Oral analgesia for relieving post-caesarean pain

  • Protocol
  • Intervention

Authors

  • Nondumiso Mkontwana,

    Corresponding author
    1. East London Hospital Complex, Department of Obstetrics and Gynaecology, East London, Eastern Cape, South Africa
    • Nondumiso Mkontwana, Department of Obstetrics and Gynaecology, East London Hospital Complex, East London, Eastern Cape, 5200, South Africa. ndumym@webmail.co.za.

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  • Natalia Novikova

    1. Walter Sisulu University, Department of Obstetrics and Gynaecology, East London Hospital Complex, East London, South Africa
    Search for more papers by this author

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness (adequate pain relief as reported by the woman, or by determination of more than 50% relief of pain (either stated by the woman or calculated using a formula), or the need for additional pain relief with a different drug, re-admission due to incisional pain, incisional pain at six weeks after surgery), safety (e.g. adverse effects of drugs, effect on breastfeeding, depression, mother and child interaction) and cost-effectiveness of oral analgesics for relieving post-caesarean pain.

Background

Caesarean section is a common surgical procedure performed to deliver babies through an incision of the abdomen and uterus when vaginal delivery is contraindicated for maternal or fetal reasons or, in some cases upon request of the pregnant mother. It can either be done as an emergency or electively. The rate of caesarean section has been increasing around the world (Delbaere 2012). The rate of caesarean section differs around the world between 2% in least developed countries and 21% in developed countries and reaching 45.9% in Brazil (Betran 2007; Getahun 2009; Gibbons 2010). In the USA, caesarean section rates increased, from 20.7% in 1996 to 31.1% in 2006 for women of all ages, race, gestational ages, and in all states MacDorman 2008.

Caesarean section is associated with more postpartum pain than vaginal birth (Kainu 2010) and leads to more acute and chronic postpartum pain (Ingrid 2006). Postpartum pain has various negative consequences including:

  • it causes significant discomfort to women, which can lead to difficulties in mobility and subsequent problems, such as, an increased risk of venous thrombosis, and by interfering with optimal interaction with the newborn in the immediate postpartum period;

  • shallow breathing and splinting may result in atelectasis and predispose to pneumonia;

  • pain has psychological sequelae (Berghella 2012; DeMatteo 1996);

  • it may reduce the ability of the mother to initiate or continue with breastfeeding effectively Gadsden 2005.

Effective post-caesarean pain relief is important to avoid the above-mentioned problems. Different interventions have been proposed for post-caesarean pain relief, e.g. oral, intravenous and rectal analgesia with various drugs and various doses, regional analgesia, transversus abdominis plane block and combinations of the above-mentioned interventions.

The review will compare the effectiveness and safety of different classes of oral analgesia for post-caesarean pain relief.

Description of the condition

Post-caesarean pain is a result of incisional pain as well as pain from the uterus (e.g. uterine contraction after birth). Incisional pain is experienced by women following caesarean section due to tissue trauma from surgical incision, dissection and burns or direct nerve damage from nerve transection, stretching or compression Kelly 2001. Tissue trauma causes release of local inflammatory mediators that can produce augmented sensitivity to stimuli in the area surrounding an injury, i.e. hyperalgesia or misperception pain to non-noxious stimuli. The patient senses pain through the afferent pathway. Pharmacologic agents target these pathways Woolf 1993.

Pain varies in intensity and the onset of the post-operative pain depends on form of anaesthesia used during the procedure. This pain almost always requires some form of analgesia Kodali 2012.

Description of the intervention

Oral analgesia is a simple, easy to administer, well-tolerated and cost-effective type of pain relief that is offered to women after caesarean section.

Oral analgesia for post-caesarean pain includes the following (SAMF 2012; Solomon 2012).

1. Opioid analgesics

  • Natural opioids (codeine, dyhydrocodeine, morphine)

  • Diphenylpropylamine derivatives (dextropropoxyphene, dipipanone)

  • Other opioids (tramadol, tilidine)

2. Non-opioid analgesics

A. Para-aminophenol derivatives (paracetamol or acetaminophen)

B. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs)

  • Acetylated salicylates (aspirin or acetylsalicylic acid)

  • Propionic acid (ibuprofen)

  • Acetic acids (diclofenac)

  • Oxicams (meloxicam)

  • Fenamates (mefenamic acid)

C. Alpha-2 agonists

D. Anti-convulsants

3. Combination drugs (e.g., paracetamol/codeine, paracetamol/tramadol, paracetamol/codeine/ibuprofen etc.).

Oral analgesics have various side-effects. The adverse effects of these drugs include nausea, vomiting, constipation, diarrhoea, drowsiness, respiratory depression, pruritis (itch), rash, fluid retention.

How the intervention might work

Different types of oral analgesics have different ways of achieving an analgesic (painkiller) effect.

Analgesic effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. Opioids act through binding to specific opioid receptors in the nervous system and other tissues. Opioids reduce the perception of pain by activating pain-inhibitory neurons and inhibiting pain transmission neurons (Chahl 1996).

Non-opioid analgesics act by reducing the nocioreceptive response to the endogenous inflammatory mediators released at the sites of tissue damage (Kuo 2006). NSAIDs block cyclo-oxygenase (COX), an enzyme responsible for the synthesis of prostaglandins (Chandrasekharan 2002). Pharmacological inhibition of COX can provide relief from symptoms of inflammation and pain by inhibition of prostaglandin synthesis.

Combination drugs (e.g. paracetamol/codeine, paracetamol/codeine) 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 Gordh 1989; Kodali 2012. There are reports suggesting that alpha-2 agonists such as clonidine and dexmedetomidine have a potent analgesic response, and that their potency is increased by concomitant opioid therapy Kodali 2012. Alpha-2 agonists have been reported to decrease post-operative pain Hidalgo 2005; Sung 2000.

Anticonvulsant agents such as gabapentin are gamma-aminobutyric acid analogues and have also been reported to have analgesic effects as well as opioid-sparing effects Kodali 2012. Although the main use of anticonvulsants is for chronic pain, there are reports supporting their adjunctive role in post-operative pain Mathiesen 2007; Moore 2009.

Why it is important to do this review

Many drugs with various mechanisms of action are used for post-caesarean pain relief. Although the response to pain relief is sometimes believed to be individual, it is very important to establish the most effective with the least adverse effects type of oral analgesia for women after caesarean section .

Optimal pain control post-caesarean section will benefit not only the mother and her baby, but also a healthcare system. Optimal pain control may shorten the time spent in hospital after caesarean section and, therefore, reducing healthcare costs Shang 2003.

Objectives

To determine the effectiveness (adequate pain relief as reported by the woman, or by determination of more than 50% relief of pain (either stated by the woman or calculated using a formula), or the need for additional pain relief with a different drug, re-admission due to incisional pain, incisional pain at six weeks after surgery), safety (e.g. adverse effects of drugs, effect on breastfeeding, depression, mother and child interaction) and cost-effectiveness of oral analgesics for relieving post-caesarean pain.

Methods

Criteria for considering studies for this review

Types of studies

We will only include randomised controlled trials (RCTs), including cluster-randomised trials. Quasi-randomised and cross-over trials will be excluded.

Types of participants

All women requiring pain relief in the early postpartum period following caesarean section.

Types of interventions

Interventions will include oral medication given to women for post-caesarean pain relief.

The comparison will be:

  1. opioid analgesics versus placebo/no drug treatment;

  2. non-opioid analgesics versus placebo/no drug treatment;

  3. combination drugs verus placebo/no drug treatment;

  4. opioid analgesics versus non-opioid analgesics;

  5. opioid analgesics versus combination analgesics;

  6. non-opioid analgesics versus combination analgesics.

Types of outcome measures

We will assess outcomes developed in the Cochrane generic protocol on drugs for perineal pain in the early postpartum period (Chou 2009).

Primary outcomes
  1. Adequate pain relief as reported by the woman, or by determination of more than 50% relief of pain (as either stated by the woman or calculated using a formula)*.

  2. Need for additional pain relief with a different drug.

Secondary outcomes
  1. Maternal drug adverse effects, e.g. nausea, vomiting, sedation, constipation, diarrhoea, drowsy, sleepy, psychological impact.

  2. Number of days in the hospital post-operatively.

  3. Rehospitalisation due to incisional pain.

  4. Fully breastfeeding at discharge.

  5. Mixed feeding at discharge.

  6. Incisional pain at six weeks after caesarean section.

  7. Maternal postpartum depression.

  8. Effect (negative) on mother and baby interaction.

  9. Cost of treatment.

* Assessment of 50% pain relief via SPID (summed pain intensity difference) scores (1.23 x SPID %max - 2.3 = proportion with 50%) (Cooper 1991; Moore 1967; Moore 1967a).

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL,  MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.

Any studies published in an abstract form will be included if they satisfy the inclusion criteria. We will contact the authors of such studies for additional information if necessary.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

 (2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertaken. We will exclude the data from the analysis if more than 20% of data are missing for primary or secondary outcomes.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their standard errors using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions [Section 16.3.4 or 16.3.6] Higgins 2011 using an estimate of the intra cluster correlation 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 other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a subgroup analysis to investigate the effects of the randomisation unit.

Cross-over trials

We do not anticipate any cross-over studies on this topic. However, should we find any, we will exclude them.

Trials with multiple treatment groups

Studies with multi-group analysis will be included in the review. Only the groups relevant to this review will be included into the analysis. We will combine all relevant experimental intervention groups of the study into a single group and all relevant control intervention groups into a single control group. For dichotomous outcomes, both the sample sizes and the numbers of people with events will be summed across groups. For continuous outcomes, means and standard deviations will be combined using methods described in Chapter 7 (Section 7.7.3.8) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If considered necessary, we will include each pair-wise comparison separately, but with shared intervention groups divided out approximately evenly among the comparisons Higgins 2011.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

If more than 20% of data are missing for primary or secondary outcomes, we will exclude the results of that study from analysis.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if the I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

Where we suspect reporting bias (see ’Selective reporting bias’ above), we will attempt to contact study authors to ask them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess
funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software RevMan 2011. We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We will conduct planned subgroup analyses.

  1. Drugs compatible with breastfeeding versus those that are not compatible with breastfeeding because they have adverse effects on the infant.

  2. Primiparous versus multiparous women.

  3. Emergency versus elective caesarean section.

  4. Primary versus repeat caesarean section.

  5. Different drugs within the same group.

  6. High versus low doses of the same drug.

We will assess primary outcomes in subgroup analysis.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011). We will report the results of subgroup analyses
quoting the χ2 statistic and p-value, and the interaction test I² value.

Sensitivity analysis

We will perform the sensitivity analysis to explore the effect of trial quality for primary outcomes in the review. If the included trials have a high risk or unclear risk of bias this will be explored by sensitivity analysis. Primary outcomes will be compared for studies with low risk and high risk and unclear risk of bias. We will carry out sensitivity analysis to explore the effects of fixed-effect or random-effects analyses for outcomes with statistical heterogeneity.

Acknowledgements

Lynn Hampson, Kellie Frances, Sonja Henderson and the Cochrane Pregnancy and Childbirth team for administrative and technical support.

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

Contributions of authors

Nondumiso Mkontwana is the guarantor of the review. She designed and wrote the protocol, provided clinical and policy perspective.

Natalia Novikova provided advice on the protocol, assisted in writing of the protocol, provided clinical and methodological perspectives.

Declarations of interest

None known.

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