Mkontwana Et Al-2015-Cochrane Database of Systematic Reviews

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Oral analgesia for relieving post-caesarean pain (Review)
Mkontwana N, Novikova N
Mkontwana N, Novikova N.
Oral analgesia for relieving post-caesarean pain.
Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010450.
DOI: 10.1002/14651858.CD010450.pub2.
www.cochranelibrary.com

Oral analgesia for relieving post-caesarean pain (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
BACKGROUND.............................................................................................................................................................................................. 4
OBJECTIVES.................................................................................................................................................................................................. 5
METHODS..................................................................................................................................................................................................... 5
RESULTS........................................................................................................................................................................................................ 8
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 11
Figure 3.................................................................................................................................................................................................. 12
DISCUSSION.................................................................................................................................................................................................. 15
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 16
ACKNOWLEDGEMENTS................................................................................................................................................................................ 16
REFERENCES................................................................................................................................................................................................ 17
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 21
DATA AND ANALYSES.................................................................................................................................................................................... 36
Analysis 1.1. Comparison 1 Opioid versus placebo, Outcome 1 Need for additional pain relief with a different drug.................... 36
Analysis 1.2. Comparison 1 Opioid versus placebo, Outcome 2 Adverse drug effects...................................................................... 37
Analysis 2.1. Comparison 2 Non-opioid analgesics versus placebo, Outcome 1 Need for additional pain relief............................. 37
Analysis 2.2. Comparison 2 Non-opioid analgesics versus placebo, Outcome 2 Maternal drug effects........................................... 39
Analysis 3.1. Comparison 3 Combination versus placebo, Outcome 1 Need for additional pain relief........................................... 39
Analysis 3.2. Comparison 3 Combination versus placebo, Outcome 2 Maternal drug effects.......................................................... 40
Analysis 4.1. Comparison 4 Opioid versus non-opioid, Outcome 1 Need for additional pain relief with a different drug............... 41
Analysis 4.2. Comparison 4 Opioid versus non-opioid, Outcome 2 Maternal adverse effects.......................................................... 41
Analysis 5.1. Comparison 5 Opioid analgesics versus combination analgesics, Outcome 1 Need for additional pain relief........... 41
Analysis 5.2. Comparison 5 Opioid analgesics versus combination analgesics, Outcome 2 Maternal adverse effects................... 42
Analysis 6.1. Comparison 6 Non-opioid versus combination analgesics, Outcome 1 Need for additional pain relief with a 42
different drug........................................................................................................................................................................................
Analysis 7.1. Comparison 7 Non-opioid analgesics versus placebo (subgroup analysis by high and low doses of the same drug), 43
Outcome 1 Need for additional pain relief..........................................................................................................................................
Analysis 8.1. Comparison 8 Opioid analgesics versus placebo (subgroup analysis by high and low doses of the same drug), 44
Outcome 1 Need for additional pain relief..........................................................................................................................................
WHAT'S NEW................................................................................................................................................................................................. 44
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 44
DECLARATIONS OF INTEREST..................................................................................................................................................................... 44
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 45
INDEX TERMS............................................................................................................................................................................................... 45
Oral analgesia for relieving post-caesarean pain (Review) i

Informed decisions.

[Intervention Review]
Oral analgesia for relieving post-caesarean pain
Nondumiso Mkontwana1, Natalia Novikova1
1Department of Obstetrics and Gynaecology, East London Hospital Complex, Walter Sisulu University, East London, South Africa
Contact address: Nondumiso Mkontwana, Department of Obstetrics and Gynaecology, East London Hospital Complex, Walter Sisulu
University, East London, Eastern Cape, 5200, South Africa. ndumy.ngxola@gmail.com.
Editorial group: Cochrane Pregnancy and Childbirth Group

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2015.
Citation: Mkontwana N, Novikova N. Oral analgesia for relieving post-caesarean pain. Cochrane Database of Systematic Reviews 2015,
Issue 3. Art. No.: CD010450. DOI: 10.1002/14651858.CD010450.pub2.
ABSTRACT
Background
Oral analgesia is a convenient and widely used form of pain relief following caesarean section. It includes various medications used at
different doses alone or in adjunction to other form of analgesia.
Objectives
To determine the effectiveness, safety and cost-effectiveness of oral analgesia for post-caesarean pain relief.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014) and reference lists of retrieved studies.
Selection criteria
Randomised controlled trials (RCTs). Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and
cross-over trials were not eligible for inclusion.
Interventions included oral medication given to women for post-caesarean pain relief compared with oral medication, or placebo/no
treatment.
Data collection and analysis

Two review authors independently assessed for inclusion all the potential studies and independently assessed trial quality, extracted the
data using the agreed data extraction form, and checked them for accuracy.
Main results
Eight small trials involving 962 women (out of 13 included trials) contributed data to the analysis, of which only four trials had low risk
of bias.
None of the included studies reported on 'adequate pain relief', which is one of this review's primary outcomes.
1. Opiod analgesics versus placebo
Based on one trial involving 120 women, the effect of opioids versus placebo was not significant in relation to the need for additional pain
relief (primary outcome) (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.06 to 1.92), and the effect in terms of adverse drug effects
outcomes was also uncertain (RR 6.58, 95% CI 0.38 to 113.96).
Oral analgesia for relieving post-caesarean pain (Review) 1

Informed decisions.

Low (75 mg) and high (150 mg) doses of tramadol had a similar effect on the need for additional pain relief (RR 0.67, 95% CI 0.12 to 3.78
and RR 0.14, 95% CI 0.01 to 2.68, respectively, one study, 80 women).
2. Non-opioid analgesia versus placebo
The confidence interval for the lower requirement for additional analgesia (primary outcome) with the non-opioid analgesia group was
wide and includes little or no effect (average RR 0.70, 95% CI 0.48 to 1.01, six studies, 584 women). However, we observed substantial
heterogeneity due to the variety of non-opioid drugs used (I2 = 85%). In a subgroup analysis of different drugs, only gabapentin use resulted
in less need for additional pain relief (RR 0.34, 95% CI 0.23 to 0.51, one trial, 126 women). There was no difference in need for additional
pain relief with the use of celexocib, ibuprofen, ketoprofen, naproxen, paracetamol. Maternal drug effects were more common with the use
of non-opioid analgesics (RR 11.12, 95% CI 2.13 to 58.22, two trials, 267 women).
Gabapentin 300 mg (RR 0.25, 95% CI 0.13 to 0.49, one study, 63 women) and 600 mg (RR 0.44, 95% CI 0.27 to 0.71, one study, 63 women)
as well as ketoprofen 100 mg (RR 0.55, 95% CI 0.39 to 0.79, one study 72 women) were both more effective than placebo with respect to
the need for additional pain relief. However, the 50 mg ketoprofen group and the placebo group did not differ in terms of the number of
women requiring additional pain relief (RR 0.82, 95% CI 0.64 to 1.07, one study, 72 women).
3. Combination analgesics versus placebo
Our pooled analysis for the effect of combination analgesics on the need for additional pain relief was RR 0.70 (95% CI 0.35 to 1.40, three
trials, 242 women, I2 = 69%). When comparing different drugs within the combination oral analgesics versus placebo comparison we
observed subgroup differences (P = 0.05; I2 = 65.8%). One trial comparing paracetamol plus codeine versus placebo resulted in fewer women
requiring additional pain relief (RR 0.44, 95% CI 0.23 to 0.82, one trial, 65 women). However, there were no differences in the the number of
women requiring additional pain relief when comparing paracetamol plus oxycodone versus placebo, or paracetamol plus propoxyphene
(RR 1.00, 95% CI 0.78 to 1.28, one trial, 96 women and RR 0.65, 95% CI 0.11 to 3.69, one trial, 81 women, respectively).
Maternal drug effects were more common in combination analgesics group versus placebo (RR 13.18, 95% CI 2.86 to 60.68, three trials,
252 women).
4. Opioid analgesics versus non-opioid analgesics
The confidence interval for the effect on additional pain relief between opioid and non-opioid drugs was very wide (RR 0.51, 95% CI 0.07
to 3.51, one trial, 121 women). Side effects were more common with the use opioids versus non-opioids analgesics (RR 2.32, 95% CI 1.15
to 4.69, two trials 241 women).
5. Opioid analgesics versus combination analgesics
There was no difference in need for additional pain relief in opioid analgesics versus combination analgesics based on one study involving
121 women comparing tramadol and paracetamol plus propoxyphene (RR 0.51, 95% CI 0.07 to 3.51). Maternal adverse effects also did not
differ between the two groups (RR 6.74, 95% CI 0.39 to 116.79).
6. Non-opioid versus combination analgesics
The need for additional pain relief was greater in the group of women who received non-opoid analgesics (RR 0.87, 95% CI 0.81 to 0.93,
one trial, 192 women) compared with the group of women who received combination analgesics.
Secondary outcomes not reported in the included studies
No data were found on the following secondary outcomes: number of days in hospital post-operatively, re-hospitalisation due to incisional
pain, fully breastfeeding on discharge, mixed feeding at discharge, incisional pain at six weeks after caesarean section, maternal post
partum depression, effect (negative) on mother and baby interaction and cost of treatment.
Authors' conclusions
Eight trials with 962 women were included in the analysis, but only four trials were of high quality. All the trials were small. We carried out
subgroup analysis for different drugs within the same group and for high versus low doses of the same drug. However, the relatively few
studies (one to two trials) and numbers of women (40 to 136) limits the reliability of these subgroup analyses.
Due to limited data available no conclusions can be made regarding the safest and the most effective form of oral analgesia for post-
caesarean pain. Further studies are necessary.
PLAIN LANGUAGE SUMMARY
Pain tablets taken by mouth for post-caesarean pain

Informed decisions.

Tablets are convenient and easy to take to ease the pain after caesarean section, which involves cutting through the abdomen and uterus
to deliver the baby. We aimed to assess the effectiveness, safety and cost-effectiveness of different types of tablets for the pain. Different
types of pain tablets relieve the pain in different ways. Opioids decrease the feeling of pain, decrease reaction to pain as well as increase
pain tolerance by their action on the nervous system. Some non-opioid pain tablets act on the tissues to reduce the response to the
inflammatory substances released at the site of tissue damage. Combination drugs (such as paracetamol and codeine) may have more
pronounced effects because of the different mechanism of action of their components. We do not know how some other tablets, such as
alpha-2 agonists (clonidine) and gabapentin (usually used for nerve pain that follows shingles and long-term pain) relieve pain. Good pain
control may shorten the time spent in hospital after caesarean section, improve satisfaction and reduce healthcare costs.
Searching the literature we found 63 articles assessing post-caesarean pain but only 13 studies met our inclusion criteria, of which only
eight studies (involving 962 women) reported on outcomes that we assessed in this review. Of the eight trials contributing data to our
review, only four trials had low risk of bias. All of the included studies involved small numbers of women (40 to 136 women).
We compared non-opioid, opioid and combination oral tablets with placebo or no treatment. There was insufficient evidence to determine
the effect of additional pain killers (tablets or injections) among women who took opioid or non-opioid or combination pain killers in
comparison to placebo. There was also insufficient evidence to establish the effect of opioid versus non-opioid drugs and opioid versus
combination drugs on requirement for additional pain relief. When assessing different non-opioid drugs individually, we found some
evidence that gabapentin resulted in less need for additional pain relief in comparison to placebo, but the analysis of data for other tablets
(celexocib, ibuprofen, ketoprofen, naproxen, paracetamol) gave more uncertain results. The use of paracetamol plus codeine resulted in
less need for additional pain relief in comparison to placebo. We found that high and low dose of gabapentin, and high dose of ketoprofen
were more effective than placebo in relation to the need for additional pain relief. On the other hand, low dose of ketoprofen as well as
high and low dose of tramadol did not differ with placebo with in effect on the need for additional pain relief. However, it is important
to note that these additional analyses (i.e. different drugs and different doses) are based on relatively few studies (one to two trials) and
numbers of women (40 to 136).
Women developed more side effects including nausea, vomiting and drowsiness with the use of opioid, non-opioid or combination
painkillers in comparison to placebo or no treatment. All trials used additional pain relief as a standard and for breakthrough pain and
they all used different drugs.
No studies reported on the following outcomes: adequate pain relief, number of days in hospital post operatively, re-hospitalisation due
to incisional pain, fully breast feeding on discharge, mixed feeding at discharge, maternal postpartum depression and cost-effectiveness
of the studied interventions.
Due to limited data available no conclusions can be made regarding the safest and the most effective form of oral analgesia for post-
caesarean pain. Further studies are necessary. More research is needed to compare different types of pain killers and in relation to different
outcomes such as safety, efficacy and cost.

Informed decisions.

BACKGROUND Description of the intervention

Caesarean section is a common surgical procedure performed to Oral analgesia is a simple, easy to administer, well-tolerated and
deliver babies through an incision of the abdomen and uterus when cost-effective type of pain relief that is offered to women after
vaginal delivery is contraindicated for maternal or fetal reasons or, caesarean section.
in some cases upon request of the pregnant mother. It can either be
Oral analgesia for post-caesarean pain includes the following (SAMF
done as an emergency or electively. The rate of caesarean section
2012; Solomon 2012).
has been increasing around the world (Delbaere 2012). The rate
of caesarean section differs around the world between 2% in least 1. Opioid analgesics
developed countries and 21% in developed countries and reaching
45.9% in Brazil (Betran 2007; Getahun 2009; Gibbons 2010). In the • Natural opioids (codeine, dihydrocodeine, morphine)
USA, caesarean section rates increased, from 20.7% in 1996 to • Diphenylpropylamine derivatives (dextro propoxyphene,
31.1% in 2006 for women of all ages, race, gestational ages, and in dipipanone)
all states (MacDorman 2008). • Other opioids (tramadol, tilidine)
Caesarean section is associated with more postpartum pain than 2. Non-opioid analgesics
vaginal birth (Kainu 2010) and leads to more acute and chronic
postpartum pain (Ingrid 2006). Postpartum pain has various A. Para-aminophenol derivatives (paracetamol or acetaminophen)
negative consequences including:
B. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs)
• it causes significant discomfort to women, which can lead
• Acetylated salicylates (aspirin or acetylsalicylic acid)
to difficulties in mobility and subsequent problems, such as,
an increased risk of venous thrombosis, and by interfering • Propionic acid (ibuprofen, ketoprofen)
with optimal interaction with the newborn in the immediate • Acetic acids (diclofenac)
postpartum period; • Oxicams (meloxicam)
• shallow breathing and splinting may result in atelectasis and • Fenamates (mefenamic acid)
predispose to pneumonia;
• pain has psychological sequelae (Berghella 2012; DiMatteo C. Alpha-2 agonists (clonidine)
1996);
D. Anti-convulsants (gabapentin)
• it may reduce the ability of the mother to initiate or continue
with breastfeeding effectively (Gadsden 2005). 3. Combination drugs (e.g. paracetamol/codeine, paracetamol/
tramadol, paracetamol/codeine/ibuprofen, etc.)
Effective post-caesarean pain relief is important to avoid the
above-mentioned problems. Different interventions have been Oral analgesics have various side effects. The adverse effects of
proposed for post-caesarean pain relief, e.g. oral, intravenous and these drugs include nausea, vomiting, constipation, diarrhoea,
rectal analgesia with various drugs and various doses, regional drowsiness, respiratory depression, pruritis (itch), rash, fluid
analgesia, transversus abdominis plane block, wound infiltration retention.
and combinations of the above-mentioned interventions (Ismail
2012). How the intervention might work
Different types of oral analgesics have different ways of achieving
The review aimed to compare the effectiveness and safety of
an analgesic (painkiller) effect.
different classes of oral analgesia for post-caesarean pain relief.
Analgesic effects of opioids are due to decreased perception of
Description of the condition pain, decreased reaction to pain as well as increased pain tolerance.
Post-caesarean pain is a result of incisional pain as well as pain Opioids act through binding to specific opioid receptors in the
from the uterus (e.g. uterine contraction after birth). Incisional nervous system and other tissues. Opioids reduce the perception
pain is experienced by women following caesarean section due to of pain by activating pain-inhibitory neurons and inhibiting pain
tissue trauma from surgical incision, dissection and burns or direct transmission neurons (Chahl 1996).
nerve damage from nerve transection, stretching or compression
(Kelly 2001). Tissue trauma causes release of local inflammatory Non-opioid analgesics act by reducing the nocioreceptive response
mediators that can produce augmented sensitivity to stimuli in to the endogenous inflammatory mediators released at the sites
the area surrounding an injury, i.e. hyperalgesia or misperception of tissue damage (Kuo 2006). NSAIDs block cyclo-oxygenase
pain to non-noxious stimuli. The patient senses pain through the (COX), an enzyme responsible for the synthesis of prostaglandins
afferent pathway. Pharmacologic agents target these pathways (Chandrasekharan 2002). Pharmacological inhibition of COX can
(Woolf 1993). provide relief from symptoms of inflammation and pain by
inhibition of prostaglandin synthesis.
Pain varies in intensity and the onset of the post-operative pain
depends on form of anaesthesia used during the procedure. This Combination drugs (e.g. paracetamol/codeine, paracetamol/
pain almost always requires some form of analgesia (Kodali 2012). ibuprofen) exhibit enhanced effects due to the different mechanism
of action of their components (SAMF 2012).
The exact mechanism of analgesic effect of alpha-2 agonists is

unknown, though the release of acetylcholine may play a role
Informed decisions.

(Gordh 1989; Kodali 2012). There are reports suggesting that 5. opioid analgesics versus combination analgesics;
alpha-2 agonists such as clonidine and dexmedetomidine have a 6. non-opioid analgesics versus combination analgesics.
potent analgesic response, and that their potency is increased by
concomitant opioid therapy (Kodali 2012). Alpha-2 agonists have Types of outcome measures
been reported to decrease post-operative pain (Hidalgo 2005; Sung
We assessed outcomes developed in the Cochrane generic protocol
2000).
on drugs for perineal pain in the early postpartum period (Chou
Anticonvulsant agents such as gabapentin are gamma- 2009).
aminobutyric acid analogues and have also been reported to have
Primary outcomes
analgesic effects as well as opioid-sparing effects (Kodali 2012).
Although the main use of anticonvulsants is for chronic pain, there 1. Adequate pain relief as reported by the woman, or by
are reports supporting their adjunctive role in post-operative pain determination of more than 50% relief of pain (as either stated
(Mathiesen 2007; Moore 2009). by the woman or calculated using a formula)*.
2. Need for additional pain relief with a different drug.
Why it is important to do this review
Secondary outcomes
Many drugs with various mechanisms of action are used for
post-caesarean pain relief. Although the response to pain relief 1. Maternal drug adverse effects, e.g. nausea, vomiting, sedation,
is sometimes believed to be individual, it is very important to constipation, diarrhoea, drowsy, sleepy, psychological impact.
establish the most effective with the least adverse effects type of 2. Number of days in the hospital post-operatively.
oral analgesia for women after caesarean section.
3. Rehospitalisation due to incisional pain.
Optimal pain control post-caesarean section will benefit not only 4. Fully breastfeeding at discharge.
the mother and her baby, but also a healthcare system. Optimal 5. Mixed feeding at discharge.
pain control may shorten the time spent in hospital after caesarean 6. Incisional pain at six weeks after caesarean section.
section and, therefore, reduce healthcare costs (Shang 2003).
7. Maternal postpartum depression.
OBJECTIVES 8. Effect (negative) on mother and baby interaction.
9. Cost of treatment.
To determine the effectiveness (adequate pain relief as reported by
the woman, or by determination of more than 50% relief of pain * Assessment of 50% pain relief via SPID (summed pain intensity
(either stated by the woman or calculated using a formula), or the difference) scores (1.23 x SPID %max - 2.3 = proportion with 50%)
need for additional pain relief with a different drug, re-admission (Cooper 1991; Moore 1967; Moore 1967a).
due to incisional pain, incisional pain at six weeks after surgery),
safety (e.g. adverse effects of drugs, effect on breastfeeding, Search methods for identification of studies
depression, mother and child interaction) and cost-effectiveness of The following methods section of this review is based on a standard
oral analgesics for relieving post-caesarean pain. template used by the Cochrane Pregnancy and Childbirth Group.
METHODS Electronic searches
Criteria for considering studies for this review We contacted the Trials Search Co-ordinator to search the Cochrane
Pregnancy and Childbirth Group’s Trials Register (31 July 2014).
Types of studies
The Cochrane Pregnancy and Childbirth Group’s Trials Register is
We included randomised controlled trials (RCTs). Cluster-
maintained by the Trials Search Co-ordinator and contains trials
randomised trials were eligible for inclusion but none were
identified from:
identified. Quasi-randomised and cross-over trials were not eligible
for inclusion. 1. monthly searches of the Cochrane Central Register of Controlled
Trials (CENTRAL);
Types of participants
2. weekly searches of MEDLINE (Ovid);
All women requiring pain relief in the early postpartum period 3. weekly searches of Embase (Ovid);
following caesarean section.
4. handsearches of 30 journals and the proceedings of major
Types of interventions conferences;
5. weekly current awareness alerts for a further 44 journals plus
Interventions included oral medication given to women for post-
monthly BioMed Central email alerts.
caesarean pain relief.
Details of the search strategies for CENTRAL, MEDLINE and Embase,
The comparisons are:
the list of handsearched journals and conference proceedings, and
1. opioid analgesics versus placebo/no drug treatment; the list of journals reviewed via the current awareness service can
be found in the ‘Specialized Register’ section within the editorial
2. non-opioid analgesics versus placebo/no drug treatment;
information about the Cochrane Pregnancy and Childbirth Group.
3. combination drugs verus placebo/no drug treatment;
4. opioid analgesics versus non-opioid analgesics; Trials identified through the searching activities described above
are each assigned to a review topic (or topics). The Trials Search Co-
Informed decisions.

ordinator searches the register for each review using the topic list We assessed the methods as:
rather than keywords.
• low risk of bias (e.g. telephone or central randomisation;
Searching other resources consecutively numbered sealed opaque envelopes);
We searched reference lists of retrieved studies. • high risk of bias (open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth);
We did not apply any language or date restrictions. • unclear risk of bias.
Data collection and analysis (3.1) Blinding of participants and personnel (checking for
possible performance bias)
The following methods section of this review is based on a standard
template used by the Cochrane Pregnancy and Childbirth Group. We described for each included study the methods used, if any, to
blind study participants and personnel from knowledge of which
Selection of studies intervention a participant received. We considered that studies
Two review authors independently assessed for inclusion all the were at low risk of bias if they were blinded, or if we judged that
potential studies we identify as a result of the search strategy. We the lack of blinding would be unlikely to affect results. We assessed
resolved any disagreement through discussion or, if required, we blinding separately for different outcomes or classes of outcomes.
consulted a third person.
We assessed the methods as:
Any studies published in an abstract form were included if they
• low, high or unclear risk of bias for participants;
satisfied the inclusion criteria. We contacted the authors of such
studies for additional information if necessary. • low, high or unclear risk of bias for personnel.
Data extraction and management (3.2) Blinding of outcome assessment (checking for possible
detection bias)
We designed a form to extract data. For eligible studies, two
review authors extracted the data using the agreed form. We We described for each included study the methods used, if any, to
resolved discrepancies through discussion (had it been necessary, blind outcome assessors from knowledge of which intervention a
we would have consulted a third person if we were unable to resolve participant received. We assessed blinding separately for different
discrepancies through discussion). We entered data into Review outcomes or classes of outcomes.
Manager software (RevMan 2014) and checked for accuracy. We assessed methods used to blind outcome assessment as:
When information regarding any of the above is unclear, we • low, high or unclear risk of bias.
attempted to contact authors of the original reports to provide
further details. (4) Incomplete outcome data (checking for possible attrition
bias due to the amount, nature and handling of incomplete
Assessment of risk of bias in included studies outcome data)
Two review authors independently assessed risk of bias for each We described for each included study, and for each outcome or
study using the criteria outlined in the Cochrane Handbook for class of outcomes, the completeness of data including attrition
Systematic Reviews of Interventions (Higgins 2011). We resolved any and exclusions from the analysis. We stated whether attrition and
disagreement by discussion or by involving a third assessor. exclusions were reported and the numbers included in the analysis
(1) Random sequence generation (checking for possible at each stage (compared with the total randomised participants),
selection bias) reasons for attrition or exclusion where reported, and whether
missing data were balanced across groups or were related to
We described for each included study the method used to generate outcomes. Where sufficient information was reported, or could
the allocation sequence in sufficient detail to allow an assessment be supplied by the trial authors, we re-included missing data in
of whether it should produce comparable groups. the analyses which we undertook. We excluded the data from the
analysis if more than 20% of data were missing for primary or
We assessed the method as: secondary outcomes.
• low risk of bias (any truly random process, e.g. random number We assessed methods as:
table; computer random number generator);
• high risk of bias (any non-random process, e.g. odd or even date • low risk of bias (e.g. no missing outcome data; missing outcome
of birth; hospital or clinic record number); data balanced across groups);
• unclear risk of bias. • high risk of bias (e.g. numbers or reasons for missing
data imbalanced across groups; ‘as treated’ analysis done
(2) Allocation concealment (checking for possible selection bias) with substantial departure of intervention received from that
We described for each included study the method used to conceal assigned at randomisation);
allocation to interventions prior to assignment and assessed • unclear risk of bias.
whether intervention allocation could have been foreseen in
advance of, or during recruitment, or changed after assignment.

Informed decisions.

(5) Selective reporting (checking for reporting bias) co-efficient (ICC) derived from the trial (if possible), from a similar
trial or from a study of a similar population. If we use ICCs from
We described for each included study how we investigated the
other sources, we will report this and conduct sensitivity analyses
possibility of selective outcome reporting bias and what we found.
to investigate the effect of variation in the ICC. If we identify
We assessed the methods as: both cluster-randomised trials and individually-randomised trials,
we plan to synthesise the relevant information. We will consider
• low risk of bias (where it is clear that all of the study’s pre- it reasonable to combine the results from both if there is little
specified outcomes and all expected outcomes of interest to the heterogeneity between the study designs and the interaction
review have been reported); between the effect of intervention and the choice of randomisation
• high risk of bias (where not all the study’s pre-specified unit is considered to be unlikely.
outcomes have been reported; one or more reported primary
We will also acknowledge heterogeneity in the randomisation unit
outcomes were not pre-specified; outcomes of interest are
and perform a subgroup analysis to investigate the effects of the
reported incompletely and so cannot be used; study fails to
randomisation unit.
include results of a key outcome that would have been expected
to have been reported); Cross-over trials
• unclear risk of bias.
We did not find any cross-over studies. We do not anticipate any
(6) Other bias (checking for bias due to problems not covered by cross-over studies on this topic. However, should we find any, we
(1) to (5) above) will exclude them.
We described for each included study any important concerns we Trials with multiple treatment groups
have about other possible sources of bias.
Studies with multi-group analysis were included in the review.
We assessed whether each study was free of other problems that Only the groups relevant to this review were included into the
could put it at risk of bias: analysis. We combined all relevant experimental intervention
groups of the study into a single group and all relevant control
• low risk of other bias; intervention groups into a single control group. For dichotomous
• high risk of other bias; outcomes, both the sample sizes and the numbers of people with
• unclear whether there is risk of other bias. events were summed across groups. For continuous outcomes, we
planned to combine means and standard deviations using methods
(7) Overall risk of bias described in Chapter 7 (Section 7.7.3.8) of the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins 2011). If considered
We made explicit judgements about whether studies were at necessary, we included each pair-wise comparison separately, but
high risk of bias, according to the criteria given in the Cochrane with shared intervention groups divided out approximately evenly
Handbook for Systematic Reviews of Interventions (Higgins 2011). among the comparisons (Higgins 2011). In the studies with two
With reference to (1) to (6) above, we assessed the likely magnitude interventions groups and one control group we divided the number
and direction of the bias and whether we considered it was likely to* of participants and effects by half for dichotomous outcome. If
impact on the findings. We explored the impact of the level of bias continuous outcomes had been measured, we would have left the
through undertaking sensitivity analyses - see Sensitivity analysis. mean difference and standard deviation the same as described
Measures of treatment effect in Chapter 16 (Section 16.5.4) of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011).
Dichotomous data
Dealing with missing data
For dichotomous data, we present results as summary risk ratio
with 95% confidence intervals. For included studies, we noted levels of attrition. We explored the
impact of including studies with high levels of missing data in the
Continuous data overall assessment of treatment effect by using sensitivity analysis.
For continuous data, we planned to use the mean difference if For all outcomes, we carried out analyses, as far as possible,
outcomes were measured in the same way between trials. In future on an intention-to-treat basis, i.e. we attempted to include all
updates of this review we will use the standardised mean difference participants randomised to each group in the analyses, and all
to combine trials that measure the same outcome, but use different participants were analysed in the group to which they were
methods. allocated, regardless of whether or not they received the allocated
intervention.
Unit of analysis issues
Cluster-randomised trials If more than 20% of data were missing for primary or secondary
outcomes, we excluded the results of that study from analysis.
We did not identify any cluster-randomised trials for inclusion. In
future updates of this review, if we identify any cluster-randomised Assessment of heterogeneity
trials we will include cluster-randomised trials in the analyses along
with individually-randomised trials. We will adjust their standard We assessed statistical heterogeneity in each meta-analysis using
errors using the methods described in the Cochrane Handbook the Tau2, I2 and Chi2 statistics. We regarded heterogeneity as
for Systematic Reviews of Interventions [Section 16.3.4 or 16.3.6] substantial if the I2 was greater than 30% and either the Tau2 was
(Higgins 2011) using an estimate of the intra cluster correlation
Informed decisions.

greater than zero, or there was a low P value (less than 0.10) in the 1. Drugs compatible with breastfeeding versus those that are
Chi2 test for heterogeneity. not compatible with breastfeeding because they have adverse
effects on the infant.
Assessment of reporting biases 2. Primiparous versus multiparous women.
Where we suspected reporting bias (see ’Selective reporting bias’ 3. Emergency versus elective caesarean section.
above), we attempted to contact study authors to ask them to 4. Primary versus repeat caesarean section.
provide missing outcome data. Where this was not possible, and
5. Different drugs within the same group.
the missing data were thought to introduce serious bias, the impact
of including such studies in the overall assessment of results was 6. High and low doses of the same drug.
explored by a sensitivity analysis. Only two subgroup analyses were possible, e.g. different drugs
In future updates of this review, if there are 10 or more studies within the same group and high and low doses of the same drug. No
in the a meta-analysis, we will investigate reporting biases (such other planned subgroup analysis were possible due to insufficient
as publication bias) using funnel plots. We will assess funnel data. All trials used baseline analgesia. Our other planned subgroup
plot asymmetry visually. If asymmetry is suggested by a visual analyses will be performed the in future updates of this review.
assessment, we will perform exploratory analyses to investigate it. Subgroup analyses were restricted to primary outcomes of the
Data synthesis review.
We carried out statistical analysis using the Review Manager We assessed subgroup differences by interaction tests available
software (RevMan 2014). We used fixed-effect meta-analysis within RevMan (RevMan 2014). We reported the results of subgroup
for combining data where it was reasonable to assume that analyses quoting the Chi2 statistic and P value, and the interaction
studies were estimating the same underlying treatment effect: test I2 value.
i.e. where trials were examining the same intervention, and
the trials’ populations and methods were judged sufficiently Sensitivity analysis
similar. If there was clinical heterogeneity sufficient to expect Planned sensitivity analyses were not performed due to insufficient
that the underlying treatment effects differed between trials, data. In future updates, we will carry out sensitivity analysis to
or if substantial statistical heterogeneity was detected, we used explore the effect of trial quality for primary outcomes in the review.
random-effects meta-analysis to produce an overall summary, if If the included trials have a high risk or unclear risk of selection
an average treatment effect across trials was considered clinically bias or attrition bias we will explore this by conducting sensitivity
meaningful. The random-effects summary was treated as the analysis. We will also carry out sensitivity analysis to explore the
average range of possible treatment effects and we discussed the effects of fixed-effect or random-effects analyses for outcomes with
clinical implications of treatment effects differing between trials. If statistical heterogeneity.
the average treatment effect was not clinically meaningful, we did
not combine trials. RESULTS
Where we used random-effects analyses, the results are presented Description of studies
as the average treatment effect with 95% confidence intervals, and
the estimates of Tau2 and I2. Results of the search
The search of the Cochrane Pregnancy and Childbirth Group's Trials
Subgroup analysis and investigation of heterogeneity
Register retrieved 63 reports (see: Figure 1). After assessing the full
For outcomes with substantial heterogeneity, we investigated it text and grouping together reports of the same trial, there were
using subgroup analyses and sensitivity analyses. We considered 54 studies. We included 13 studies in the review and excluded 41
whether an overall summary was meaningful, and if it was, used studies. Five out of 13 included trials did not report data that could
random-effects analysis to produce it. be included in the meta-analysis. Eight studies (962 participants)
provided data for meta-analysis.
We planned the following subgroup analyses.


Informed decisions.

Figure 1. Study flow diagram.

Informed decisions.

Included studies • two studies compared patient-controlled analgesia versus

midwife-administered analgesia (Sibilla 1994; Snell 2006);
We included 13 studies but only eight studies (involving 962
women) contributed data for our analyses. • two studies compared oral analgesia and epidural opioids (Choi
2003; Liu 2011);
One study compared opioid analgesics with placebo and with • one study compared food effect on analgesic response to non-
combination analgesia (Sunshine 1992). opioids (Sunshine 1997b);
• one study investigated epidural opioids compared with oral
Nine studies assessed non-opioid analgesics versus placebo
opioids for post opioids pruritus (Stuart 1995);
(Angle 2002; Bjune 1996; Carvalho 2006; Fong 2008; Goheen 2000;
Lee 2004; Pagnoni 1996; Sunshine 1993; Sunshine 1992). • one study investigated pre-emptive administration of a plant
extract on post-caesarean pain (Gharabaghi 2011);
Two studies compared non-opioid and combination oral • one study compared combination drugs and patient-controlled
analgesics (Munishankar 2008; Sunshine 1993). analgesia with morphine (Davis 2006);
• one study investigated non-opioid analgesics to reduce opioid
Two studies assessed other oral preparations for relieving post-
use post-caesarean section and had 40% of incomplete data
caesarean pain, e.g. clonidine (Palmer 2000) and gabapentin (Short
(Esper 2005);
2012).
• one study compared oral celecoxib and intravenous ketamine
One study compared opioid and non-opioid analgesics (Sammour or their combination (Tan 2007) and this review assess only oral
2011).Only data for adverse effects could be used from this study. analgesia;
Data for adequate pain relief could not be used because pain • one study compared patient-controlled epidural analgesia
scores were described as mean +- SD of additional medication (PCEA) and celecoxib (Nakou 2010);
requested, they did not use visual analogue scales (VAS) even • one study investigated the use of celecoxib for prevention of
though in their methods they stated that they would use VAS. Data opioid induced pruritus (Samimi 2011);
for breastfeeding scores could not be used because they were not • one study investigated the effectiveness of gabapentin use at
as pre-specified. delivery of neonate for pain response during intramuscular
Data from five trials have not been included for analysis in this injection (Shah 2010);
review due to different reasons, e.g. one trial reported only one • one study was excluded because 28% of participants were
outcome (e.g. use of morphine patient-controlled analgesia as an excluded for protocol violation (Moore 2011);
additional pain relief), which was not pre-specified in our protocol • one study investigated standard administered analgesics and
(i.e. we assess need for additional analgesia (number of women) patient-administered (East 2007) and our review does not have
(Palmer 2000); one trial did not report the number of participants this subgroup;
in each group; it was published as letter to the editor (Fong 2008); • one study assessed premedication with clonidine in reducing
three trials reported outcomes that differ to the pre-specified morphine requirements post-caesarean section (Yanagidate
outcomes in the review (Carvalho 2006; Goheen 2000; Munishankar 2001);
2008). • one study was published as a letter to the publisher; the study
was terminated after enrolling five participants because of high
Section Characteristics of included studies has the details on the
VAS scores (Ortner 2011);
above-mentioned studies.
• one study assessed the effectiveness of adjunct analgesia to
Excluded studies PCEA following a caesarean delivery. The interventions included
a combination of intravenous and oral medication versus
We excluded 41 studies for following reasons:
placebo and therefore the results could not be interpreted
• four studies compared intravenous, intramuscular or separately for oral analgesia (Paech 2014).
subcutaneous opioids with oral non-opioids (Alhashemi 2006;
Risk of bias in included studies
Danesh 2009; Dieterich 2012; Marzida 2009);
Risk of bias of included studies is presented in Figure 2 and Figure 3.


Informed decisions.

Figure 2. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.


Informed decisions.

Figure 2. (Continued)

Figure 3. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.

Allocation Sunshine 1992; Sunshine 1993) and in four studies the risk of
performance was unclear (Bjune 1996; Fong 2008; Goheen 2000;
Sequence generation was assessed as low risk of bias in eight
Palmer 2000).
studies, the majority of which used computer-generated random
numbers (Angle 2002; Bjune 1996; Carvalho 2006; Fong 2008; Three studies had high risk of detection bias (Munishankar 2008;
Munishankar 2008; Sammour 2011; Short 2012; Sunshine 1992) and Sammour 2011; Short 2012). Four studies had low risk of detection
unclear risk of bias in five studies where the details of sequence bias (Angle 2002; Carvalho 2006; Pagnoni 1996; Sunshine 1993) and
generation were not described (Goheen 2000; Lee 2004; Pagnoni in six studies the risk of detection bias was unclear (Bjune 1996;
1996; Palmer 2000; Sunshine 1993). Fong 2008; Goheen 2000; Lee 2004; Palmer 2000; Sunshine 1992).
Allocation concealment was assessed as low risk of bias in eight Incomplete outcome data
studies, with the majority of them using opaque sealed envelopes
(Angle 2002; Carvalho 2006; Munishankar 2008; Pagnoni 1996; Eight studies had low risk of attrition bias (Angle 2002; Bjune 1996;
Sammour 2011; Short 2012; Sunshine 1992; Sunshine 1993). Five Carvalho 2006; Munishankar 2008; Pagnoni 1996; Sammour 2011;
studies did not describe the process of allocation concealment Short 2012; Sunshine 1992). Four studies had high risk of attrition
that they used and, therefore, we considered their allocation bias (Fong 2008; Goheen 2000; Palmer 2000; Sunshine 1993) and
concealment bias unclear (Bjune 1996; Fong 2008; Goheen 2000; one study had unclear risk of attrition bias (Lee 2004).
Lee 2004; Palmer 2000).
Selective reporting
Blinding One study was assessed as having a low risk of reporting bias (Short
Two studies had high risk of performance bias (Munishankar 2008; 2012). However, the other 12 studies had unclear risk of reporting
Sammour 2011). Seven studies had low risk of performance bias bias (Angle 2002; Bjune 1996; Carvalho 2006; Fong 2008; Goheen
(Angle 2002; Carvalho 2006; Lee 2004; Pagnoni 1996; Short 2012;

Informed decisions.

2000; Lee 2004; Munishankar 2008; Pagnoni 1996; Palmer 2000; Need for additional pain relief with a different drug
Sammour 2011; Sunshine 1992; Sunshine 1993). Based on one study (Sunshine 1992, involving 120 women) there
Other potential sources of bias was no difference in the need for additional pain relief between
group of women who received tramadol and the women in the
Two studies used patient-controlled analgesia morphine in control group (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.06
addition to the study drugs (Munishankar 2008; Palmer 2000). to 1.92, one trial, 120 women) Analysis 1.1.
One study used ketoprofen 100 mg intramuscularly as rescue Secondary outcome

medication and adverse events (none) reported only for the six-
Maternal drug adverse effects, e.g. nausea, vomiting, sedation,
hour study period (Pagnoni 1996).
constipation, diarrhoea, drowsy, sleepy, psychological impact
One study used Tylenol, a combination of acetaminophen 300 mg, There was no clear difference in the rate of maternal adverse drug
caffeine 15 mg and codeine 30 mg, one to two tablets every three effects between the group of women who received tramadol versus
to four hours as needed and intramuscular morphine as needed placebo (RR 6.58, 95% CI 0.38 to 113.96, one trial, 120 women)
(Angle 2002). Analysis 1.2.
One study used Brufen 600 to 1200 mg or intramuscular No data were available within the comparison of opioids and
ketobemidone 5 mg as rescue medication (Bjune 1996). placebo for other outcomes, e.g. number of days in the hospital
post-operatively, re-hospitalisation due to incisional pain, fully
One study used two tablets of dologesic (paracetamol and breastfeeding at discharge, mixed feeding at discharge, incisional
dextropoxyphene) every six hours for rescue pain relief (Lee 2004). pain at six weeks after caesarean section, maternal postpartum
depression, effect (negative) on mother and baby interaction, cost
One study used a combination of hydrocodone 5 mg/
of treatment.
acetaminophen 500 mg or oxycodone 5 mg/acetaminophen 500
mg and intravenous morphine for resistant pain.The sample size Subgroup analysis
calculation suggested that 37 women per study group were
required to detect a 30% reduction in incisional pain scores on • High versus low dose of the same drug
movement at 36 hours. However, due to the safety concerns with
COX-2 inhibitors reported in the literature at the time, this study was No difference between low (75 mg) and high (150 mg) doses of
terminated early (Carvalho 2006). tramadol in relation to need for additional pain relief was observed
RR 0.67, 95% CI 0.12 to 3.78 and RR 0.14, 95% CI 0.01 to 2.68,
One study was published only in a form of a letter to the editor (Fong respectively) Analysis 8.1.
2008).
Non-opioid analgesics versus placebo - comparison 2
One study was published only as an abstract (Goheen 2000).
Primary outcomes
One study used parenteral morphine in the first two hours Adequate pain relief
post-operatively and in the ward on request, they received
oral paracetamol-dextropoxyphene; 10 women dropped out from No data available.
tramadol at fixed intervals group and five dropped out from
Need for additional analgesia
tramadol on request group, but the data were presented inclusive
of these women (Sammour 2011). Six studies reported on the need for additional pain relief (Angle
2002; Bjune 1996; Lee 2004; Pagnoni 1996; Short 2012; Sunshine
One study used 2 mg of intravenous morphine at five-minute 1993). Overall, more women required additional analgesia (primary
intervals for the first two hours in the post-anaesthesia care unit outcome) in the placebo group in comparison with the non-opioid
(PACU), then 50 mg oral diclofenac every eight hours and 1 G analgesia group, but this difference was not statistically significant
acetaminophen every six hours for 72 hours. Breakthrough pain (average RR 0.70, 95% CI 0.48 to 1.01, six studies, 584 women, Tau2
was managed with 2 mg subcutaneous morphine on request = 0.18, I2 = 85%) Analysis 2.1. However, we observed substantial
and subsequently the women received 10 mg oral morphine as heterogeneity, likely to be related to different non-opioid drugs
required. This was an underpowered study (Short 2012). (naproxen 50 mg 12 hours following caesarean section in Angle
One study also used rescue medication (Sunshine 1992). 2002, paracetamol in Bjune 1996 and Sunshine 1993, celexocib in
Lee 2004, ibuprofen in Pagnoni 1996, gabapentin in Short 2012), as
In one study, participants received repeated doses if they well as different baseline pain-relief used in different studies.
complained of pain two hours after receiving the study medication
Subgroup analysis
(Sunshine 1993).
• Different drugs within the same group
Effects of interventions
When comparing different drugs, we observed subgroup
Opioid analgesia versus placebo - comparison 1
differences (Chi2 = 27.49, df = 5 (P < 0.0001); I2 = 81.8%). Only
Primary outcomes gabapentin resulted in less need for additional pain relief versus
placebo (RR 0.34, 95% CI 0.23 to 0.51, one trial, 126 women).There
Adequate pain relief
was no difference in the need for additional pain relief associated
No data available on this outcome. with the use of celecoxib (RR 0.89, 95% CI 0.59 to 1.35, one study,
Informed decisions.

60 participants), ibuprofen (RR 0.66, 95% CI 0.41 to 1.07, one study, Secondary outcome
62 women), ketoprofen (RR 1.05, 95% CI 0.86 to 1.28, one trial,
Adverse drug effects
120 women), naproxen (RR 0.11, 95% CI 0.01 to 2.00, one study, 80
women), or paracetamol (RR 0.77, 95% CI 0.43 to 1.40, two studies, There was an incidence of adverse drug effects in the combination
136 women) Analysis 2.1. oral analgesics group compared to the placebo control, but the
difference was not statistically significant (RR 13.18, 95% CI 02.86 to
• High versus low dose of the same drug 60.68, three studies, 252 women) Analysis 3.2.
When we compared high and low doses of the same drug, we The following outcomes were not reported in any studies for
observed a significant test for subgroup differences (Chi2 = 14.06, this comparison: number of days in the hospital post-operatively,
df = 3 (P = 0.003), I2 = 78.7%). Gabapentin 300 mg (RR 0.25, 95% CI re-hospitalisation due to incisional pain, fully breastfeeding at
0.13 to 0.49, one study, 63 women) and 600 mg (RR 0.44, 95% CI discharge, mixed feeding at discharge, incisional pain at six weeks
0.27 to 0.71, one study, 63 women) were both more effective than after caesarean section, maternal postpartum depression, effect
placebo with respect to the need for additional pain relief. Similarly, (negative) on mother and baby interaction, cost of treatment.
ketoprofen 100 mg resulted in fewer women needing additional
pain relief (RR 0.55, 95% CI 0.39 to 0.79, one study 72 women) Opioid analgesics versus non-opioid - comparison 4
compared to placebo. In contrast, there was no difference between
Primary outcome
the 50 mg ketoprofen group and placebo group in terms of the
number of women requiring additional pain relief (RR 0.82, 95% CI Adequate pain relief
0.64 to 1.07, one study 72 women). See Analysis 7.1. No data available.
Secondary outcomes Need for additional analgesia
Adverse effects There was no difference in the need for additional pain relief with
More side effects were reported with the use of non-opioid a different drug in woman who received acetaminophen versus
analgesics versus placebo (RR 11.12, 95% CI 2.13 to 58.22, two tramadol (RR 0.51, 95% CI 0.07 to 3.51, one study, 121 women)
studies, 267 women) Analysis 2.2. Analysis 4.1.
The following outcomes were not reported in any studies: number Secondary outcomes
of days in the hospital post-operatively, re-hospitalisation due to Maternal drug adverse effects, e.g. nausea, vomiting, sedation,
incisional pain, fully breastfeeding at discharge, mixed feeding at constipation, diarrhoea, drowsy, sleepy, psychological impact
discharge, incisional pain at six weeks after caesarean section,
maternal postpartum depression, effect (negative) on mother and Adverse effects were more common with the use of combination
baby interaction, cost of treatment. analgesics versus placebo (RR 2.32, 95% CI 1.15 to 4.69, two trials,
241 women) Analysis 4.2.
Combination oral analgesics versus placebo - comparison 3
The following outcomes were not reported in any studies in this
Primary outcome comparison: number of days in the hospital post-operatively,
Adequate pain relief re-hospitalisation due to incisional pain, fully breastfeeding at
discharge, mixed feeding at discharge, incisional pain at six weeks
The study (Bjune 1996) in this group did not report on this outcome. after caesarean section, maternal postpartum depression, effect
(negative) on mother and baby interaction, cost of treatment.
There was no difference in the need for additional pain relief with Opioid analgesics versus combination analgesics - comparison
the use of combination analgesics versus placebo (average 0.70 5
( 95% CI 0.35 to 1.40, three trials, 242 women, Tau2 = 0.24, I2 = 69%) Primary outcome
Analysis 3.1.
Adequate pain relief
Subgroup analysis
No data available.
• Different drugs within the same group
When comparing different drugs within the combination oral Based on one study comparing tramadol and paracetamol plus
analgesics versus placebo comparison, we observed subgroup propoxyphene, opioid analgesics versus combination analgesics
differences (Chi2 = 5.86, df = 2. (P = 0.05); I2 = 65.8%). Only did not differ in regards to need for additional pain relief (RR 0.51,
paracetamol plus codeine versus placebo resulted in fewer women 95% CI 0.07 to 3.51, one trial, 121 women) Analysis 5.1.
requiring additional pain relief (RR 0.44, 95% CI 0.23 to 0.82, one
trial, 65 women) whereas there was no difference in the need for Secondary outcomes
additional analgesia for the comparisons of either paracetamol plus
oxycodone versus placebo or paracetamol plus propoxyphene (RR Maternal adverse effects also did not differ between the two groups
1.00, 95% CI 0.78 to 1.28, one trial, 96 women and RR 0.65, 95% CI (RR 6.74, 95% CI 0.39 to 116.79, one trial, 121 women) Analysis 5.2.
0.11 to 3.69, one trial, 81 women, respectively) Analysis 3.1.

Informed decisions.

Non-opioid analgesics versus combination - comparison 6 opioid analgesics versus placebo, likely to be due to different non-
opioid drugs being compared (celexocib, gabapentin, ibuprofen,
Primary outcome
ketoprofen, naproxen, paracetamol). Subgroup analysis of different
Adequate pain relief drugs within the same group has found that only gabapentin
resulted in statistically significant decrease in the need for
No data available.
additional pain relief in comparison to placebo, but not other non-
Need for additional pain relief with a different drug opioid drugs such as celexocib, ibuprofen, ketoprofen, naproxen,
paracetamol. In the comparison of combination analgesia with
There need for additional pain relief was greater in the group of placebo only paracetamol plus codeine (but not paracetamol
women who received non-opoid analgesics compared with the plus oxycodone or plus propoxyphene) resulted in less need for
group of women who received combination analgesics (RR 0.87, additional pain relief.
95% CI 0.81 to 0.93, one trial, 192 women) Analysis 6.1.
Maternal side effects were more common with the use of opioids,
Secondary outcomes non-opioids and combination analgesics in comparison to placebo,
No data were available for any of the secondary outcomes in this and with opioids versus non-opioids analgesics.
comparison.
Subgroup analysis of different doses of the same drug found
DISCUSSION that gabapentin 300 mg and 600 mg were both more effective
than placebo with respect to the need for additional pain relief.
Oral analgesia is an effective and convenient form of pain relief Similarly, ketoprofen 100 mg resulted in fewer women needing
following caesarean section. We planned to assess adequate additional pain relief compared to placebo. In contrast, there was
pain relief and the need for additional analgesia as the primary no difference between the 50 mg ketoprofen group, 75 mg tramadol
outcomes to establish the efficacy of different types of oral and 150 mg tramadol groups versus placebo group in terms of the
analgesia. The included studies contributed data only on the number of women requiring additional pain relief.
outcome of need for additional pain relief. Although five studies
reported on adequate pain relief (Angle 2002; Carvalho 2006; Overall completeness and applicability of evidence
Goheen 2000; Pagnoni 1996; Short 2012) using various definitions Only seven studies including 816 participants reported on the
for assessment of pain relief, e.g. Angle 2002 used a visual analogue primary outcome and only two of the secondary outcomes were
scale (VAS) at rest 36 hours following caesarean section, Pagnoni reported in the included trials. No data were found on the following
1996 included participants with a baseline VAS above 60 mm, secondary outcomes: number of days in hospital post-operatively,
Carvalho 2006 used a scale of 0 to 10 for VAS and we multiplied re-hospitalisation due to incisional pain, fully breastfeeding on
by 10, Goheen 2000 and Short 2012 used VAS at rest at 24 hours, discharge, mixed feeding at discharge, incisional pain at six weeks
the data could not be used as our pre-specified primary outcome after caesarean section, maternal post partum depression, effect
measure was the adequate pain relief as reported by the woman, (negative) on mother and baby interaction and cost of treatment.
or by determination of more than 50% relief of pain (as either
stated by the woman or calculated using a formula). None of the All included trials were undertaken in high-resource settings.
studies comparing non-opioids and placebo reported the data on
this outcome. Only one of our pre-specified secondary outcomes All the trials used other forms of additional analgesia as a
were reported in the included studies, e.g. maternal drug effects. No standard and for breakthrough pain and they all used different
other outcomes (number of days in the hospital post-operatively, drugs. We have not included the data from four trials included in
re-hospitalisation due to incisional pain, fully breastfeeding at the review due to different reasons, e.g. one trial used patient-
discharge, mixed feeding at discharge, incisional pain at six weeks controlled analgesia morphine in milligrams (mg) for additional
after caesarean section, maternal postpartum depression, effect pain relief (Palmer 2000), one trial did not report the number of
(negative) on mother and baby interaction, cost of treatment) were participants in each group (Fong 2008), two studies used a different
reported in included trials. definition of adequate pain relief to that pre-specified in the review
(Goheen 2000; Sammour 2011). Three of the included studies were
Summary of main results published in abstract form only (Fong 2008; Goheen 2000; Palmer
2000).
Despite identifying a large number (63) of reports for post-
caesarean pain relief, few trials (13) satisfied the inclusion criteria. Quality of the evidence
Since the trials investigated different types of oral analgesia, meta-
analysis was possible only on a few outcomes. Only eight small Eight trials with 962 participants were included in the analysis,
trials involving 962 women (out of 13 included trials) contributed of which only four trials (Angle 2002; Pagnoni 1996; Short 2012;
data to the analysis, of which only four trials had low risk of bias. Sunshine 1992) were considered to be of high quality. All the
The evidence in most of our comparisons is based on a small trials were small. There was high level of heterogeneity for need
number of women and the results should be interpreted with of additional pain relief in a comparison between non-opioid
caution. oral analgesia and placebo, due to various drugs with different
mechanisms of action combined in the analysis (naproxen,
No difference in the need for additional pain relief was seen ibuprofen, paracetamol, celexocib, gabapentin). Although the need
between the use of opioids versus placebo, non-opioids versus for additional pain relief was more common with the use of
placebo, combination analgesics versus placebo, opioids versus naproxen, ibuprofen, paracetamol, celecoxib and gabapentin, this
non-opioids, opioids versus combination analgesics. It is important difference reached statistical significance only with the use of
to note the high level of heterogeneity in the comparison non- gabapentin. There was a low level of missing data in the included
Informed decisions.

trials except for one trial comparing combination oral analgesia caution due to the small numbers and other shortcomings, the
versus placebo (Bjune 1996) with 16% of participants excluded for absence of efficacy of oral analgesics in comparison to placebo may
protocol violation. suggest the need for other forms of analgesia to be used for post-
caesarean pain relief. Further well-designed studies are necessary
Potential biases in the review process to establish the safe and effective form of oral analgesia for post-
caesarean pain.
We have performed meta-analysis of studies using different forms
of baseline pain relief without taking into consideration the
Implications for research
differences. We carried out subgroup analysis for different drugs
within the same group and for high versus low doses of the same Because of the risk of bias and small numbers in the studies
drug. However, with relatively few studies (one to two trials) and reviewed, adequately sized and well-designed trials are needed to
numbers of participating women (40 to 136) this limits the reliability assess different types of oral analgesia for post-caesarean pain.
of these subgroup analyses. Further research is needed to compare opioid analgesics versus
placebo/no drug treatment, non-opioid analgesics versus placebo/
Agreements and disagreements with other studies or no drug treatment, combination drugs verus placebo/no drug
reviews treatment, opioid analgesics versus non-opioid analgesics, opioid
analgesics versus combination analgesics, non-opioid analgesics
We did not identify any other meta-analysis assessing oral
versus combination analgesia in relation to pain relief. In addition,
analgesia for post-caesarean pain. There is a large number
other important outcomes should be considered, e.g. side effects,
of studies assessing other modalities of pain relief following
number of days in the hospital post-operatively, incisional pain,
caesarean section, e.g. systemic (intravenous and intramuscular
breastfeeding, maternal postpartum depression, effect on mother
analgesics, nerve block techniques, wound infiltration (Ismail
and baby interaction and cost of treatment comparing in group
2012). Although the results of this review should be interpreted with
of women who primiparous and multiparous, undergoing elective
caution due to small numbers and other shortcomings, the absence
and emergency caesarean section, with and without baseline pain
of efficacy of oral analgesics in comparison to placebo may suggest
relief.
the need for other forms of analgesia to be used for post-caesarean
pain relief. ACKNOWLEDGEMENTS
AUTHORS' CONCLUSIONS Cochrane Pregnancy and Childbirth editorial team for
administrative and technical support.
Implications for practice
No conclusions on the best available option for oral analgesia for As part of the pre-publication editorial process, this review has
pain relief post-caesarean section can be drawn from this review. been commented on by three peers (an editor and two referees
Although the results of this review should be interpreted with who are external to the editorial team) and the Group's Statistical
Adviser.

Informed decisions.

REFERENCES

References to studies included in this review Palmer 2000 {published data only}
Angle 2002 {published data only} Palmer CM, Nogami W, Alves D. Oral clonidine: use with
intrathecal morphine for post-cesarean analgesia [abstract].
Angle PJ, Halpern S, Leighton B, Wilson DS, Gnanendran K,
Anesthesiology 2000;92 Suppl:Abstract no: A57.
Kronberg J. Naproxen improves post cesarean analgesia after
spinal morphine [abstract]. Anesthesia & Analgesia 2000;90 Sammour 2011 {published data only}
Suppl:Abstract no: 281.
Sammour R, Ohel G, Cohen M, Gonen R. Tramadol versus
* Angle PJ, Halpern SH, Leighton BL, Szalai JP, Gnanendran K, naproxen for post-cesarean section analgesia - a randomized
Kronberg JE. A randomized controlled trial examining the effect trial. American Journal of Obstetrics and Gynecology 2009;201(6
of naproxen on analgesia during the second day after cesarean Suppl 1):S63.
delivery. Anesthesia & Analgesia 2002;95:741-9.
* Sammour RN, Ohel G, Cohen M, Gonen R. Oral naproxen
Bjune 1996 {published data only} versus oral tramadol for analgesia after cesarean
delivery. International Journal of Gynecology & Obstetrics
Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additive analgesic
2011;113(2):144-7.
effect of codeine and paracetamol can be detected in strong,
but not moderate, pain after caesarean section Baseline pain- Short 2012 {published data only}
intensity is a determinant of assay-sensitivity in a postoperative
Short J, Downey K, Bernstein P, Shah V, Carvalho JCA. A
analgesic trial [see comments]. Acta Anaesthesiologica
single preoperative dose of gabapentin does not improve
Scandinavica 1996;40(4):399-407.
postcesarean delivery pain management: A randomized,
Carvalho 2006 {published data only} double-blind, placebo-controlled dose-finding trial. Anesthesia
& Analgesia 2012;115(6):1336-42.
* Carvalho B, Chu L, Fuller A, Cohen SE, Riley ET. Valdecoxib
for postoperative pain management after cesarean delivery: Sunshine 1992 {published data only}
a randomized, double-blind, placebo-controlled study.
Sunshine A, Olson NZ, Zighelboim I, DeCastro A, Minn FL.
Anesthesia & Analgesia 2006;103(3):664-70.
Analgesic oral efficacy of tramadol hydrochloride in
Fuller AJ, Brummel C, Saxena A, Chu L, Riley ET, Cohen SE, et al. postoperative pain. Clinical Pharmacology and Therapeutics
Valdecoxib for postoperative pain management after cesarean 1992;51(6):740-6.
section: a randomized, double-blinded, placebo-controlled
Sunshine 1993 {published data only}
study [abstract]. Anesthesiology 2005;102(Suppl 1):15.
Sunshine A, Olson NZ, Zighelboim I, De Castro A. Ketoprofen,
Fong 2008 {published data only} acetaminophen plus oxycodone, and acetaminophen in
Fong WP, Yang LC, Wu JI, Chen HS, Tan PH. Does celecoxib have the relief of postoperative pain. Clinical Pharmacology and
pre-emptive analgesic effect after caesarean section surgery?. Therapeutics 1993;54:546-55.
British Journal of Anaesthesia 2008;100(6):861-2.

Goheen 2000 {published data only} References to studies excluded from this review
Goheen MSLB, Ong BY, Wahba RF, Lucy SJ. Effect of oral Abboud 1990 {published data only}
naproxen on pain following cesarean section [abstract]. Abboud TK, Afrasiabi A, Davidson J, Zhu J, Reyes A, Khoo N,
Anesthesiology 2000;92 Suppl:Abstract no: A39. et al. Prophylactic oral naltrexone with epidural morphine:
effect on adverse reactions and ventilatory responses to carbon
Lee 2004 {published data only}
dioxide. Anesthesiology 1990;72:233-7.
Lee LHY, Irwin MG, Lim J, Wong CK. The effect of celecoxib on
intrathecal morphine-induced pruritis in patients undergoing Abboud TK, Lee K, Chai M, Zhu J, Afrasiabi A, Mantilla M, et al.
caesarean section. Anaesthesia 2004;59:876-80. Prophylactic oral naltrexone with intrathecal morphine for
cesarean section: effects on adverse reactions and analgesia.
Munishankar 2008 {published data only} Anesthesiology 1989;71:Abstract no: A836.
Munishankar B, Fettes P, Moore C, McLeod GA. A double-
blind randomised controlled trial of paracetamol, diclofenac * Abboud TK, Lee K, Zhu J, Reyes A, Afrasiabi A, Mantilla M, et
or the combination for pain relief after caesarean section. al. Prophylactic oral naltrexone with intrathecal morphine for
International Journal of Obstetric Anesthesia 2008;17(1):9-14. cesarean section: effects on adverse reactions and analgesia.
Anesthesia and Analgesia 1990;71:367-70.
Pagnoni 1996 {published data only}
Alhashemi 2006 {published data only}
Pagnoni B, Vignali M, Colella S, Monopoli R, Tiengo N.
Comparative efficacy of oral ibuprofen arginine and Alhashemi JA, Alotaibi QA, Mashaat MS, Kaid TM, Mujallid RH,
intramuscular ketorolac in patients with postcaesarean section Kaki AM. Intravenous acetaminophen vs oral ibuprofen in
pain. Clinical Drug Investigation 1996;11:15-21. combination with morphine PCIA after cesarean delivery.
Canadian Journal of Anesthesia 2006;53(12):1200-6.

Informed decisions.

Bloomfield 1993 {published data only} cesarean delivery [abstract]. American Journal of Obstetrics and
Bloomfield SS, Cissell GB, Mitchell J, Barden TP, Kaiko RF, Gynecology 2005;193(6 Suppl):S124.
Fitzmartin RD, et al. Analgesic efficacy and potency of two
Ganem 2003 {published data only}
oral controlled-release morphine preparations. Clinical
Pharmacology & Therapeutics 1993;53(4):469-78. Ganem EM, Modolo NSP, Ferrari F, Cordon FCO, Koguti ES,
Castiglia YMM. Effects of low spinal morphine doses associated
Carvalho 2007 {published data only} to intravenous and oral ketoprofen in patients submitted
Carvalho B, Roland LM, Chu LF, Campitelli III VA, Riley ET. Single- to cesarean sections [Efeitos da associacao entre pequenas
dose, extended-release epidural morphine (DepoDur) compared doses subaracnoideas de morfina e cetoprofeno venoso e oral
to conventional epidural morphine for post-cesarean pain. em pacientes submetidas a cesariana]. Revista Brasileira de
Anesthesia & Analgesia 2007;105(1):176-83. Anestesiologia 2003;53(4):431-9.
Carvalho 2008 {published data only} Gharabaghi 2011 {published data only}
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post-operative pain after cesarean section. ClinicalTrials.gov Ouladesahebmadarek E, Del Azar A, et al. Evaluation of the
(http://clinicaltrials.gov/) (accessed 20 February 2008). effect of preemptive administration of Rosa damascena extract
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Journal of Pharmacy and Pharmacology 2011;5(16):1950-5.
Choi 2003 {published data only}
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* Choi DM, Kliffer AP, Douglas MJ. Dextromethorphan and
intrathecal morphine for analgesia after caesarean section Liu Q, Zhao JN, Chen HX, Zhong TD. [Oral controlled-release
under spinal anaesthesia. BJA: British Journal of Anaesthesia oxycodone for uterine cramping pain after cesarean section].
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2011;91(30):2132-4.
Choi DMA, Kliffer AP, Douglas MJ. Oral dextromethorphan and
intrathecal morphine for analgesia after caesarean section Marzida 2009 {published data only}
[abstract]. Anesthesiology 2000;92 Suppl:Abstract no: A30. Marzida M. A randomized controlled study comparing
subcutaneous pethidine with oral diclofenac for pain relief after
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oral methadone and IM pethidine for pain relief after cesarean
section. Regional Anesthesia and Pain Medicine 2009;34(5):150. McDonnell 2010 {published data only}
McDonnell NJ, Paech MJ, Browning RM, Nathan EA. A
Davis 2006 {published data only} randomised comparison of regular oral oxycodone and
Davis KM, Esposito MA, Meyer BA. Oral analgesia compared with intrathecal morphine for post-caesarean analgesia.
intravenous patient-controlled analgesia for pain after cesarean International Journal of Obstetric Anesthesia 2010; 19(1):16-23.
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Moore A, Costello J, Wieczorek P, Shah V, Taddio A, Carvalho JC.
De Lia 1986 {published data only} Gabapentin improves postcesarean delivery pain management:
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flurbiprofen, intramuscular morphine sulfate, and placebo in 2011;112(1):167-73.
the treatment of gynecologic postoperative pain. American
Journal of Medicine 1986;80(3A):60-4. Morrison 1986 {published data only}
Morrison JC, Harris J, Sherrill J, Heilman CJ, Bucovaz E T,
Dieterich 2012 {published data only} Wiser WL. Comparative study of flurbiprofen and morphine for
Dieterich M, Muller-Jordan K, Stubert J, Kundt G, Wagner K, postsurgical gynecologic pain. American Journal of Medicine
Gerber B. Pain management after cesarean: a randomized 1986;80(3A):55-9.
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Archives of Gynecology and Obstetrics 2012;286(4):859-65. Nakou 2010 {published data only}
Nakou M, Matsota P, Kalimeris K, Batistaki C, Pandazi A,
East 2007 {published data only} Kostopanagiotou. A single dose of celecoxib improves pain
East N, Dube J, Perreault EL. Postpartum pain relief: a scores and quality of patient controlled epidural analgesia
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standard administration. Journal of Obstetrics and Gynaecology 2010;35(5):E142-3.
Canada 2007;29(12):975-81.
Olson 1984 {published data only}
Esper 2005 {published data only} Olson N, Sunshine A, Roure C, Colon A, Laska EM, Santiago H,
Esper D, Boggess K, Potter C, Arnette R, Mayer D. A pilot study et al. Analgesic efficacy of suprofen, codeine and placebo. Pain
of valdecoxib for reduction of postoperative opioid use after 1984;2 Suppl:238.

Informed decisions.

Ortner 2011 {published data only} Sunshine 1985a {published data only}
Ortner CM. Patient-controlled oral analgesia following cesarean Sunshine A, Roure C, Zorrilla C, Laska EM, Olson N, Rivera J. The
section: tramadol versus a combination of tramadol and analgesic efficacy of ibuprofen, codeine and placebo. Clinical
acetaminophen. Acta Obstetricia et Gynecologica Scandinavica Pharmacology and Therapeutics 1985;37:232.
2011;90(8):925-6.
Sunshine 1985b {published data only}
Paech 2014 {published data only} Sunshine A, Zighelboim I, Olson NZ, De Sarrazin C, Laska E. A
Paech MJ, McDonnell NJ, Sinha A, Baber C, Nathan EA. A comparative oral analgesic study of indoprofen, aspirin, and
randomised controlled trial of parecoxib, celecoxib and placebo in postpartum pain. Journal of Clinical Pharmacology
paracetamol as adjuncts to patient-controlled epidural 1985;25(5):374-80.
analgesia after caesarean delivery. Anaesthesia & Intensive Care
2014;42(1):15-22. Sunshine 1986 {published data only}
Sunshine A, Zighelboim I, Laska E, Siegel C, Olson NZ,
Palangio 2000 {published data only} De Castro A. A double-blind, parallel comparison of ketoprofen,
Palangio M, Wideman GL, Keffer M, Landau CJ, Morris E, aspirin, and placebo in patients with postpartum pain. Journal
Doyle RTJ, et al. Combination hydrocodone and ibuprofen of Clinical Pharmacology 1986;26(8):706-11.
versus combination oxycodone and acetaminophen in the
treatment of postoperative obstetric or gynecologic pain. Sunshine 1987 {published data only}
Clinical Therapeutics 2000;22:600-12. Sunshine A, Roure C, Olson N, Laska EM, Zorrilla C, Rivera J.
Analgesic efficacy of two ibuprofen-codeine combinations
Samimi 2011 {published data only} for the treatment of postepisiotomy and postoperative pain.
* Samimi S, Davari Tanha F, Malekian M. A blinded study using Clinical Pharmacology and Therapeutics 1987;42:374-80.
celecoxib for prevention of morphine induced pruritus in
patients undergoing cesarean section. Journal of Family and Sunshine 1988 {published data only}
Reproductive Health 2011;5(2):35-9. Sunshine A, Axtmayer R, Olson NZ, Laska E, Ramos I. Analgesic
efficacy of pentazocine versus a pentazocine-naloxone
Samimi Sadeh S, Davari F, Malekian M. A blinded study using combination following oral administration. Clinical Journal of
celecoxib for prevention of morphine induced pruritus in Pain 1988;4(1):35-40.
patients undergoing cesarean section. Regional Anesthesia and
Pain Medicine 2012;37(5 Suppl 1):E307. Sunshine 1989 {published data only}
Sunshine A, Laska E, Siegel C, Zighelboim I, De Castro A,
Shah 2010 {published data only}
Sorrentino J, et al. Analgesic adjuvancy of caffeine with
Shah VS, Gerges S, Moore A, Carvalho J, Taddio A. The ibuprofen in three different postpartum pain populations.
effectiveness of maternal gabapentin therapy at the time of Clinical Pharmacology and Therapeutics 1989;45:174.
delivery on neonatal pain response during intramuscular
injection. Pediatric Academic Societies' 2010 Annual Meeting; Sunshine 1997a {published data only}
2010 May 1-4; Vancouver, Canada. 2010. Sunshine A, Olson NZ, O'Neill E, Ramos I, Doyle R. Analgesic
efficacy of a hydrocodone with ibuprofen combination
Sibilla 1994 {published data only}
compared with ibuprofen alone for the treatment of acute
Sibilla C, Albertazzi P, Zatelli R, Lupi G, Marchi M, Campobasso C, postoperative pain. Journal of Clinical Pharmacology
et al. Pain relief after caesarean section: comparison of different 1997;37:908-15.
techniques of morphine administration. International Journal of
Obstetric Anesthesia 1994;3:203-7. Sunshine 1997b {published data only}
* Sunshine A, Olsen NZ, Zighelboim I, Wajdula JS. A food
Snell 2006 {published data only}
interaction study of bromfenac, naproxen sodium and placebo
Snell P, Hicks C. An exploratory study in the UK of the in caesarean section patients. Clinical Pharmacology and
effectiveness of three different pain management regimens for Therapeutics 1997;61:PIII-9.
post-caesarean section women. Midwifery 2006;22:249-61.
Sunshine A, Olson NZ, Zighelboim I, Wajdula JS. A food
Stuart 1995 {published data only} interaction study of bromfenac, naproxen sodium, and placebo
Stuart AL, Carter JB, Roberson CR, Morton GH, O'Rear JA, in cesarean section patients [abstract]. Primary Care Update for
Dutton DA. Epidural butorphanol and oral naltrexone reduce Ob/Gyns 1998;5(4):195.
pruritus from epidural morphine after Cesarean birth.
Anesthesia and Analgesia 1995;80:S479. Tan 2007 {published data only}
Tan PH, Wu JI, Yang LC. Analgesic effect of pre-incisional
Sunshine 1983 {published data only} celecoxib, ketamine and their combination for caesarean
Sunshine A, Olson JZ, Siegel C, Laska EM. Oral analgesic study section [abstract]. Regional Anesthesia and Pain Medicine
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Pharmacology and Therapeutics 1983;33:154.

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Wittels B, Glosten B, Faure E, Moawad A, Ismail M, Hibbard J, DiMatteo MR, Morton SC, Lepper HS, Damush TM,
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Anesthesia and Analgesia 1993;77:925-32.
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Pregabalin for acute and chronic pain in adults. Cochrane

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Angle 2002
Methods Randomised controlled trial, two arms (placebo and naproxen).
Participants 80 ASA I and II women scheduled for elective caesarean delivery were recruited into the study. Exclu-
sion criteria included contraindication to spinal anaesthesia, diabetes, and pre-eclampsia.
Interventions Group 1 (40 women): placebo group - received Anusol suppository and there after oral lactose capsules
every 12 hours for 6 doses.
Group 2 (40 women): Naproxen sodium 500 mg suppository followed by oral naproxen sodium 550 mg
every 12 hours for 6 doses.
Outcomes Primary outcomes - incisional pain on sitting in 48 hours.
Secondary outcomes - VAS pain scores, analgesic requirements, quality of analgesia and side effects.
Notes

Informed decisions.

Angle 2002 (Continued)
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Computer-generated randomisation tables (block randomised in random
tion (selection bias) groups of 4 and 8). Pharmacy staff maintained randomisation key until com-
pletion of the study).
Allocation concealment Low risk Randomisation codes concealed in sequentially ordered sealed opaque en-
(selection bias) velopes.
Blinding of participants Low risk Staff, participants and interviewers were blinded to treatment groups. Phar-
and personnel (perfor- macy supplied identical drug forms for administration.
mance bias)
All outcomes
Blinding of outcome as- Low risk The interviewers were blinded.

sessment (detection bias)
All outcomes
Incomplete outcome data Low risk No missing data reported.

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk No prior registration of the trial protocol.
porting bias)
Other bias Unclear risk This study used Tylenol, a combination of acetaminophen 300 mg, caffeine 15
mg and codeine 30 mg, 1 to 2 tablets every 3 to 4 hours as needed and intra-
muscular morphine as needed as a baseline analgesia.

Bjune 1996
Methods Randomised controlled trial, three arms.
Participants 125 women with strong or moderate pain according to the VAS were enrolled to the study after in-
formed consent was obtained at day 1 or 2 post-caesarean section. Excluded were women with severe
pre-eclampsia and those with children in the NICU.
Interventions Paracetamol 800 mg + codeine 60 mg (50 women), paracetamol 1000 mg (50 women) and placebo (25
women).
Ibuprofen 600-1200 mg or Ketobemidone 5 mg intramuscularly were used as rescue analgesics. Rescue

medication was given at least 1 hour after intake of the study drug, and then pain intensity at time of
rescue analgesic intake was used as an estimate of the pain intensity for the remaining 6-hour observa-
tions.
Outcomes Satisfaction with pain, side effects.
Notes 17 (16%) women were excluded for protocol violation, 108 women were included in the analysis of
need for additional analgesia and all 125 in the data for adverse effects.
Risk of bias

Informed decisions.

Bjune 1996 (Continued)
Random sequence genera- Low risk 125 women were randomised into blocks of 25 and 10 to receive paracetamol
tion (selection bias) 800 mg plus codeine 60 mg and paracetamol 1 g, respectively and 5 to receive
placebo.
Allocation concealment Unclear risk Not described.

(selection bias)
Blinding of participants Unclear risk Double-blinded, however, no details were given.

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Not specified.

All outcomes
Incomplete outcome data Low risk No reported incomplete data outcome.

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk No prior trial registration.

porting bias)
Other bias High risk This study used Brufen 600-1200 mg or intramuscular ketobemidone 5 mg as
rescue medication. The same number of women reported on side effects in
both intervention groups. 17 of 125 women were excluded due to protocol vio-
lation before the opening of randomisation code and analysis of the effect on
data.

Carvalho 2006
Methods Randomised controlled trial, two groups.
Participants 48 ASA I and II women undergoing an elective caesarean section under spinal anaesthesia were en-
rolled into the study. 1 woman was withdrawn by her obstetrician who desired to give her NSAIDs.
Interventions Group 1 (23 women): oral valdecoxib 20 mg given 90 minutes after spinal block and every 12 hours for a
total of 6 doses over 72 hours.
Group 2 (25 women): placebo.
Hydrocodone 5 mg and acetaminophen 500 mg, oxycodone 5 mg and acetaminophen 500 mg and IV
morphine for severe or resistant pain.
Outcomes Pain intensity ratings using VPS scores, post-operative analgesic consumption.
Secondary outcomes included: time to first analgesia, women requiring post-operative IV medication.
Notes The results presented in this paper could not be used in the meta-analysis due to difference in the out-
comes reported by authors and pre-specified in the review.
Risk of bias

Informed decisions.

Carvalho 2006 (Continued)
Random sequence genera- Low risk Computer-generated sequence was used.
tion (selection bias)
Allocation concealment Low risk Opaque envelopes were used.

(selection bias)
Blinding of participants Low risk Double blinding. The intervention and placebo looked the same.
mance bias)
All outcomes
Blinding of outcome as- Low risk The assessor was blinded to the intervention.
All outcomes
Incomplete outcome data Low risk 1 patient was withdrawn by her obstetrician due to desire of administrating
(attrition bias) NSAIDs, but the data for this participant were included as per intention-to-
All outcomes treat analysis.
Selective reporting (re- Unclear risk No pre-trial registration of protocol.

porting bias)
Other bias High risk This study used a combination of hydrocodone 5 mg/acetaminophen 500 mg
or oxycodone 5 mg/acetaminophen 500 mg and IV morphine for resistant pain.
The sample size calculation suggested that 37 women per study group were
required to detect a 30% reduction in incisional pain scores on movement at
36 hours. However, due to the safety concerns with COX-2 inhibitors reported
in literature at the time, this study was terminated early.

Fong 2008
Methods Randomised controlled trial, three groups.
Participants 60 women undergoing caesarean delivery under spinal anaesthesia.
Interventions Pre-operative group received celecoxib 400 mg 30 minutes before anaesthesia and a placebo tablet af-
ter wound closure.
Post-operative group received a placebo tablet 30 minutes before anaesthesia and celecoxib 400 mg af-
ter wound closure.
Control group received placebo 30 minutes before anaesthesia and after wound closure.
Number of women in each group was not reported.
Outcomes Total morphine consumption, time to first analgesic demand, side effects.
Notes It is not stated how many were allocated in each group and therefore data cannot be used for meta-
analysis. This study was published only as a letter to the editor.
Risk of bias

Informed decisions.

Fong 2008 (Continued)
Random sequence genera- Low risk Allocation to groups by random numbers.

(selection bias)
Blinding of participants Unclear risk Not described except double blind.

mance bias)
All outcomes
Blinding of outcome as- Unclear risk Not described-details about analysis not explained.
All outcomes
Incomplete outcome data High risk The number of participants in each group is not stated. The number of out-
(attrition bias) comes reported in each groups is not reported.
All outcomes
Selective reporting (re- Unclear risk No prior protocol registration.

porting bias)
Other bias High risk This study was published only in a form of a letter to the editor.

Goheen 2000
Participants 102 women undergoing caesarean section under spinal anaesthesia (bupivacaine 0.75%, fentanyl 15
mcg, morphine 150 mcg).
Interventions Each group received 2 pills in PACU and then 1 pill every 8 hours. The groups were naproxen at PACU
and naproxen 250 mg every 8 hours in the ward (35 women), placebo at PACU and placebo in the ward
(33 women) or naproxen at PACU and placebo in the ward (34 women).
Additional analgesic medication was used in women requiring that and it not specified.
Outcomes VAS scores 4 hours post spinal injection, post-operative days 1, 2 and 3 at rest and ambulating.
Notes No results from this study contributed to the meta-analysis due to a differences in presented outcomes.
The study was published in abstract form only.
Risk of bias
Random sequence genera- Unclear risk No description of sequence generation.

Allocation concealment Unclear risk No description of allocation concealment.

(selection bias)
Blinding of participants Unclear risk Not described, except naproxen and placebo were visually identical.
mance bias)

Informed decisions.

Goheen 2000 (Continued)
All outcomes
Blinding of outcome as- Unclear risk Not described.

All outcomes
Incomplete outcome data High risk 110 women were randomised, however, "the records of 102 women were eli-
(attrition bias) gible for data analysis". The authors did not state why the other records were
All outcomes not eligible.
Selective reporting (re- Unclear risk No prior protocol registration.

porting bias)
Other bias Unclear risk This study was published only as an abstract.

Lee 2004
Methods Randomised double-blinded trial, two arms.
Participants 60 women who are class ASA 1 or 2 who are undergoing a caesarean delivery under spinal anaesthesia.
Interventions Group 1 (30 women): celecoxib 200 mg after delivery of the baby.
Outcomes Need for additional pain relief.
Notes
Risk of bias
Random sequence genera- Unclear risk Random number allocation, the details not described.

(selection bias)
Blinding of participants Low risk Capsule of celecoxib was used as a study drug and empty capsule was used as
and personnel (perfor- placebo. Double-blinded, e.g. the women and the anaesthetist were blinded to
mance bias) the intervention. The intervention and the placebo looked identical.
All outcomes
Blinding of outcome as- Unclear risk Not clearly stated.

All outcomes
Incomplete outcome data Unclear risk Not noted.

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk No prior registration of protocol.

porting bias)

Informed decisions.

Lee 2004 (Continued)
Other bias Unclear risk Study used 2 tablets of dologesic (paracetamol and dextropoxyphene) every
6 hours for rescue pain relief. The aim of this study was to assess the effect of
celexocib on intrathecal morphine induced pruritis in women undergoing elec-
tive caesarean section.

Munishankar 2008
Participants 78 women undergoing an elective caesarean section between ages 18-45 years were registered for the
study. Exclusion criteria included significant maternal medical history, obstetric illness and any evi-
dence of fetal compromise.
Interventions Group 1 (26 women): paracetamol 1 G suppository then 1 G orally 6 hourly and placebo 8 hourly.
Group 2 (26 women): diclofenac 100 mg suppository then 50 mg orally, 8 hourly and placebo 6 hourly.
Group 3 (26 women): received, paracetamol 1 G and diclofenac 100 mg suppository, then diclofenac 50
mg 8 hourly and paracetamol 1 G 6 hourly.
All women had caesarean section under spinal anaesthesia with 5 mg/mL of bupivacaine with dextrose
80 mg/mL in a volume of 2.25 to 2.5 mL for those < 170 cm and 2.5 to 2.75 mL for those > 170 cm mixed
with fentanyl 12.5 mcg.
PCA morphine was given to all participants at 1 mg every 5 minutes.
Outcomes Pain at rest and on movement, side effects such as nausea and vomiting, time taken from end of
surgery to drink, defecate, mobilise and overall patient satisfaction.
Notes
Risk of bias
Random sequence genera- Low risk Computer-generated random numbers.

Allocation concealment Low risk Randomisation number were kept in sealed envelopes in the hospital pharma-
(selection bias) cy till the end of the day.
Blinding of participants High risk Double-blinded. At the end of the surgery, the sealed envelope containing the
and personnel (perfor- drug allocation information was handed over to the surgical nurse who admin-
mance bias) istered the medication. This nurse had no further involvement with the patient
All outcomes and with the study. The oral study drug were distributed to the wards in 2 plas-
tic dispensing bags (1 bag contained 4 tablets of either paracetamol or place-
bo and the other one 3 tablets of either diclofenac or placebo). We consider
that there was a risk of disclosure of group allocations by the surgical nurse as
well as due to differences in number of tablets administered to each group as
well as the different time of administration (8 hourly diclofenac group and 6
hourly paracetamol group).
Blinding of outcome as- High risk Person who administered medication was blinded. See justification above.
All outcomes

Informed decisions.

Munishankar 2008 (Continued)
Incomplete outcome data Low risk No missing data.
(attrition bias)
All outcomes

porting bias)
Other bias Unclear risk This studies used PCA morphine in addition to the study drugs.

Pagnoni 1996
Methods Randomised double-blind trial, three arms.
Participants 62 women above the age of 18 years who were ASA I or II undergoing a caesarean section were recruit-
ed into the study.
Contraindications were women with history of bleeding disorders, chronic drug abuse, contraindica-
tions to aspirin or ibuprofen use.
Interventions Group 1 (30 women): oral ibuprofen arginine 400 mg.
Group 2 (30 women): intramuscular ketorolac 30 mg -this group was not included as the review is on
oral analgesia.
Rescue medication was intramuscular ketoprofen 100 mg.
Outcomes Pain intensity using VAS scores, side effects.
Notes
Risk of bias
Random sequence genera- Unclear risk Not described except "randomly assigned numbers".
Allocation concealment Low risk "the clinical investigator was provided with sealed envelopes specifying the
(selection bias) treatment given; these to be opened only in an emergency."
Blinding of participants Low risk The study medication as well as a rescue pain relief were administered by clini-
and personnel (perfor- cal investigator.
mance bias)
All outcomes
Blinding of outcome as- Low risk Clinical investigator administered the drugs and adverse effects were recorded
sessment (detection bias) by a physician.
All outcomes
Incomplete outcome data Low risk Data complete.

(attrition bias)
All outcomes

Informed decisions.

Pagnoni 1996 (Continued)
porting bias)
Other bias Unclear risk 1 study used ketoprofen 100 mg intramuscularly as rescue medication.
Adverse events (none) reported only for the 6-hour study period.

Palmer 2000
Methods Randomised double-blind trial, two arms.
Participants 60 ASA I and II women undergoing non-urgent caesarean delivery under spinal anaesthesia.
Interventions Oral clonidine 0.1 mg every 12 hours and control group received placebo at same intervals.
All participants received IV morphine via PCA pump for 24 hours post-operatively for 24 hours.
There were 60 women enrolled, but no data on how many women in each group.
Outcomes PCA morphine use, side effects such as hypotension, nausea and pruritus.
Notes Only 1 patient from 1 of the groups required treatment for hypotension.
Results for additional pain relief were added as dosages for PCA in milligrams, data from this study
were not be used in the meta-analysis.
Risk of bias
Random sequence genera- Unclear risk No description of randomisation.


(selection bias)
Blinding of participants Unclear risk Not described.

mance bias)
All outcomes

All outcomes
Incomplete outcome data High risk The data presented in such form that it is not clear if there were indeed any
(attrition bias) missing data as the total numbers are not provided.
All outcomes

porting bias)
Other bias High risk This study used PCA morphine in addition to the study drugs. It was only pub-
lished in abstract form in 2000.

Informed decisions.


Sammour 2011
Methods Randomised trial, four arms.
Participants 120 women who delivered at Bnai-Zion Medical Center between August 7th 2006 and March 23rd 2009
who had either an elective or emergency caesarean section.
Interventions Tramadol 100 mg every 6 hours orally, oral tramadol 100 mg on request, oral naproxen 500 mg every 8
hours and oral naproxen 500 mg on request.
Post-operatively parenteral morphine was given to all participants. Oral paracetamol-propoxyphene

was given to those requiring additional pain relief.
30 women in each group.
Outcomes Pain using VAS scores, side effects, mobility, breastfeeding and need for rescue medication.
Notes Data could not be used as the definition for adequate pain relief used by the authors is different to the
definition in this review.
Risk of bias
Random sequence genera- Low risk Computer-generated randomisation numbers were used.
Allocation concealment Low risk Sequentially numbered opaque envelopes with the codes sealed inside were
(selection bias) used.
Blinding of participants High risk Open labelled.

mance bias)
All outcomes
Blinding of outcome as- High risk Open labelled.

All outcomes
Incomplete outcome data Low risk 10 women dropped out from tramadol at fixed intervals group and five
(attrition bias) dropped out from tramadol on request group, but the data were presented in-
All outcomes clusive of these women.

porting bias)
Other bias Unclear risk This study used parenteral morphine in the first two hours post-operatively
and the ward on request they received oral paracetamol-dextropoxyphene.

Short 2012
Methods Randomised placebo-controlled double-blind trial. three arms
Participants 132 ASA 1 or 2 women with singleton pregnancy at term admitted for elective caesarean delivery were
enrolled after informed consent, six women were excluded after randomisation (2 protocol breach, 3
failed spinal, 1 postponed).

Informed decisions.

Short 2012 (Continued)
Exclusion criteria were contraindications to neuraxial anaesthesia or to any of the medication used in
the study, history of epilepsy, central nervous system or mental disorder, chronic pain, drug abuse, or
use of neuropathic analgesics or antiepileptic drugs.
Interventions Gabapentin 600 mg, Gabapentin 300 mg and placebo.
42 women in each group
Outcomes Pain intensity at rest and on movement using VAS scores, nausea, vomiting, sedation, pruritus, difficul-
ties with breastfeeding and incisional pain at 3 months.
Notes
Risk of bias
Random sequence genera- Low risk Computer-generated randomisation tables in blocks of 6.

Allocation concealment Low risk Sequentially numbered envelopes containing 300 mg Gabapentin or lactose
(selection bias) placebo in an identical blue cover were used.
Blinding of participants Low risk Hospital pharmacist placed the study medications in identical capsules.
mance bias)
All outcomes
Blinding of outcome as- High risk Study personnel administering medications was blinded. Personnel perform-
sessment (detection bias) ing post-operative assessments were not blinded to the results.
All outcomes
Incomplete outcome data Low risk 2 women were excluded from each group after receiving intervention due to
(attrition bias) failed spinal (1 in each group), protocol breach (1 in each intervention group,
All outcomes and 1 due to protocol breach in control group.
Selective reporting (re- Low risk Trial protocol registered at www.clinicaltrials.gov NCT01094925.
porting bias)
Other bias Unclear risk This study used 2 mg of IV morphine at 5 minutes interval for the first 2 hours
in PACU, then 50 mg oral diclofenac every 8 hours and 1 g acetaminophen
every 6 hours for 72 hours. Breakthrough pain was managed with 2 mg subcu-
taneous morphine on request and subsequently received 10 mg oral morphine
as required.
Underpowered study.

Sunshine 1992
Methods Randomised trial, four arms
Participants 161 post-caesarean women of legal age who were able to communicate meaningfully with a nurse-ob-
server and who gave consent were considered for the study.
Interventions Tramadol 75 mg (40 women), tramadol 150 mg (40 women), acetaminophene 650 mg and
propoxyphene (40 women) and placebo (41 women).

Informed decisions.

Sunshine 1992 (Continued)
Outcomes Pain relief and adverse effects.
Notes Data for adequacy of pain relief could not be used, standard deviation for the means (SPID) not stated.
This study contributed data on need for additional analgesia and adverse reactions for main compari-
son and subgroup analysis (tramadol 50 versus 100 mg).
Risk of bias
Random sequence genera- Low risk Computer-generated randomisation in blocks of 8. Parallel design. 2 women
tion (selection bias) received each treatment.
Allocation concealment Low risk Following randomisation each patient received a single unit dose, consisting
(selection bias) of 2 blue opaque capsules.
Blinding of participants Low risk Not described - but all unit doses had identical appearance and packaging.
and personnel (perfor- Stated that "medication was administered in "double-blind manner".
mance bias)
All outcomes

All outcomes
Incomplete outcome data Low risk No missing data reported.

(attrition bias)
All outcomes

porting bias)
Other bias Unclear risk Use of rescue medication.

Sunshine 1993
Methods Randomised trial, five arms.
Participants 240 women who were at least 18 years old and who reported severe post-operative pain after caesare-
an section.
Exclusion criteria included, hypersensitivity to any of the study drugs, breastfeeding mothers, serious
physical or mental illness, history of drug or alcohol abuse or those who received any other investiga-
tional drug within 1 month before enrolment in the study.
Interventions Group 1: 100 mg ketoprofen.
Group 2: 50 mg ketoprofen.
Group 3: 650 mg acetaminophen plus 10 mg oxycodone hydrochloride.
Group 4: 650 mg acetaminophen.
Group 5: placebo.
48 women in each group.

Informed decisions.

Sunshine 1993 (Continued)
Outcomes Pain intensity and side effects.
Notes Data not presented in full, e.g. no SD for means.
Complex study design, e.g. 5 groups. women requiring re medication before 1 hour after the first dose
of study medication were dropped from the study and replaced. 3 treatment groups in the repeat-
ed-dose phase.
Risk of bias
Random sequence genera- Unclear risk Methods of sequence generation were not described. Parallel design. Women
tion (selection bias) who received acetaminophen alone or placebo were re-assigned randomly to
receive 1 of the 2 doses of ketoprofen or acetaminophen with oxycondone.
Allocation concealment Low risk All drugs were identical in appearance.

(selection bias)
Blinding of participants Low risk Personel were blinded.

mance bias)
All outcomes
Blinding of outcome as- Low risk Assessors were blinded to the group allocation.
All outcomes
Incomplete outcome data High risk 3 women did not enter repeated doses study; 13 did not receive repeat med-
(attrition bias) ications for 2 days and were excluded, 10 participants withdrew from repeat-
All outcomes ed doses study because they did not have pain, 2 withdrew due to fever and 1
withdrew due to reasons unrelated to the study.

porting bias)
Other bias High risk The design of the trial with 5 groups and second randomisation is complex
and likely to have introduced bias. Participants received repeated doses if they
complained of pain 2 hours after receiving study medication.
COX-2: cyclooxygenase 2 inhibitor

IV: intravenous
NICU: neonatal intensive care unit
NSAIDs: non-steroidal anti-inflammatories
PACU: postanaesthesia care unit
PCA: patient-controlled analgesia
SD: standard deviation
SPID: summed pain intensity difference
VAS: visual analogue score
VPS: verbal pain scores

Characteristics of excluded studies [ordered by study ID]


Informed decisions.

Study Reason for exclusion
Abboud 1990 Prophylactic oral naltrexone was compared with intrathecal morphine for caesarean section. This
review assesses oral analgesia only, and does not include intrathecal analgesia.
Alhashemi 2006 The study assessed intravenous acetaminophen versus oral ibuprofen and in our review only as-
sess oral analgesia for post-caesarean pain.
Bloomfield 1993 The study assessed women undergoing caesarean section or abdominal hysterectomy and the re-
sults were not interpreted separately for each group. Our review only assesses oral analgesia for
post-caesarean pain.
Carvalho 2007 This study assessed Extended-Release Epidural Morphine compared with conventional morphine
for post-caesarean pain and our review only assesses oral analgesia for post-caesarean pain.
Carvalho 2008 This is only a protocol of the study, but not the study itself.
Choi 2003 The study assessed oral dextrometorphan and intrathecal morphine for analgesia after caesarean
section and our review only assesses oral analgesia for post-caesarean pain.
Danesh 2009 This study assessed oral methadone and intramuscular pethidine for post-caesarean pain and our
review only assesses oral analgesia.
Davis 2006 This study assessed oral analgesics compared to intravenous PCA for post-caesarean pain and our
review assesses oral analgesia.
De Lia 1986 This study assessed women post-caesarean section, post vaginal and abdominal hysterectomy and
the results were not interpreted separately. Our review only assesses oral analgesia for post-cae-
sarean pain.
Dieterich 2012 The study assesses oral analgesics and intravenous patient-control analgesia and in our review we
are only looking at oral analgesics.
East 2007 This study assesses standard administered analgesia and self-administered but in our review we do
not have this subgroup.
Esper 2005 This study assesses Valdecoxib for reducing post-operative opioid use and patient-control analge-
sia morphine is used for pain relief but our review assesses oral analgesics for post-caesarean pain.
Ganem 2003 The study assesses effects of low spinal morphine associated to intravenous and oral ketoprofen
post-caesarean section and in our review we are looking at only oral analgesia for post-caesarean
pain.
Gharabaghi 2011 This study assesses natural plant Rosa damascene for pain relief and in our review only assesses
pharmacological drugs.
Liu 2011 Combined oral oxycodone hydrochloride controlled-release tablets plus paracetamol and tra-
madol was compared with epidural analgesia with respect to uterine cramping, pain control and
side effects after caesarean section. Epidural analgesia is not part of our review.
Marzida 2009 The study assessed oral diclofenac and subcutaneous pethidine but our review only assesses oral
analgesia.
McDonnell 2010 The study assessed oral oxycodone and intrathecal morphine but our review only assesses oral
analgesia.
Moore 2011 In this study 28% of women were excluded because of protocol violation.

Informed decisions.

Morrison 1986 This study assessed women post-caesarean section, post vaginal and abdominal hysterectomy but
the results were not interpreted separately.
Nakou 2010 This study compared oral celecoxib and patient-controlled epidural analgesia, which is not part of
our review.
Olson 1984 The study assessed women post episiotomy, dysmenorrhoea and post-caesarean section and the
results were not interpreted for each group.
Ortner 2011 This study has been published as a letter to the publisher, the study was terminated after enrolling
5 women because of a high VAS score.
Paech 2014 This study assessed the effectiveness of adjunct analgesia with patient-controlled epidural analge-
sia following a caesarean delivery. The interventions included a combination of intravenous and
oral medication versus placebo and, therefore, the results could not be interpreted separately for
oral analgesia.
Palangio 2000 This study assessed a combination of hydrocodone and ibuprofen versus oxycodone and aceta-
minophen for post-operative obstetrics and gynaecological pain including caesarean section but
the results were not interpreted separately.
Samimi 2011 The study assessed celecoxib for prevention of morphine-induced pruritus in women undergoing
caesarean section and in our review we are looking at oral analgesics for post-caesarean pain.
Shah 2010 This study assessed effectiveness of maternal gabapentin therapy at the time of delivery of neona-
tal pain response during intramuscular injection, which is not part of our review.
Sibilla 1994 This study looked at different types of morphine administration for post-caesarean pain and in our
review we are looking at only oral analgesics for post-caesarean pain.
Snell 2006 This study looked at oral morphine patient or midwife-administered and intramuscular morphine
for post-caesarean pain and in our review we are looking at oral analgesia for post-caesarean pain.
Stuart 1995 Epidural opioids were compared with an oral regimen to reduce pruritis after epidural morphine.
Epidural is not part of our review.
Sunshine 1983 This study assessed ketoprofen or aspirin or placebo for post partum pain, i.e. post episiotomy or
post-caesarean section or postpartum uterine cramping and our review assesses post-caesarean
pain.
Sunshine 1985a This study assessed oral ibuprofen with and without codeine and placebo for incisional pain post
episiotomy or post-caesarean section and our review assesses post-caesarean pain.
Sunshine 1985b This study assessed oral analgesia for postpartum pain and results for women who had a caesare-
an section were not interpreted separately.
Sunshine 1986 The study assessed oral Ketoprofen, aspirin and placebo for postpartum pain including caesarean
section but results are not interpreted separately.
Sunshine 1987 The study assessed pain resulting from episiotomy, caesarean section, and gynaecological surgery
and the results were not presented separately for each group.
Sunshine 1988 The study looked oral Pentazocine versus pentazocine-Naloxone for post-operative pain and re-
sults were not interpreted separately for caesarean section.

Informed decisions.

Sunshine 1989 In this study women with episiotomy, post-caesarean and uterine cramp were studied, however,
the data for post-caesarean pain were not presented separately.
Sunshine 1997a Hydrocodone and ibuprofen were compared for post-caesarean, post-gynaecological surgery and
the data were not interpreted separately.
Sunshine 1997b The study assessed hydrocodone with ibuprofen and ibuprofen alone for acute post-operative pain
including caesarean section but results are not interpreted separately for caesarean section and in
our review we are looking at oral analgesics for post-caesarean pain.
Tan 2007 The study assessed oral celecoxib or intravenous ketamine or their combination for post-caesarean
pain and in our review we only assess oral analgesia.
Wittels 1993 This study looked at effects of epidural butorphanol, epidural nalbuphine and oral naltrexone on
post-caesarean epidural morphine and post-surgery women were randomised to intravenous PCA
with either morphine or meperidine. In our review we are only looking at oral analgesia for post-
caesarean pain.
Yanagidate 2001 This study assessed clonidine premedication, to see if it reduces morphine requirements after a
caesarean section without affecting newborn’s outcome and our review assesses oral analgesia for
post-caesarean pain.
PCA: patient-controlled analgesia

VAS: visual analogue scale

DATA AND ANALYSES

Comparison 1. Opioid versus placebo
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Need for additional pain relief with a 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.06, 1.92]
different drug
2 Adverse drug effects 1 120 Risk Ratio (M-H, Fixed, 95% CI) 6.58 [0.38, 113.96]

Analysis 1.1. Comparison 1 Opioid versus placebo, Outcome 1 Need for additional pain relief with a different drug.
Study or subgroup Opioid Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Sunshine 1992 2/80 3/40 100% 0.33[0.06,1.92]

Total (95% CI) 80 40 100% 0.33[0.06,1.92]
Total events: 2 (Opioid), 3 (Placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=1.23(P=0.22)
Favours opioid 0.01 0.1 1 10 100 Favours placebo

Informed decisions.


Analysis 1.2. Comparison 1 Opioid versus placebo, Outcome 2 Adverse drug effects.
Study or subgroup Opioid Placebo Risk Ratio Weight Risk Ratio
Sunshine 1992 6/80 0/40 100% 6.58[0.38,113.96]

Total (95% CI) 80 40 100% 6.58[0.38,113.96]
Total events: 6 (Opioid), 0 (Placebo)
Favours opioid 0.01 0.1 1 10 100 Favours placebo

Comparison 2. Non-opioid analgesics versus placebo

studies partici-
pants
1 Need for additional pain relief 6 584 Risk Ratio (M-H, Random, 95% 0.70 [0.48, 1.01]
CI)
1.1 Celexocib versus placebo 1 60 Risk Ratio (M-H, Random, 95% 0.89 [0.59, 1.35]
CI)
1.2 Gabapentin versus placebo 1 126 Risk Ratio (M-H, Random, 95% 0.34 [0.23, 0.51]
CI)
1.3 Ibuprofen versus placebo 1 62 Risk Ratio (M-H, Random, 95% 0.66 [0.41, 1.07]
CI)
1.4 Ketoprofen versus placebo 1 120 Risk Ratio (M-H, Random, 95% 1.05 [0.86, 1.28]
CI)
1.5 Naproxen versus placebo 1 80 Risk Ratio (M-H, Random, 95% 0.11 [0.01, 2.00]
CI)
1.6 Paracetamol versus placebo 2 136 Risk Ratio (M-H, Random, 95% 0.77 [0.43, 1.40]
CI)
2 Maternal drug effects 2 267 Risk Ratio (M-H, Fixed, 95% CI) 11.12 [2.13, 58.22]

Analysis 2.1. Comparison 2 Non-opioid analgesics versus placebo, Outcome 1 Need for additional pain relief.
Study or subgroup Non-opioids Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
2.1.1 Celexocib versus placebo
Lee 2004 17/30 19/30 15.94% 0.89[0.59,1.35]
Subtotal (95% CI) 30 30 15.94% 0.89[0.59,1.35]
Total events: 17 (Non-opioids), 19 (Placebo)
Favours non-opioid 0.01 0.1 1 10 100 Favours control

Informed decisions.



2.1.2 Gabapentin versus placebo
Short 2012 22/84 32/42 16.22% 0.34[0.23,0.51]
Subtotal (95% CI) 84 42 16.22% 0.34[0.23,0.51]
Test for overall effect: Z=5.27(P<0.0001)

2.1.3 Ibuprofen versus placebo
Pagnoni 1996 13/30 21/32 14.92% 0.66[0.41,1.07]
Subtotal (95% CI) 30 32 14.92% 0.66[0.41,1.07]

2.1.4 Ketoprofen versus placebo
Sunshine 1993 84/96 20/24 18.95% 1.05[0.86,1.28]
Subtotal (95% CI) 96 24 18.95% 1.05[0.86,1.28]

2.1.5 Naproxen versus placebo
Angle 2002 0/40 4/40 1.5% 0.11[0.01,2]
Subtotal (95% CI) 40 40 1.5% 0.11[0.01,2]

2.1.6 Paracetamol versus placebo
Bjune 1996 14/43 12/21 13.54% 0.57[0.32,1.01]
Sunshine 1993 40/48 21/24 18.92% 0.95[0.78,1.16]
Subtotal (95% CI) 91 45 32.46% 0.77[0.43,1.4]
Heterogeneity: Tau2=0.14; Chi2=3.99, df=1(P=0.05); I2=74.96%

Total (95% CI) 371 213 100% 0.7[0.48,1.01]
Heterogeneity: Tau2=0.18; Chi2=40.77, df=6(P<0.0001); I2=85.28%
Test for subgroup differences: Chi2=27.49, df=1 (P<0.0001), I2=81.81%
Favours non-opioid 0.01 0.1 1 10 100 Favours control


Informed decisions.

Analysis 2.2. Comparison 2 Non-opioid analgesics versus placebo, Outcome 2 Maternal drug effects.
Bjune 1996 10/50 1/25 62.64% 5[0.68,36.9]
Sunshine 1993 0/48 0/24 Not estimable
Sunshine 1993 41/96 0/24 37.36% 21.39[1.36,335.82]

Total (95% CI) 194 73 100% 11.12[2.13,58.22]
Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%
Test for overall effect: Z=2.85(P=0)
Favours non-opioids 0.01 0.1 1 10 100 Favours placebo

Comparison 3. Combination versus placebo

studies partici-
pants
1 Need for additional pain relief 3 242 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.35, 1.40]
1.1 Paracetamol plus codeine versus 1 65 Risk Ratio (M-H, Random, 95% CI) 0.44 [0.23, 0.82]
placebo
1.2 Paracetamol plus oxycodone 1 96 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.78, 1.28]
versus placebo
1.3 Paracetamol plus propoxyphene 1 81 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.11, 3.69]
versus placebo
2 Maternal drug effects 3 252 Risk Ratio (M-H, Fixed, 95% CI) 13.18 [2.86, 60.68]

Analysis 3.1. Comparison 3 Combination versus placebo, Outcome 1 Need for additional pain relief.
Study or subgroup Combination Placebo Risk Ratio Weight Risk Ratio
analgesics
3.1.1 Paracetamol plus codeine versus placebo
Bjune 1996 11/44 12/21 37.28% 0.44[0.23,0.82]
Subtotal (95% CI) 44 21 37.28% 0.44[0.23,0.82]
Total events: 11 (Combination analgesics), 12 (Placebo)

3.1.2 Paracetamol plus oxycodone versus placebo
Sunshine 1993 35/48 35/48 50.21% 1[0.78,1.28]
Subtotal (95% CI) 48 48 50.21% 1[0.78,1.28]
Favours combination 0.01 0.1 1 10 100 Favours placebo

Informed decisions.


analgesics
Test for overall effect: Not applicable

3.1.3 Paracetamol plus propoxyphene versus placebo
Sunshine 1992 2/41 3/40 12.51% 0.65[0.11,3.69]
Subtotal (95% CI) 41 40 12.51% 0.65[0.11,3.69]

Total (95% CI) 133 109 100% 0.7[0.35,1.4]
Heterogeneity: Tau2=0.24; Chi2=6.54, df=2(P=0.04); I2=69.44%
Test for subgroup differences: Chi2=5.86, df=1 (P=0.05), I2=65.85%
Favours combination 0.01 0.1 1 10 100 Favours placebo

Analysis 3.2. Comparison 3 Combination versus placebo, Outcome 2 Maternal drug effects.
analgesics
Bjune 1996 10/50 1/25 72.73% 5[0.68,36.9]
Sunshine 1992 0/41 0/40 Not estimable
Sunshine 1993 17/48 0/48 27.27% 35[2.16,565.92]

Total (95% CI) 139 113 100% 13.18[2.86,60.68]
Heterogeneity: Tau2=0; Chi2=1.38, df=1(P=0.24); I2=27.35%
Favours combination drugs 0.01 0.1 1 10 100 Favours placebo

Comparison 4. Opioid versus non-opioid

studies partici-
pants
1 Need for additional pain relief with a dif- 1 121 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.07, 3.51]
ferent drug
2 Maternal adverse effects 2 241 Risk Ratio (M-H, Fixed, 95% CI) 2.32 [1.15, 4.69]


Informed decisions.

Analysis 4.1. Comparison 4 Opioid versus non-opioid,

Outcome 1 Need for additional pain relief with a different drug.
Study or subgroup Opioid Non-opioid Risk Ratio Weight Risk Ratio
Sunshine 1992 2/80 2/41 100% 0.51[0.07,3.51]

Total (95% CI) 80 41 100% 0.51[0.07,3.51]
Total events: 2 (Opioid), 2 (Non-opioid)
Favours opioids 0.01 0.1 1 10 100 Favours non-opioids

Analysis 4.2. Comparison 4 Opioid versus non-opioid, Outcome 2 Maternal adverse effects.
Study or subgroup Opioid Non-opioid Risk Ratio Weight Risk Ratio
Sammour 2011 18/60 9/60 93.18% 2[0.98,4.09]
Sunshine 1992 6/80 0/41 6.82% 6.74[0.39,116.79]

Total (95% CI) 140 101 100% 2.32[1.15,4.69]
Total events: 24 (Opioid), 9 (Non-opioid)
Heterogeneity: Tau2=0; Chi2=0.7, df=1(P=0.4); I2=0%
Favours opioids 0.01 0.1 1 10 100 Favours non-opioids

Comparison 5. Opioid analgesics versus combination analgesics

studies partici-
pants
1 Need for additional pain relief 1 121 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.07, 3.51]
1.1 Tramadol versus paracetamol plus 1 121 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.07, 3.51]
propoxyphene
2 Maternal adverse effects 1 121 Risk Ratio (M-H, Fixed, 95% CI) 6.74 [0.39, 116.79]

Analysis 5.1. Comparison 5 Opioid analgesics versus combination
analgesics, Outcome 1 Need for additional pain relief.
Study or subgroup Opioids Combination Risk Ratio Weight Risk Ratio
5.1.1 Tramadol versus paracetamol plus propoxyphene
Sunshine 1992 2/80 2/41 100% 0.51[0.07,3.51]
Subtotal (95% CI) 80 41 100% 0.51[0.07,3.51]
Favours Opioids 0.01 0.1 1 10 100 Favours Combination

Informed decisions.


Total events: 2 (Opioids), 2 (Combination)

Total (95% CI) 80 41 100% 0.51[0.07,3.51]

Analysis 5.2. Comparison 5 Opioid analgesics versus combination analgesics, Outcome 2 Maternal adverse effects.
Sunshine 1992 6/80 0/41 100% 6.74[0.39,116.79]

Total (95% CI) 80 41 100% 6.74[0.39,116.79]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Comparison 6. Non-opioid versus combination analgesics
Outcome or subgroup title No. of No. of par- Statistical method Effect size
studies ticipants
1 Need for additional pain relief with a different 1 192 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.81, 0.93]
drug

Analysis 6.1. Comparison 6 Non-opioid versus combination analgesics,
Outcome 1 Need for additional pain relief with a different drug.
Study or subgroup Non-opioid Combination Risk Ratio Weight Risk Ratio
analgesics analgesics
Sunshine 1993 124/144 48/48 100% 0.87[0.81,0.93]

Total (95% CI) 144 48 100% 0.87[0.81,0.93]
Total events: 124 (Non-opioid analgesics), 48 (Combination analgesics)
Favours non-opioids 0.01 0.1 1 10 100 Favours combination

Informed decisions.

Comparison 7. Non-opioid analgesics versus placebo (subgroup analysis by high and low doses of the same drug)

studies partici-
pants
1 Need for additional pain relief 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Gapapentin 300 mg 1 63 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.13, 0.49]
1.2 Gabapentin 600 mg 1 63 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.27, 0.71]
1.3 Ketoprofen 50 mg 1 72 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.64, 1.07]
1.4 Ketoprofen 100 mg 1 72 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.39, 0.79]

Analysis 7.1. Comparison 7 Non-opioid analgesics versus placebo (subgroup analysis
by high and low doses of the same drug), Outcome 1 Need for additional pain relief.
7.1.1 Gapapentin 300 mg
Short 2012 8/42 16/21 100% 0.25[0.13,0.49]
Subtotal (95% CI) 42 21 100% 0.25[0.13,0.49]
Test for overall effect: Z=4.07(P<0.0001)

7.1.2 Gabapentin 600 mg
Short 2012 14/42 16/21 100% 0.44[0.27,0.71]
Subtotal (95% CI) 42 21 100% 0.44[0.27,0.71]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

7.1.3 Ketoprofen 50 mg
Sunshine 1993 33/48 20/24 100% 0.83[0.64,1.07]
Subtotal (95% CI) 48 24 100% 0.83[0.64,1.07]

7.1.4 Ketoprofen 100 mg
Sunshine 1993 22/48 20/24 100% 0.55[0.39,0.79]
Subtotal (95% CI) 48 24 100% 0.55[0.39,0.79]
Test for subgroup differences: Chi2=14.06, df=1 (P=0), I2=78.67%
Favours non-opioids 0.01 0.1 1 10 100 Favours placebo


Informed decisions.

Comparison 8. Opioid analgesics versus placebo (subgroup analysis by high and low doses of the same drug)

studies partici-
pants
1 Need for additional pain relief 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Tramadol 75 mg 1 80 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.12, 3.78]
1.2 Tramadol 150 mg 1 80 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.68]

Analysis 8.1. Comparison 8 Opioid analgesics versus placebo (subgroup analysis
by high and low doses of the same drug), Outcome 1 Need for additional pain relief.
Study or subgroup Opioids Placebo Risk Ratio Weight Risk Ratio
8.1.1 Tramadol 75 mg
Sunshine 1992 2/40 3/40 100% 0.67[0.12,3.78]
Subtotal (95% CI) 40 40 100% 0.67[0.12,3.78]
Total events: 2 (Opioids), 3 (Placebo)

8.1.2 Tramadol 150 mg
Sunshine 1992 0/40 3/40 100% 0.14[0.01,2.68]
Subtotal (95% CI) 40 40 100% 0.14[0.01,2.68]
Total events: 0 (Opioids), 3 (Placebo)
Test for subgroup differences: Chi2=0.79, df=1 (P=0.38), I2=0%
Favours opioids 0.01 0.1 1 10 100 Favours placebo

WHAT'S NEW

Date Event Description
1 April 2015 Amended Amended contact person's email address.

CONTRIBUTIONS OF AUTHORS
Nondumiso Mkontwana is the guarantor of the review. She designed and wrote the protocol, searched for trials, assessed the trials,
extracted and analysed the data, wrote the review.
Natalia Novikova provided advice on the protocol, assisted in writing of the protocol, provided clinical and methodological perspectives,
assessed the trials, extracted data, provided guidance in analysis and writing of the review.
DECLARATIONS OF INTEREST
None known.

Informed decisions.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW
We have clarified our criteria for carrying out sensitivity analysis, in future updates of this review, see Sensitivity analysis.
INDEX TERMS
Medical Subject Headings (MeSH)

Administration, Oral; Analgesia [*methods]; Analgesics, Non-Narcotic [administration & dosage]; Analgesics, Opioid [*administration
& dosage]; Cesarean Section [*adverse effects]; Drug Therapy, Combination [methods]; Pain, Postoperative [*drug therapy];
Randomized Controlled Trials as Topic
MeSH check words

Adult; Female; Humans; Pregnancy


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Oral analgesia for relieving post-caesarean pain (Review) i

Oral analgesia for relieving post-caesarean pain

Nondumiso Mkontwana1, Natalia Novikova1

Editorial group: Cochrane Pregnancy and Childbirth Group

Data collection and analysis

1. Opiod analgesics versus placebo

Oral analgesia for relieving post-caesarean pain (Review) 1

2. Non-opioid analgesia versus placebo

3. Combination analgesics versus placebo

4. Opioid analgesics versus non-opioid analgesics

5. Opioid analgesics versus combination analgesics

6. Non-opioid versus combination analgesics

Secondary outcomes not reported in the included studies

Pain tablets taken by mouth for post-caesarean pain

Oral analgesia for relieving post-caesarean pain (Review) 2

Oral analgesia for relieving post-caesarean pain (Review) 3

BACKGROUND Description of the intervention

The exact mechanism of analgesic effect of alpha-2 agonists is

Oral analgesia for relieving post-caesarean pain (Review) 6

Oral analgesia for relieving post-caesarean pain (Review) 8

Figure 1. Study flow diagram.

Oral analgesia for relieving post-caesarean pain (Review) 9

Included studies • two studies compared patient-controlled analgesia versus

Oral analgesia for relieving post-caesarean pain (Review) 10

Oral analgesia for relieving post-caesarean pain (Review) 11

Oral analgesia for relieving post-caesarean pain (Review) 12

One study used ketoprofen 100 mg intramuscularly as rescue Secondary outcome

Oral analgesia for relieving post-caesarean pain (Review) 14

Oral analgesia for relieving post-caesarean pain (Review) 16

Oral analgesia for relieving post-caesarean pain (Review) 17

Oral analgesia for relieving post-caesarean pain (Review) 18

Oral analgesia for relieving post-caesarean pain (Review) 19

Wittels 1993 {published data only} DiMatteo 1996

* Wittels B, Glosten B, Faure EAM, Moawad AH, Ismail M, Gadsden 2005

Betran 2007 Gordh 1989

Chahl 1996 Hidalgo 2005

Cooper 1991 Ismail 2012

Kodali 2012 Database of Systematic Reviews 2009, Issue 3. [DOI:

Characteristics of included studies [ordered by study ID]

Outcomes Primary outcomes - incisional pain on sitting in 48 hours.

Oral analgesia for relieving post-caesarean pain (Review) 21

Bias Authors' judgement Support for judgement

Blinding of outcome as- Low risk The interviewers were blinded.

Incomplete outcome data Low risk No missing data reported.

Ibuprofen 600-1200 mg or Ketobemidone 5 mg intramuscularly were used as rescue analgesics. Rescue

Outcomes Satisfaction with pain, side effects.

Bias Authors' judgement Support for judgement

Oral analgesia for relieving post-caesarean pain (Review) 22

Allocation concealment Unclear risk Not described.

Blinding of participants Unclear risk Double-blinded, however, no details were given.

Blinding of outcome as- Unclear risk Not specified.

Incomplete outcome data Low risk No reported incomplete data outcome.

Selective reporting (re- Unclear risk No prior trial registration.

Group 2 (25 women): placebo.

Bias Authors' judgement Support for judgement

Oral analgesia for relieving post-caesarean pain (Review) 23

Allocation concealment Low risk Opaque envelopes were used.

Selective reporting (re- Unclear risk No pre-trial registration of protocol.

Participants 60 women undergoing caesarean delivery under spinal anaesthesia.

Number of women in each group was not reported.

Bias Authors' judgement Support for judgement

Oral analgesia for relieving post-caesarean pain (Review) 24

Allocation concealment Unclear risk Not described.