Post-caesarean analgesia: What is new?

Adequate post-operative analgesia after caesarean section (CS) is vital as it impacts the distinct surgical recovery requirements of the parturient. Although newer analgesic modalities and drugs for post-caesarean analgesia have been introduced over the recent years, review of the literature suggests suggests that we are far from achieving the goals of optimum post-operative analgesia. We conducted a systematic review of recent advances in modalities for post-caesarean analgesia. After systematic search and quality assessment of studies, we included a total of 51 randomised controlled trials that evaluated the role of opioids, transversus abdominis plane (TAP) block, wound infiltration/infusion, ketamine, gabapentin and ilioinguinal-iliohypogastric nerve block (II-IH NB) for post-caesarean analgesia. Administration of opioids still remains the gold standard for post-operative analgesia, but the associated troublesome side effects have led to the mandatory incorporation of non-opioid analgesics in post-CS analgesia regime. Among the non-opioid techniques, TAP block is the most investigated modality of the last decade. The analgesic efficacy of TAP block as a part of multimodal analgesia is established in post-CS cases where intrathecal morphine is not employed and in CS under general anaesthesia. Among non-steroidal anti-inflammatory drugs, COX-I inhibitors and intravenous paracetamol are found to be useful in post-operative analgesic regimen. The perioperative use of ketamine is found useful only in CS done under spinal anaesthesia; no benefit is seen where general anaesthesia is employed. Wound infiltration with local anaesthetics, systemic gabapentin and II-IH NB need further trials to assess their efficacy.

INTRODUCTION

Pain is ranked highest among undesirable clinical outcomes associated with caesarean section (CS).[1] Adequate post-operative analgesia in the obstetric patients is crucial as they have different surgical recovery needs which include breastfeeding and care of the newborn; these can be impaired if analgesia is unsatisfactory. The ideal post-CS analgesic regime should be efficacious without impacting the ability of mother to take care of the neonate and with minimal drug transfer through breast milk. However, observational data from developing as well as developed countries have shown that we are far from achieving these goals. In developing countries, limited availability of drugs, equipment and expertise are the major issues in providing adequate post-CS analgesia.[2] In the past 5 years, there has been a surge in studies describing newer post-operative analgesic modalities. Some of these modalities require less expertise and reduce consumption of opioids in post-operative period.

LITERATURE SEARCH

This systematic review examined the recent advances in modalities for post-operative analgesia after CS. We searched US National Library of Medicine database, Cochrane Central Register of Controlled Trials, EMBASE and CINAHL for randomised controlled trials (RCTs) that evaluated various analgesic modalities after CS. The terms post-operative analgesia, CS, post-caesarean analgesia were searched. The search was performed without any limits or language restrictions. The last search was performed on 15 October 2016. It revealed a total of 738 results. The RCTs published before 2010, review articles, retrospective studies, case reports and letter to the editor were excluded. After this, a total of 102 RCTs on various types of analgesic were available [Figure 1].

Figure 1

Flow diagram of review

RESULTS

The various analgesic modalities identified were transversus abdominis plane (TAP) block, local anaesthetic wound infiltration, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, ilioinguinal-iliohypogastric nerve blocks (II-IH NBs), intrathecal additives, epidural analgesia, ketamine and gabapentin. The quality of the selected RCTs was assessed by two independent reviewers using the Jadad scale. Based on consensus of all authors, the studies scoring >3 on the Jadad scale were selected for data collection and further review.

A standardised data collection form was used for outcome data extraction. Data recorded were trial characteristics including sample number, anaesthesia technique, post-operative regimen employed and outcome measures such as post-operative opioid consumption, pain scores and side effects. Based on this data, we describe the utility of intrathecal and epidural opioids, TAP block, II-IH NB and wound infiltration, ketamine, NSAIDs, acetaminophen and gabapentin for post-CS analgesia.

INTRATHECAL AND EPIDURAL OPIOIDS

In the present review, we found 13 RCTs on various intrathecal opioids used for post-caesarean analgesia; eight trials were excluded after evaluating them. The remaining five RCTs [Table 1] were taken up for review; out of these two trials evaluated the different doses of intrathecal morphine (ITM) while three studied lipophilic opioids fentanyl and sufentanil.

Table 1

Opioids administered through various routes for post-caesarean analgesia

The efficacy of ITM for post-CS pain control is well established, but the optimal dose is still debated. Previous investigators reported 100 µg ITM to be equivalent to higher doses both in terms of analgesia and side effects.[3] A further lower dose of 50 µg with 100 µg ITM was evaluated in two studies and found to be equally efficacious.[45] These results showed that there is no direct relationship between the dose of ITM and the quality of analgesia. Similar results were demonstrated in previous studies by other investigators.[36] The incidence of pruritus after ITM was found to increase linearly with increasing dose while other side effects such as urinary retention, nausea and vomiting were found to bear no relation with either the use or the dose of ITM. Neither of the two studies reported respiratory depression or sedation which may be attributed to the small sample size of the studies.

Lipophilic opioids such as fentanyl and sufentanil given intrathecally, when compared to ITM, were found to provide only early post-operative analgesia.[7] The comparison of intrathecal fentanyl and sufentanil showed that sufentanil provides longer post-operative analgesia without increased incidence of side effects.[89]

We found one RCT each on epidural morphine and lipophilic opioids [Table 1]. Traditionally, the dose of epidural morphine used for post-CS analgesia is 2–3 mg.[10] Recently an RCT on epidural morphine compared traditional dose of 3 mg to a lower dose of 1.5 mg. The authors found the 1.5 mg of epidural morphine to be equally efficacious and associated with lower incidence of nausea and pruritus.[11]

Vora et al. studied a combination of epidural lipophilic opioid with a small amount of hydrophilic opioid and observed the additional benefit of immediate onset as compared to morphine alone.[12]

PATIENT CONTROLLED EPIDURAL ANALGESIA

Patient-controlled epidural analgesia (PCEA) has shown effective post-CS analgesia in three studies using opioids with local anaesthetic (LA) agents [Table 1]. Satisfactory post-operative analgesia has been reported with dilute concentrations of ropivacaine 0.025%–0.15% and 0.15% levobupivacaine.[13] Combining a lipophilic opioid like fentanyl or sufentanil to ropivacaine has an LA sparing effect with lower incidence of motor blockade in parturients.[14] However, with the addition of fentanyl to levobupivacaine, greater dizziness and pruritus and less paraesthesia is reported than with PCEA levobupivacaine alone.[15] Pure levobupivacaine could be an alternative regimen for the parturient who is concerned about opioid-related adverse events.

CURRENT STATUS OF ORAL OPIOIDS

Traditionally, oral opioids are employed as a step down analgesics for post-operative analgesia when the severity of pain decreases. Recently, there has been growing interest in their use as the primary post-caesarean analgesic method on the first post-operative day itself. The potential benefits of this approach include higher maternal acceptability, ease of administration and avoidance of complications associated with parenteral or neuraxial opioids. Oral oxycodone is the preferred opioid for such an approach, as it has a higher and more predictable oral bioavailability than morphine.[16] Oral oxycodone-based post-operative oral regime has been found equianalgesic to ITM after CS.[17]

For oral methadone and tramadol; we could not find any study scoring >3 on Jaded scale in the present review.

REGIONAL NERVE INFILTRATION TECHNIQUE: TRANSVERSUS ABDOMINIS PLANE BLOCK

A total of 14 studies [Table 2] employing TAP block for post-CS analgesia were identified.[1819202122232425262728293031] Most of the investigators used ultrasound-guided TAP block; only in two studies TAP block was performed by anatomical landmark technique.[2021]

Table 2

Studies using transversus abdominis plane block for post-caesarean analgesia

There are three studies where TAP block was compared to control for post-CS analgesia and all three demonstrated block to be effective.[182122] In two of these studies, CS was performed under general anaesthesia while in the third study spinal anaesthesia was administered. However, when compared to ITM, TAP block was reported to be ineffectual in three studies.[192023] There was also no advantage of supplementing ITM with TAP block as concluded in two trials.[2931] The researchers also studied various other approaches to increase the efficacy of TAP block in comparison to ITM. These included adding clonidine or fentanyl and increasing the dose of LA, but all of them failed to show any benefit.[242730] When TAP block was compared as a part of multimodal analgesia comprising epidural morphine, less consumption of patient-controlled analgesia (PCA) morphine was noted.[28] In two other studies, TAP block was observed to be equally effective in comparison to wound infiltration for analgesia.[2526]

TAP block as a part of multimodal analgesia after CS is useful in reducing opioid consumption and their side effects only in parturient receiving general anaesthesia or in situ ations where ITM is not used. The probable explanation for this may be that since ITM already provides effective analgesia for somatic and visceral afferents, post-operative analgesia is not improved by adding TAP block to ITM. Further, larger studies with adequate power and evaluation of lower dose of ITM with TAP block need to be evaluated.

ILIOINGUINAL-ILIOHYPOGASTRIC NERVE BLOCK

There are five studies on II-IH NB for post-CS analgesia [Table 3].[3233343536] In three studies,[323334] the block was performed by the blind bilateral multilevel II-IH NB technique described by Bell et al.[37] In one trial[35] a single injection as described by Huffnagle et al.[38] was used and, in another, an ultrasound-guided block[36] was performed. In all these trials, except the one using ultrasound for nerve blockade, II-IH NB was seen to be effective for post-CS analgesia. The authors attribute the negative result to use of ITM for spinal anaesthesia which they considered 'standard of care'. However, Wolfson et al. found the landmark-based II-IH NB in addition to ITM to be effective in enhancing analgesia after CS.[34] The ultrasound-guided block is of moderate level difficulty and needs accurate visualisation of nerves. The drug is placed by out of plane approach till the nerves are seen to be completely surrounded by the drug. Further studies involving ultrasound-guided II-IH NBs are warranted to establish its analgesic efficacy.

Table 3

Studies on ilioinguinal-iliohypogastric nerve block for post-caesarean analgesia

WOUND INFILTRATION/CONTINUOUS WOUND INFUSION WITH LOCAL ANAESTHETICS

There are two studies[3940] of single shot wound infiltration and four RCTs of continuous wound infusion[41424344] for post-caesarean analgesia [Table 4]. The drug used for infusion/infiltration is LA in six while in one study tramadol infiltration was compared to LA.[40]

Table 4

Studies using wound infiltration technique for post-caesarean analgesia

The trials comparing LA for continuous wound infusion have conflicting results. Most trials found continuous wound infusion to be less effective as compared to placebo[41] or ITM[42] or epidural levobupivacaine[40] whereas one found it to be equally effective to epidural morphine in post-operative analgesic requirement.[43] Rackleboom et al. demonstrated that placement of catheter for continuous wound infusion between transversalis fascia and peritoneum is more efficacious for analgesia as compared to placement above the fascia.[44] However, in the present review, the location of catheter is not the only determinant influencing analgesic efficacy as in only 1 out of 3 trials where the catheter was placed sub fascially reported a positive outcome. The other factors responsible could be the dose of LA used or continuous versus the intermittent boluses of LA through catheter. High concentration–low volume administration of ropivacaine (0.5%, 50 ml) is found to be more effective than low concentration and high volume (0.2%, 125 ml) for direct wound infiltration.[39] Further large-sized studies are required to establish the role of continuous wound infusion with LA in post-caesarean analgesia.

KETAMINE FOR POST-CAESAREAN PAIN

Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor that inhibits central sensitisation and has a pre-emptive analgesic effect to relieve post-operative pain. In particular, even when ketamine is administered in sub-anaesthetic low doses, it suppresses facilitation of pain related to (NMDA) receptors. A total of eight studies involving evaluation of analgesic efficacy of administration of intravenous ketamine in parturient undergoing CS were identified [Table 5].[4546474849505152] Most of the trials (6 out of 8) used spinal anaesthesia for CS. The timing and the dose of ketamine administered were observed to be variable. In two studies where general anaesthesia was used, ketamine was given before induction of anaesthesia[5052] whereas in three trials, involving spinal anaesthesia ketamine was administered immediately after subarachnoid block[444748] while in three it was given after delivery of the baby.[464951] Continuous infusion of ketamine was employed in two studies[4749] and in the remaining trials, bolus doses of ketamine varying from 1 to 0.15 mg/kg were used.

Table 5

Studies using perioperative low-dose ketamine for post-caesarean analgesia

The reported outcomes were variable in these studies; two studies reported a negative outcome,[5051] two found ketamine to be effective in decreasing consumption of analgesics at 2 h post-operatively[4752] whereas five studies reported a positive outcome.

These inconsistent results may be related to differences in anaesthesia technique, the dose and technique of ketamine administered and the post-operative analgesic regime used in trials. A recent meta-analysis observed the efficacy of perioperative ketamine in studies where it was administered during regional anaesthesia but not in the studies where the CSs were performed under general anaesthesia.[53] Another important consideration is the plasma volume expansion during pregnancy which can result in insufficient plasma ketamine levels.[54] Therefore, using a higher dose of ketamine or maintaining continuous infusion for longer time might result in adequate plasma levels. However, the psychomimetic side effects of ketamine may preclude this strategy as it impairs the ability of mother to care for newborn in the immediate post-operative period.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND ACETAMINOPHEN/PARACETAMOL

NSAIDs and acetaminophen are commonly added to a post-caesarean analgesic regimen along with opioid medications to improve post-caesarean pain and reduce opioid requirements. There are two studies investigating role of oral/intravenous acetaminophen either alone or in combination with an NSAIDs as a part of multimodal post-operative analgesic regime.[5556] Both acetaminophen and diclofenac, when used as a part of post-operative multimodal analgesia, resulted in reduced post-operative analgesic consumption. The combination of diclofenac-tramadol resulted in lower post-operative pain scores compared to diclofenac-acetaminophen.[55] Akhavanakbari et al. showed that diclofenac and indomethacin suppositories resulted in less rescue analgesic consumption compared to acetaminophen.[56] These results are consistent with previous studies. There are three studies using COX-2 inhibitors for post-CS analgesia.[575859] One study evaluated single dose of oral celecoxib 200 mg added to PCEA and compared it to analgesia provided by PCEA only.[57] There was no difference in the total drug consumption in either group. In a study by Wong et al., intravenous parecoxib was found to be as effective as ketorolac for post-CS analgesia.[58] It resulted in 22% PCA morphine reduction in the first post-operative day. Paech et al. compared the combination of oral celecoxib and intravenous parecoxib to paracetamol for post-CS analgesia.[59] They found that the combination of COX-2 inhibitors to be more effective in reducing analgesic requirement. Celecoxib and parecoxib provide a safe profile for both surgical patients and breastfeeding mothers.

GABAPENTIN FOR ACUTE AND/OR CHRONIC PAIN FOLLOWING CAESAREAN SECTION

Gabapentin is an anticonvulsant drug with significant analgesic properties. It binds to presynaptic voltage-gated calcium channels in the dorsal root ganglia of the spinal cord and prevents release of excitatory neurotransmitter. It is an established analgesic in chronic and neuropathic pain conditions. The pre-operative use of oral gabapentin has been shown to decrease acute pain after various surgical procedures. There are only two studies in literature exploring the role of gabapentin in post-CS analgesia, and both have conflicting results.[6061] While one study concluded significant improvement in pain score and maternal satisfaction in first 48 h postoperatively with a single dose of 600 mg, the other study failed to show any beneficial effect of gabapentin. Thus, a definitive conclusion about the use of gabapentin cannot be drawn at this stage, and further studies are warranted to evaluate the effect of gabapentin on acute and/or chronic pain after caesarean section.

CONCLUSION

From the present review, it is evident that multimodal analgesia including paracetamol, NSAIDs and oral opioids such as oxycodone should be given to all patients unless there are specific contraindications to any of these. Intraoperative interventions which should be considered are first, intrathecal or epidural morphine if regional anaesthesia has been used; and second, TAP block for CS under general anaesthesia. When ITM is included in post-CS analgesic regime, a dose of 50–75 µg balances desirable analgesia with fewer side effects. In future, the possibility of a further lower dose of epidural morphine and role of oral oxycodone as a primary post-operative analgesic regime may be explored. Further studies are needed to define the role of gabapentin, wound infiltration techniques and II-IH NB for post-CS analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.