg, n=23 (4) Flurbiprofen 50 mg, n=42 (5) Flurbiprofen 100 mg, n=41 (6) Placebo, n=44 (1) Paraceta- (1) 2/39 mol+codeine 300/ (3) 4/41 30 mg, n=39 (2) Aspirin+butalbital+caffeine+codeine 325/50/40/30 mg, n=43 (3) Placebo, n=41 (1) Paraceta- (1) 9/24 mol+codeine 650/ (2) 7/27 60 mg, n=24 (5) 5/25 (2) Paracetamol 650 mg, n=27 (3) Flurbiprofen 50 mg, n=25 (4) Flurbiprofen 100 mg, n=22 (5) Placebo, n=25
None
None reported
3 lost to follow up, 5 had invalid data
Desjardins 1986
None
None
14 pts did not medicate, lost to follow up, invalid data
Dionne 1994
None
None reported
Forbes 1982
(1) Paraceta- 15% None mol+codeine 600/ in total reported ad60 mg, n=31 verse events (2) Paracetamol 600 mg, n=34 (3) Diusinal 500 mg, n=32 (4) Diusinal 1000 mg, n=32 (5) Placebo, n=30 (1) Paraceta- (1) 11/26 mol+codeine 600/ (2) 11/26 60 mg, n=26 (5) 4/26 (2) Paracetamol 600 mg, n=26 None reported
None
Forbes 1983
None
None
80
(Continued)
(3) Diusinal 500 mg, n=26 (4) Diusinal 1000 mg, n=28 (5) Placebo, n=26 Forbes 1986 (1) Paraceta- (1) 6/46 mol+codeine 300/ (2) 9/46 30 mg, n=43 (2) Aspirin+butalbital+caffeine+codeine 325/50/40/15 mg, n=41 (3) Placebo, n=38 (1) Paraceta- (1) 1/17 mol+codeine 600/ (2) 3/26 60 mg, n=17 (4) 2/26 (2) Paracetamol 600 mg, n=22 (3) Flurbiprofen 100 mg, n=26 (4) Placebo, n=23 (1) Paraceta- (1) 9/31 mol+codeine 600/ (4) 5/34 60 mg, n=27 (2) Aspirin 650 mg, n=32 (3) Ketorolac 10 mg, n=37 (4) Placebo, n=32 (1) Paraceta- (1) 8/40 mol+codeine 600/ (2) 5/41 60 mg, n=38 (6) 0/38 (2) Paracetamol 600 mg, n=36 (3) Ketorolac 10 mg, n=31 (4) Ketorolac 20 mg, n=35 (5) Ibuprofen 400 mg, n=32 (6) Placebo, n=34 (1) Paraceta- (1) 18/107 mol+codeine 300/ (3) 10/65 30 mg, n=93 None None 1 pt lost to follow up, 17 had invalid data
Forbes 1989
None
None
Forbes 1990a
None
None
1 lost to follow up, 14 had invalid data
Forbes 1990b
None
None
Forbes 1994
None
None
1 pt lost to follow up, 59 had invalid data
81
(Continued)
(2) Paracetamol+hydrocodone bitartrate 500/7.5 mg, n=94 (3) Placebo, n=45 Gertzbein 1986 (1) Paraceta- (1) 13/47 mol+codeine 1000/ (2) 13/46 60 mg, n=45 (2) Paracetamol 1000 mg, n=45 None None 1 pt withdrew consent, 2 pts had invalid data (2 paracetamol+codeine group, 1 paracetamol group) No data
Heidrich 1985
(1) Paraceta- No sig diff between No data mol+codeine 300/ groups 30 mg, n=40 (2) Ibuprofen 400 mg, n=40 (3) Placebo, n=40 (1) Paraceta- No data mol+codeine 600/ 60 mg, n=30 (2) Paracetamol 600 mg, n=28 (3) Codeine 60 mg, n=28 (4) Placebo, n = 30 (1) Paraceta- Within 10 days: mol+codeine 600/ (1) 25/50 60 mg, n=50 (4) 18/50 (2) Etoricoxib 120 mg, n=50 (3) Naproxen sodium 550 mg, n= 50 (4) Placebo, n=50 (1) Paraceta- no data mol+codeine 600/ 60 mg, n=23 (2) Placebo, n=26 (1)ParacetaNo single dose data mol+codeine 300/ 30 mg, n = 109 (2) Paracetamol+tramadol 325/ None reported
None
Honig 1984
None reported
None reported
Malmstrom 2004
None
None
4 pts lost to follow up (2 paracetamol+codeine group, 1 placebo group)
Pande 1996a
None
None reported
None reported
Smith 2004
No single dose data
No single dose data
1 pt had invalid data
82
(Continued)
37.5 mg, n = 98 (3) Placebo n = 98 Stubhaug 1995 (1) Paraceta- (1) 10/37 mol+codeine 1000/ (2) 15/36 60 mg, n=36 (2) Tramadol 50 mg, n=33 (3) Tramadol 100 mg, n=35 (4) Placebo, n=33 (1) Paraceta- (1) 3/31 mol+codeine 650/ (2) 1/30 60 mg, n=31 (6) 1/30 (2) Paracetamol 650 mg, n=30 (3) Flurbiprofen 50 mg, n=31 (4) Flurbiprofen 100 mg, n=29 (5) Zomepirac 100 mg, n=31 (6) Placebo, n=30 (1) Paraceta- (1) 11/39 mol+codeine 650/ (4) 4/41 60 mg, n=39 (2) Ketoprofen 50 mg, n=41 (3) Ketoprofen 150 mg, n=39 (4) Placebo, n=41 (1) Paraceta- (1) 21/49 mol+codeine 300/ (3) 6/27 30 mg, n=49 (2) Ibuprofen+hydrocodone 200/75 mg, n=49 (3) Placebo, n= 27 None None reported 7 pts had invalid data
Sunshine 1986
None
None reported
None
Turek 1988
None
None
1 placebo pt had invalid data
Ziccardi 2000
None
No data
None reported
83
APPENDICES Appendix 1. MEDLINE search strategy

1. acetaminophen [single term MESH] AND codeine [single term MESH] 2. (acetaminophen OR paracetamol) AND codeine 3. OR/1-2 4. PAIN, POSTOPERATIVE [single term MeSH] 5. ((postoperative adj4 pain$) or (post-operative adj4 pain$) or post-operative-pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post-operative adj4 analgesi$) or (post-operative analgesi$)) [in title, abstract or keywords] 6. ((post-surgical adj4 pain$) or (post surgical adj4 pain$) or (post-surgery adj4 pain$))[in title, abstract or keywords] 7. ((pain-relief after surg$) or (pain following surg$) or (pain control after)) [in title, abstract or keywords] 8. ((post surg$ or post-surg$) AND (pain$ or discomfort)) [in title, abstract or keywords] 9. ((pain$ adj4 after surg$) or (pain$ adj4 after operat$) or (pain$ adj4 follow$ operat$) or (pain$ adj4 follow$ surg$))[in title, abstract or keywords] 10. ((analgesi$ adj4 after surg$) or (analgesi$ adj4 after operat$) or (analgesi$ adj4 follow$ operat$) or (analgesi$ adj4 follow$ surg$)) 11. OR/4-10 12. randomized controlled trial.pt. 13. controlled clinical trial.pt. 14. randomized controlled trials.sh. 15. random allocation.sh. 16. double-blind method.sh. 17. clinical trial.pt. 18. exp clinical trials/ 19. (clin$ adj25 trial$) [in title, abstract or keywords] 20. ((doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)) [in title, abstract or keywords] 21. placebos.sh. 22. placebo$ [in title, abstract or keywords] 23. random$ [in title, abstract or keywords] 24. research design.sh. 25. OR/12-24 26. 3 AND 11 AND 25
Appendix 2. EMBASE search strategy

1. acetaminophen [single term MESH] AND codeine [single term MESH] 2. (acetaminophen OR paracetamol) AND codeine 3. OR/1-2 4. PAIN, POSTOPERATIVE [single term MeSH] 5. ((postoperative adj4 pain$) or (post-operative adj4 pain$) or post-operative-pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post-operative adj4 analgesi$) or (post-operative analgesi$)) 6. ((post-surgical adj4 pain$) or (post surgical adj4 pain$) or (post-surgery adj4 pain$)) 7. ((pain-relief after surg$) or (pain following surg$) or (pain control after)) 8. ((post surg$ or post-surg$) AND (pain$ or discomfort)) 9. ((pain$ adj4 after surg$) or (pain$ adj4 after operat$) or (pain$ adj4 follow$ operat$) or (pain$ adj4 follow$ surg$)) 10. ((analgesi$ adj4 after surg$) or (analgesi$ adj4 after operat$) or (analgesi$ adj4 follow$ operat$) or (analgesi$ adj4 follow$ surg$)) 11. OR/4-10 12. clinical trials [exp MESH term] 13. controlled clinical trials [exp MESH term] 14. randomized controlled trial [exp MESH term] 15. double-blind procedure [single term MESH]
16. (clin$ adj25 trial$) 17. ((doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)) 18. placebo$ 19. random$ 20. OR/12-19 21. 3 AND 11 AND 20
Appendix 3. Cochrane search strategy

1. acetaminophen [single term MESH] AND codeine [single term MESH] 2. (acetaminophen OR paracetamol) AND codeine [ti, ab, kw] 3. OR/1-2 4. PAIN, POSTOPERATIVE [single term MeSH] 5. ((postoperative adj4 pain$) or (post-operative adj4 pain$) or post-operative-pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post-operative adj4 analgesi$) or (post-operative analgesi$)) [ti, ab, kw] 6. ((post-surgical adj4 pain$) or (post surgical adj4 pain$) or (post-surgery adj4 pain$)) [ti, ab, kw] 7. ((pain-relief after surg$) or (pain following surg$) or (pain control after)) [ti, ab, kw] 8. ((post surg$ or post-surg$) AND (pain$ or discomfort)) [ti, ab, kw] 9. ((pain$ adj4 after surg$) or (pain$ adj4 after operat$) or (pain$ adj4 follow$ operat$) or (pain$ adj4 follow$ surg$)) [ti, ab, kw] 10. ((analgesi$ adj4 after surg$) or (analgesi$ adj4 after operat$) or (analgesi$ adj4 follow$ operat$) or (analgesi$ adj4 follow$ surg$)) [ti, ab, kw] 11. OR/4-10 12. clinical trials [exp MESH term] 13. controlled clinical trials [exp MESH term] 14. randomized controlled trial [exp MESH term] 15. double-blind procedure [single term MESH] 16. (clin$ adj25 trial$) [ti, ab, kw] 17. ((doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)) [ti, ab, kw] 18. placebo$ [ti, ab, kw] 19. random$ [ti, ab, kw] 20. OR/12-19 21. 3 AND 11 AND 20
Appendix 4. Glossary
Categorical rating scale: The commonest is the ve category scale (none, slight, moderate, good or lots, and complete). For analysis numbers are given to the verbal categories (for pain intensity, none=0, mild=1, moderate=2 and severe=3, and for relief none=0, slight=1, moderate=2, good or lots=3 and complete=4). Data from different subjects is then combined to produce means (rarely medians) and measures of dispersion (usually standard errors of means). The validity of converting categories into numerical scores was checked by comparison with concurrent visual analogue scale measurements. Good correlation was found, especially between pain relief scales using crossmodality matching techniques. Results are usually reported as continuous data, mean or median pain relief or intensity. Few studies present results as discrete data, giving the number of participants who report a certain level of pain intensity or relief at any given assessment point. The main advantages of the categorical scales are that they are quick and simple. The small number of descriptors may force the scorer to choose a particular category when none describes the pain satisfactorily.
VAS:
Visual analogue scale: lines with left end labelled no relief of pain and right end labelled complete relief of pain, seem to overcome this limitation. Patients mark the line at the point which corresponds to their pain. The scores are obtained by measuring the distance between the no relief end and the patients mark, usually in millimetres. The main advantages of VAS are that they are simple and quick to score, avoid imprecise descriptive terms and provide many points from which to choose. More concentration and coordination are needed, which can be difcult post-operatively or with neurological disorders. TOTPAR: Total pain relief (TOTPAR) is calculated as the sum of pain relief scores over a period of time. If a patient had complete pain relief immediately after taking an analgesic, and maintained that level of pain relief for six hours, they would have a six-hour TOTPAR of the maximum of 24. Differences between pain relief values at the start and end of a measurement period are dealt with by the composite trapezoidal rule. The trapezoidal rule is a simple method that approximately calculates the denite integral of the area under the pain relief curve by calculating the sum of the areas of several trapezoids that together closely approximate to the area under the curve. SPID: Summed pain intensity difference (SPID) is calculated as the sum of the differences between the pain scores over a period of time. Differences between pain intensity values at the start and end of a measurement period are dealt with by the trapezoidal rule. VAS TOTPAR and VAS SPID are visual analogue versions of TOTPAR and SPID. See Measuring pain in Bandoliers Little Book of Pain, Oxford University Press, Oxford. 2003; pp 7-13.1 (Moore 2003)
WHATS NEW
Last assessed as up-to-date: 14 September 2011.
Date 15 September 2011
Event Review declared as stable
Description The authors of this review ran a quick search in April 2011 and agreed that this review would not need updating for at least ve years
HISTORY
Protocol rst published: Issue 4, 1998 Review rst published: Issue 4, 1998
Date 13 May 2009 29 August 2008
Event Amended
Description Contact details updated.
New citation required but conclusions have not changed Analysis completed. Similar results. New analyses for use of rescue medication New search has been performed New studies added. For paracetamol plus codeine versus placebo, six new studies (908 participants, 65% more) were included and six new and two old studies were
22 August 2008
86
(Continued)
excluded For paracetamol plus codeine versus paracetamol alone, two new studies (132 participants, 14% more) were included and six new studies were excluded Some references previously included in this review have also now been removed as they relate to when this review was joined with the Single dose oral paracetamol (acetaminophen) for postoperative pain in adults review 23 May 2008 25 January 2002 Amended Amended Converted to new review format. New studies found but not yet included or excluded
CONTRIBUTIONS OF AUTHORS
LT and SD identied studies for inclusion in this update and carried out data extraction, analysis and writing. RAM was involved with planning, analysis and writing, and acted as arbitrator. HJM was involved in planning and writing.
DECLARATIONS OF INTEREST
LT has no interests to declare. RAM and HJM have consulted for various pharmaceutical companies. RAM and HJM and have received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. SD, RAM and HJM have received research support from charities, government and industry sources at various times: no support other than the declared nancial support was received for this work.
SOURCES OF SUPPORT Internal sources

Oxford Pain Research Funds, UK.
External sources
NHS Cochrane Collaboration Programme Grant Scheme, UK. Funding European Union Biomed 2 Grant no. BMH4 CT95 0172, UK.
87
NOTES
This review is an update of a previous review of single dose paracetamol and codeine in postoperative pain. Originally paracetamol plus codeine was part of a larger review that included paracetamol alone, published in 1998. The original review was split into two components and both have been updated in 2008.
INDEX TERMS Medical Subject Headings (MeSH)

Acetaminophen [ administration & dosage; adverse effects]; Administration, Oral; Analgesics, Non-Narcotic [ administration & dosage; adverse effects]; Analgesics, Opioid [ administration & dosage; adverse effects]; Codeine [ administration & dosage]; Drug Therapy, Combination; Pain, Postoperative [ drug therapy]
MeSH check words

Adult; Humans
88

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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

Paracetamol with codeine

Criteria for considering studies for this review

Search methods for identication of studies

Language No language restriction was applied.

Data collection and analysis

Paracetamol with codeine versus paracetamol

Dose Included studies

Paracetamol with codeine versus placebo

Paracetamol with codeine versus placebo

Paracetamol with codeine versus paracetamol

Paracetamol with codeine versus paracetamol

Risk of bias in included studies

Paracetamol with codeine versus placebo

Paracetamol with codeine versus placebo

Paracetamol with codeine versus paracetamol

Paracetamol with codeine versus paracetamol

Number of participants achieving at least 50% pain relief

Paracetamol with codeine versus placebo

Paracetamol with codeine versus placebo

2.2 (1.8 to 2.9) 3.9 (3.3 to 4.7)

6.9 (4.8 to 12)

Paracetamol with codeine versus paracetamol

800-1000/60 1000/60 600-650/60

304 217 622

6.1 (3.6 to 19) 5.1 (3.1 to 15) 8.2 (5.0 to 23)

Paracetamol with codeine versus placebo

3.9 (3.3 to 4.8)

3.7 (2.5 to 7.2)

5.4 (3.7 to 9.7) 7.9 (4.6 to 27)

300/60 mg other 3 surgical

Paracetamol with codeine versus paracetamol

7.1 (4.1 to 150)

6.4 (4.3 to 13)

Use of rescue medication

Number of participants using rescue medication over 4 to 6 hours

Paracetamol with codeine versus placebo

657 529 Participants

5.6 (4.0 to 9.0) not calculated NNTp

Paracetamol + codeine Paracetamol (%) (%) 50 65

6.9 (4.2 to 19)

Time to use of rescue medication

Paracetamol with codeine versus placebo

hours when treated with placebo.

Paracetamol with codeine versus paracetamol

Paracetamol with codeine versus paracetamol

All doses 800-1000/60 mg 600-650/60 mg 300/30 mg

1811 209 1187 344

AUTHORS CONCLUSIONS Implications for practice

Implications for research

References to studies included in this review

References to studies excluded from this review

References to other published versions of this review

Characteristics of included studies [ordered by study ID]

Oxford Quality Score: R1, DB1, W0

Characteristics of excluded studies [ordered by study ID]

Study Becker 1990 Behotas 1992

Chung 2004 Cooper 1984

Maalaki 2002 Macleod 2002

Petti 1985 Quiding 1982a

Vangen 1988 Wittenberg 1984

DATA AND ANALYSES

Comparison 1. Paracetamol 800 to 1000 mg plus codeine 60 mg versus placebo