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1. Introduction

Management of post-operative pain isdergoing caesarean delivery, as adequate p

andcreasedversecute pnd thegimen

Multimodal analgesia utilizes analgesics acting on differentaspects of the pain pathway. Hence patients can receive the benets

sarean delivery insafe and effectivegesia with a well-and studies have

r quality analgesiaber of opioids areduration of action

providing excellent intra-operative conditions have short-livedanalgesic effects due to their high lipid solubility and rapid up-take into the dorsal horn; therefore they provide little post-operative analgesia. In contrast, morphine has low lipid solubilityand penetrates neural tissue slowly resulting in a longer duration ofaction. However, its rostral spread within the subarachnoid spaceby bulk ow could lead to complications such as delayedrespiratory depression.

* Corresponding author. KK Women's and Children's Hospital, 100 Bukit TimahRoad, 229899 Singapore, Singapore. Tel.: 65 6563941081; fax: 65 62912661.

Contents lists availab

Trends in Anaesthesi

.e

Trends in Anaesthesia and Critical Care 4 (2014) 189e194E-mail addresses: Sng.Ban.Leong@kkh.com.sg, blsngdr@yahoo.com.sg (B.L. Sng).2. Multimodal analgesiaand side effects. Intrathecal fentanyl and sufentanil whilstapproach to post-caesarean pain has evolved signicantly over theyears encompassing a wide variety of analgesics, techniques, andregimens, the current trend is towards the use of a balanced,multimodal analgesia. This review will examine the evidence forcommonly used drugs and techniques, as well as newdevelopments in post-caesarean analgesia.

Regional anaesthesia accounts for 91.8% of cae2011 in the United Kingdom.7 It provides amethod of administering neuraxial opioid analdened side effect prole. Several large reviewsconcluded that neuraxial opioids provide highecompared with the intravenous route.8e11 A numcurrently in use and they differ in their potency,pain relief with minimal maternal side effects and minimal infantexposure via breast milk, and is easy to administer. While the

3. Neuraxial analgesiamanagement.1 An ideal analgesia remothers to quickly regain mobilitynewborn. Failure to do so may inthromboembolic events, and may abreast feeding. In addition, severe alivery may progress to chronic pain ahttp://dx.doi.org/10.1016/j.tacc.2014.10.0012210-8440/ 2014 Elsevier Ltd. All rights reserved.critical in mothers un-ain relief is required forbegin to care for thethe maternal risk forly affect the success ofain after caesarean de-refore requires effectivewould provide optimal

of a variety of analgesics with differingmechanisms of actionwhichin combination can have additive or even synergistic effects butwith a reduction in side effects experienced as lower doses of eachclass of drug are needed.2 For example, non-steroidal anti-inam-matory drugs (NSAIDs) are routinely prescribed alongside neu-raxial morphine as the combination has been shown to provideimproved post-operative analgesia.3e6 Huang et al. demonstratedthat NSAIDs are particularly effective at reducing the visceral painof uterine cramps that may follow delivery.6Post-caesarean analgesia

Sarah Kwok a, Hao Wang b, Ban Leong Sng a, b, *

a Department of Women's Anaesthesia, KK Women's and Children's Hospital, Singaporeb Duke-NUS Graduate Medical School, Singapore

Keywords:Caesarean sectionPainRegional anaesthesiaOpioid

s u m m a r y

Post-caesarean section anregimen should provide oexposure via breastfeedingsince regional techniquesusing opioid based patienanaesthesia is administerenon-steroidal anti-inammanaesthetic blocks are usecially when general anaesREVIEW

journal homepage: wwwsia is centred on the concept of multimodal analgesia. The analgesical pain relief with minimal maternal side effects and minimal infanturaxial opioids (morphine, diamorphine, fentanyl, pethidine) are utilizedcommonly administered during caesarean section. Systemic analgesia

ntrolled analgesia (morphine, fentanyl) is commonly used when generalring caesarean section. To reduce opioid adverse effects, paracetamol andry agents are commonly prescribed concomitantly. Increasingly, localch as the transversus abdominis plane block to improve analgesia espe-ia is administered or neuraxial morphine is not used.

2014 Elsevier Ltd. All rights reserved.

le at ScienceDirect

a and Critical Care

lsevier .com/locate/ tacc

ia a3.1. Intrathecal opioids

Opioids administered into the subarachnoid space act on themureceptors in the substantia gelatinosa of the dorsal horn by sup-pressing excitatory neuropeptide release from C bres.12 Intra-thecal morphine has been given in doses ranging from 0.075 mg13

to 0.5 mg14 providing highly effective post-operative analgesia.However, there appears to be a ceiling analgesic effect demon-strated by several studies. A meta-analysis of intrathecal opioidsrevealed high quality analgesia provided by 0.1e0.2 mg of intra-thecal morphine but no additional benet above 0.2 mg.9 Mediantime to rst request for supplemental analgesia was 27 h (range11e29 h). Additionally, intrathecal morphine at doses of 0.05, 0.1and 0.2 mg reduced pain scores and decreased consumption ofsupplemental analgesia from 0 to 24 h postoperatively in all com-parisons. Palmer et al. randomized 108 women undergoing electivecaesarean section to receive 1 of 9 different doses of intrathecalmorphine ranging from 0.025 to 0.5 mg with intravenous (IV) pa-tient controlled analgesia (PCA) consumption as primaryoutcome.13 The authors demonstrated the 0.075 mg group used45.7 mg less morphine compared with the control group but therewas no signicant difference in PCA usewith doses above 0.075mg.Cardoso et al. concluded that a 0.1 mg dose of intrathecal morphinewas optimal but also found doses of 0.025e0.05 mg combined witha non-steroidal anti-inammatory drug to be effective.3 However,there are studies which have reported that in a small percentage ofwomen, doses of 0.1 mg may be inadequate. Swart et al. found thatin women who were given 0.1 mg intrathecal morphine duringtheir elective caesarean section, the majority used less than 10 mgof PCAmorphine in the post-operative period but 10% of them usedmore than 40 mg.15 Although intrathecal morphine is an effectiveform of analgesia, monitoring of pain scores, a dedicated acute painservice and provision of multimodal analgesia is still required.

Despite superior analgesia, the signicant adverse effects ofpruritus, nausea and vomiting, reactivation of herpes simplex,urinary retention, sedation and delayed respiratory depression,which have a higher incidence with intrathecal morphinecompared with parenteral opioids, may contribute to lower patientsatisfaction scores.9e11 Dahl et al. estimated that if a 0.1 mg dose isused, 43% of the patients will have pruritus, 12% will suffer fromvomiting and 10% from nausea; all of whom would not haveexperienced these side effects without treatment. Pruritus is oftencited as the most frequent and unpleasant adverse event. Onerandomized prospective study16 showed signicantly higher in-cidences of pruritus and nausea in doses of 0.25 mg of morphinecompared to 0.1 mg.

Respiratory depression is a rare but serious complication ofwhich the incidence in the post-caesarean population is likely to below.9 Morphine is highly ionized and does not penetrate into lipid-rich tissues and has an extended duration in the cerebrospinal uid.Morphine spreads cephalad in the spinal space from bulk owreaching the trigeminal nerve distribution in about 6e9 h afterintrathecal injection in volunteers.17 Abouleish et al. performed aprospective study investigating the analgesic and side effect proleof 0.2 mg in 856 parturients and found respiratory depression(dened by a SpO2

sia a15 min. Although epidural pethidine resulted in higher pain scoreswhen compared to intrathecal morphine 100 mcg, there is areduction in pruritus and nausea requiring treatment.28 Epiduralpethidine is a more favourable mode of delivery compared to IVpethidine with lower pain scores and less sedation.29

4. Systemic analgesia

4.1. Intravenous and intramuscular analgesia

Intravenous patient controlled analgesia (PCA) is a popularmethod of providing post-caesarean pain relief, as it providesindividualized pain relief, greater patient autonomy, and reducesthe anaesthetist and nursing workload. In general, opioid analge-sics administered via patient-controlled IV route confer lessoptimal pain relief compared to neuraxial analgesia.29e33 Morphineis the standard drug of choice. However, compared to epiduralmorphine, IV PCA morphine is associated with higher patientsatisfaction and less opioid side effects such as pruritus and delayedrespiratory depression.30,31,33 Thus IV PCA morphine may be anexcellent alternative in post-caesarean delivery patients whocannot receive neuraxial analgesia.

Fentanyl is another commonly used opioid in postsurgical PCA.A comparison of equivalent doses of morphine, fentanyl andpethidine in postsurgical PCA found no difference in patient satis-faction and the incidence of side effects except more pruritus wasexperienced in the morphine group.34 Limitations of fentanyl PCAappear to be its relatively higher cost, more programming in-terventions and lack of clinical benet over morphine.35 Pethidinehas been used in the setting of post-caesarean analgesia, andalthough studies show that they may provide equivalent pain reliefand a comparable if not better maternal side-effect prolecompared to morphine or fentanyl,32,34,36 concerns about neonatalexposure in breast-feedingmothers may limit its use. Pethidine andits active metabolite are known to accumulate in breast milk andbreast-fed infants. This is likely due to impaired neonatal meta-bolism,36,37 and PCA pethidine in nursing mothers was associatedwith signicantly poorer neonatal alertness and orientation thanmorphine.36,38 Morphine-alfentanil combination PCA has beenshown to result in faster onset of analgesia,39 but the optimalregimen needs to be further dened and there are no data on breastmilk transfer. A recent retrospective caseecontrol study found thata single dose of IV methadone given intra-operatively and post-delivery may reduce post-operative opioid consumption whilstachieving effective analgesia.40

Recently low dose IV ketamine given during spinal anaesthesia(pre-emptively) has been proposed to prolong post-caesareananalgesia and reduce opioid consumption. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, exerts its analgesic effect mainlythrough central desensitization and reducing opioid tolerance.41,42

A 2006 Cochrane review found that ketamine in sub-anaestheticdose is effective in reducing morphine requirements in the rst24 h after surgery. Evidence amongst caesarean delivery patients ismixed, primarily due to a difference in the method of anaesthesiaand concomitant modalities used. Evidence supporting the use oflow dose ketamine appears to come from studies where spinalanaesthesia was administered without the addition of long actingintrathecal opioids42,43; in comparison, when intrathecal morphinewas co-administered during spinal anaesthesia,44 or when PCAfentanyl was used post-operatively,45 low dose ketamine does notappear to have any opioid-sparing effect, nor is it associated withlower pain scores.

Intramuscular (IM) opioids are easy to administer but are foundto result in less optimal pain relief and lower patient satisfaction

S. Kwok et al. / Trends in Anaesthethan either the epidural or intravenous PCA route.30,31 A single IMdose of tramadol and diclofenac combination has been demon-strated to produce better analgesia than monotherapy or placeboand requires less morphine analgesic rescue.46

4.2. Oral analgesia

Oral opioids are used for post-operative analgesia as step-downtherapy from intravenous opioids or when newer and moreexpensive analgesic delivery regimens such as PCA are not readilyavailable.47,48 Earlier studies show that oral morphine providessatisfactory pain relief, is easy to administer and is substantially lessexpensive.47 More recent randomized trials showed oraloxycodone-paracetamol provides better pain relief and is associ-ated with less opioid side effects such as nausea, sedation andpruritus compared to IV PCA morphine.49 Compared to intrathecalmorphine, multimodal analgesia regimen based on oral oxycodoneproduces comparable post-operative pain relief with a lower inci-dence of pruritus, but was associated with lower satisfaction andmore requirements for additional analgesics.50

Tramadol is another effective analgesic in post-operative pain51

with a well-known side effect prole. It can be administeredthrough oral, IV, or IM routes, and produces less constipation andemesis than equianalgesic doses of opioids.52 Compared to oralnaproxen, oral tramadol on either a xed interval or on requestregimen affords comparable pain relief after caesarean delivery andsimilar breastfeeding scores, but is associated with a higher inci-dence of maternal adverse effects (nausea, vomiting, sedation) andrequest for additional analgesics.53 IV tramadol administered incombination with a diclofenac suppository has been shown toproduce better analgesia than an IV diclofenaceparacetamol com-bination, with few and comparable side effects except a higherincidence of nausea amongst the tramadol group.54 Both oxyco-done and tramadol can be an acceptable alternative in the setting ofmultimodal analgesia particularly in patients who do not toleratethe adverse effects of opioid analgesia.

Paracetamol is thought to produce analgesia both as a selectiveCOX-2 inhibitor as well as through central mechanisms, althoughthe exact mechanism of action is still unclear. Unlike opioids andNSAIDs, it produces very few side effects at therapeutic doses,making it a popular analgesic choice for post-operative mild tomoderate pain, frequently as part of a multimodal analgesiaregimen. A Cochrane review of 51 randomized placebo-controlledstudies shows that a single dose of paracetamol provides effectiveanalgesia for about half of the patients with acute post-operativepain, for a period of about 4 h, and is associated with few, mainlymild, adverse events.55 Recently, availability of the parenteralformulation of paracetamol provides an attractive option to treatimmediate post-surgical pain due to its faster onset and higherbioavailability. A review of 36 randomized studies comparedeither IV paracetamol or IV prodrug propacetamol with placeboand active controls. A single dose of both IV propacetamol and IVparacetamol was found to provide around 4 h of effective anal-gesia for about 37% of patients with acute post-operative pain,with few adverse events.56 When administered with PCAmorphine after major surgery, paracetamol given IV or orally isfound to have a signicant morphine-sparing effect thoughwithout signicant reduction in morphine related side-effects.57

However, the evidence is less straightforward in the setting ofpost-caesarean analgesia, where a paracetamol/diclofenac combi-nation is favoured over monotherapy with either drug, and theopioid-sparing effect of paracetamol over placebo is controver-sial.58,59 More recently, IV paracetamol has been found to reducepost-operative nausea and vomiting in patients receiving generalanaesthesia, independent from the effect of reduced opioid

nd Critical Care 4 (2014) 189e194 191consumption.60

ia aNon-steroidal anti-inammatory drugs (NSAIDs) are effective inreducing visceral pain after caesarean section and have a well-known opioid-sparing effect associated with reduced opioid-related side effects when used in multimodal analgesia.48 Due tonon-selective inhibition of COX-1 and COX-2, NSAIDs may beassociated with undesirable side effects such as platelet, gastroin-testinal, and renal dysfunction. Of the NSAIDs family, ibuprofen andketorolac are perhaps ideal agents, with low relative infant doses(

sia a7. Conclusion

Patients undergoing caesarean delivery require effective post-operative analgesia to allow early mobilisation to enhance themother's care of her newborn and facilitate breastfeeding. It needsto be safe, easy to administer and have limited transfer into breastmilk. There should be a multimodal approach with a combinationof techniques which limit adverse effects but provide high qualityanalgesia. This can be accomplishedwith neuraxial analgesiawhichhas been shown to provide superior analgesia to parenteral opioidsbut with a high incidence of side effects. In the absence of a neu-raxial technique, peripheral blocks such as the TAP block will alsoprovide effective analgesia when co-administered with systemicanalgesics.

Conict of interest

There is no conict of interest of note.

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S. Kwok et al. / Trends in Anaesthesia and Critical Care 4 (2014) 189e194194

Post-caesarean analgesia1. Introduction2. Multimodal analgesia3. Neuraxial analgesia3.1. Intrathecal opioids3.2. Epidural morphine3.3. Epidural diamorphine3.4. Epidural fentanyl3.5. Epidural pethidine

4. Systemic analgesia4.1. Intravenous and intramuscular analgesia4.2. Oral analgesia

5. Wound infiltration and peripheral nerve blocks5.1. TAP block5.2. Wound infiltration

6. Analgesia and breast feeding7. ConclusionConflict of interestReferences