Accepted Manuscript

Post-Cesarean Delivery Analgesia

Brendan Carvalho, MBBCh, FRCA, Professor, Alexander J. Butwick, MBBS, FRCA,

MS, Associate Professor

PII: S1521-6896(17)30003-4
DOI: 10.1016/j.bpa.2017.01.003
Reference: YBEAN 929

To appear in: Best Practice & Research Clinical Anaesthesiology

Received Date: 5 October 2016

Accepted Date: 4 January 2017

Please cite this article as: Carvalho B, Butwick AJ, Post-Cesarean Delivery Analgesia, Best Practice &
Research Clinical Anaesthesiology (2017), doi: 10.1016/j.bpa.2017.01.003.

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 ACCEPTED MANUSCRIPT

TITLE: Post-Cesarean Delivery Analgesia

Authors:

Brendan Carvalho, MBBCh, FRCA

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Professor*

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Email: bcarvalho@stanford.edu

Phone: 650-861-8607

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Fax: 650-725-8544

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Alexander J Butwick, MBBS, FRCA, MS AN
Associate Professor*

Email: ajbut@stanford.edu
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Phone: 650-648-5115
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Fax: 650-725-8544
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Institution:
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*Department of Anesthesiology, Perioperative and Pain Medicine

Stanford University School of Medicine

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Stanford, California 94305

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Corresponding Author:

Brendan Carvalho MBBCH, FRCA

Department of Anesthesia, Stanford University School of Medicine

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300 Pasteur Drive, Stanford, CA 94305.

Phone: 650-861-8607

Fax: 650-725-8544

Email: bcarvalho@stanford.edu

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Total of Words Used: 6150

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ABSTRACT:

Effective pain management should be a key priority in women undergoing cesarean delivery.

Suboptimal perioperative pain management is associated with chronic pain, greater opioid use,

delayed functional recovery, impaired maternal-fetal bonding, and increased postpartum

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depression. Severe acute postoperative pain is also strongly associated with persistent pain after

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cesarean delivery. Multimodal analgesia is the core principal for cesarean delivery pain

management. The use of neuraxial morphine and opioid-sparing adjuncts such as scheduled

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nonsteroidal anti-inflammatory medications and acetaminophen should be used if available for

all women undergoing cesarean delivery with neuraxial anesthesia unless contraindicated.

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Additional analgesic and opioid-sparing options such as wound instillation of local anesthetics,
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transversus abdominis plane blocks, dexamethasone, gabapentin and ketamine may be used as

appropriate in women at risk for severe postoperative pain or in women whose postoperative
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pain is not well controlled despite standard analgesic regimes.

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KEY WORDS:

Cesarean delivery; pain management; intrathecal opioids; multimodal analgesia

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Cesarean delivery is the most common major surgical procedure [1]. In the United States

in 2014, 1.28 million women underwent cesarean delivery, accounting for 32% of all births [2].

For obstetric anesthesia providers caring for women undergoing cesarean delivery, the delivery

of effective postoperative analgesia is of primary importance for several reasons. Firstly, women

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rank avoidance of pain during and after cesarean delivery as their highest priority [3]. Secondly,

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acute pain after cesarean delivery may develop into persistent pain, which may result in greater

opioid use, delayed functional recovery, and increased risk for postpartum depression [4].

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Thirdly, ensuring effective analgesia can optimize maternal-neonatal bonding and breastfeeding

after delivery [5].

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<A>CHRONIC PAIN AFTER CESAREAN DELIVERY
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Chronic incisional pain and pelvic pain are well described after cesarean delivery. The
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reported incidence of persistent incisional pain or analgesic requirements >6 months after
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cesarean delivery varies significantly [6], with reported rates ranging between 1% and 18% d [4,
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7-13]. Compared to vaginal delivery, the risk of chronic pain and impaired health-related quality

of life is higher following cesarean delivery [13, 14]. The incidence and intensity of persistent
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pain appear to be lower after cesarean delivery compared with other non-obstetric surgeries. It

has been hypothesized that pregnancy and/or oxytocin may protect against the development of
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chronic postsurgical neuropathic pain [15], however this observation requires further evaluation.
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Clinical interventions to decrease the incidence and severity of chronic post-cesarean

pain have not been consistently effective. Analgesic drugs may have only a modest effect or

studies may be underpowered to confirm positive effects because of the low incidence of chronic

pain [6]. To reduce the likelihood of chronic postoperative pain, several approaches have been
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recommended. Neuraxial and/or regional anesthesia may be associated with a lower incidence of

persistent pain after cesarean delivery and hysterectomy compared with general anesthesia [7,

16]. Multimodal perioperative analgesia consisting of intravenous ketamine and neuraxial

clonidine may reduce central sensitization and decrease the incidence or severity of chronic pain

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[17]. In one study, the incidence of chronic pain after cesarean delivery was decreased with

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higher compared with lower doses of spinal local anesthetics and the use of anti-inflammatory

drugs [18]. There are several psychosocial and pathophysiologic factors, e.g., anxiety, pain

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catastrophizing, and depression, that are associated with an increase in the likelihood of chronic

postoperative pain [19, 20]. Severe acute postoperative pain is one of the most prominent factors

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associated with persistent pain after cesarean delivery [4, 7, 19, 21]. Therefore, severe acute
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post-cesarean pain may help identify women at risk for persistent pain, and effective treatment of

acute postoperative pain may help reduce the risk for chronic pain after cesarean delivery.
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<A>NEURAXIAL OPIOIDS AND ADJUVANTS

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Neuraxial anesthesia is recommended as the preferred anesthetic modality for cesarean delivery

by the American Society of Anesthesiologists and the American Pain Society [22, 23]. Most
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cesarean deliveries in the United States are performed with neuraxial anesthesia (spinal, epidural,

or combined spinal-epidural techniques); spinal anesthesia is the most common technique for
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elective cesarean deliveries [24, 25].

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Neuraxial opioids provide high-quality post-cesarean delivery analgesia [23, 26].

Lipophilic opioids such as fentanyl can optimize the quality of intraoperative anesthesia,

however these drugs have a relatively short duration of action (median effect of neuraxial

fentanyl is 4 hours) [27, 28]. By comparison, hydrophilic opioids such as morphine provide a
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longer duration of action. Intrathecal morphine has a duration of action between 14 and 36 hours

[27, 28]. The optimal dose of intrathecal morphine remains uncertain. The intrathecal morphine

dose is related to duration of effect, but not analgesic efficacy. Doses greater than 100 mcg (up to

250 mcg) prolong time to first request for additional analgesia by a mean difference of 4.5 hours

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compared to doses between 50 and 100 mcg (time to first analgesic request was 9.7 to 26.6 hours

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for doses 50 to 100 mcg compared to 13.8 to 39.5 hours for doses greater than100) [28]. The

incidence of opioid-related side-effects, including nausea, vomiting, and pruritus, may increase

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with escalating doses of intrathecal morphine. In a 2016 meta-analysis, the odds of

nausea/vomiting (OR 0.44 [95% CI, 0.27, 0.73]) and pruritus (OR 0.34 [95% CI, 0.20,0.59])

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were lower with smaller doses of intrathecal morphine (50 to 100 mcg) compared with higher
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doses (>100 mcg) [28]. Importantly, respiratory depression was not reported in any study in this

meta-analysis. While women with obstructive sleep apnea and morbid obesity are potentially at
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increased risk for respiratory depression [29], neuraxial opioids are recommended because the
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risk of respiratory depression is higher if patients are exposed to intravenous opioids [30].
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For women with epidural labor analgesia who require intrapartum cesarean delivery

conversion of epidural analgesia to epidural anesthesia is most common mode of anesthesia [24,
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25]. In this setting, epidural morphine is recommended to optimize postoperative analgesia. Prior

studies have shown that the analgesic efficacy of epidural morphine (2 to 3 mg) is similar to
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intrathecal morphine (75 to 200 mcg) [31, 32]. The recommended optimal dose of epidural
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morphine is between 2 and 4 mg; doses greater than 4 mg have limited additional analgesic

benefit, but are associated with a higher incidence of dose-related adverse-effects [26, 33].

On occasion, preservative-free morphine has become unavailable; in this case, clinicians

may consider using intrathecal hydromorphone. High patient satisfaction rates, and similar
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adverse-effect profiles have been reported with hydromorphone compared with morphine [34].

However, because morphine is more hydrophilic, duration of analgesia after single-dose

administration is longer compared to hydromorphone. The estimated dose ratio of intrathecal

morphine to intrathecal hydromorphone is 2:1 [34].

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Neuraxial clonidine has been studied as an adjunct to local anesthetics and opioids.

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Clonidine is associated with hypotension and sedation, and its US Food and Drug Administration

(FDA) package insert has a black box warning against its use in obstetrics because of risk of

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hemodynamic instability [35]. Therefore, clonidine should be reserved for patients at risk for

severe pain after cesarean delivery, such as those with a known history of chronic pain.

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Neostigmine has historically not been recommended for neuraxial administration due to its high
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incidence of nausea [35]. The American Pain Society does not advise administering neostigmine

as a neuraxial adjuvant, citing a lack of clear benefit and insufficient evidence of safety [22].
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<B>Continuous and Patient-Controlled Epidural Infusions

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Continuous epidural infusions and patient-controlled epidural analgesia may be considered for

maintaining neuraxial analgesia beyond the perioperative period. However, postoperative

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epidural analgesia has several disadvantages: (i) maternal mobility may be reduced because of

the need to carry/transport an infusion pump; (ii) postoperative pharmacothromboprophylaxis

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becomes complicated; (iii) nursing workload is increased, and (iv) hospitals’ and patients’ costs
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are increased [36]. For most healthy women with uncomplicated cesarean delivery, intrathecal or

epidural opioids delivered by a ‘single-shot’ spinal, epidural or combined spinal-epidural

technique, in combination with systemic nonsteroidal anti-inflammatory drugs (NSAIDs),

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provides adequate post-cesarean analgesia. Epidural catheter-based techniques may be

considered in special circumstances (e.g. women with history of chronic pain).

<A>OPIOID-SPARING ANALGESIC OPTIONS

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Supplemental non-opioid medications are important for optimizing the quality of post-operative

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analgesia and lowering the requirement for oral or intravenous opioids in the postpartum period.

This is particularly important because up to 1 in 300 opioid-naïve women become persistent

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users of opioids after cesarean delivery [37]. In a opioid-naïve population, the odds of chronic

opioid use was significantly greater in women in the one-year period following cesarean delivery

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compared with a randomly-selected one-year period in non-surgical patients (odds ratio 1.28
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[95% CI, 1.12, 1.46]) [38]. The use of multimodal analgesia (e.g. NSAIDs and acetaminophen)

provides superior pain relief and decreases the need for supplemental opioid use compared to a
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single analgesic approach.

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<B>Nonsteroidal anti-inflammatory drugs

NSAIDs are a key component of multimodal postoperative pain management. NSAIDs have a
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30% to 50% opioid-sparing effect [39, 40], which may reduce the incidence of opioid-related

adverse-effects after surgery [41, 42]. For healthy women undergoing uncomplicated cesarean
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delivery, scheduled NSAIDs should be given routinely in the postpartum period. No studies have
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compared the analgesic efficacy of different NSAID formulations, and NSAID use is be based

on hospital drug availability, breastfeeding transfer and drug safety data (Table 1). There are

limited studies examining the efficacy of cyclooxygenase-2 (COX2) inhibitors for post-cesarean

delivery analgesia. Evidence suggests that COX2 inhibitors have limited post-cesarean analgesic
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efficacy [43], therefore their use should be reserved for patients intolerant of non-selective

NSAIDs.

<B>Acetaminophen

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In the perioperative setting, acetaminophen has an opioid-sparing effect of approximately 20%

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[39, 41]. By providing effective analgesia with minimal adverse effects and breastmilk transfer

[44], acetaminophen is an important component of post-cesarean multimodal analgesia.

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Although as-needed acetaminophen-opioid combination drugs are often prescribed for

breakthrough pain, scheduled acetaminophen with as-needed oral opioids is recommended. In a

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retrospective study comparing opioid use with two different multimodal regimens, cumulative
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opioid use was significantly lower among patients receiving scheduled acetaminophen regimens

(Figure 1) [45]. This approach also limits the likelihood of inadvertently prescribing
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acetaminophen doses that are higher than the daily recommended maximum dose [45].
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Combining acetaminophen and NSAIDs has an additive analgesic effect [42], and both
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drugs should be administered after cesarean delivery. Given the higher cost and lack of clear

evidence, routine administration of intravenous NSAIDs or intravenous acetaminophen is not

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recommended; oral administration is suggested [46]. However, intravenous drug delivery may be

worthwhile for patients who cannot tolerate oral formulations or for those who develop
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postoperative nausea or vomiting.

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<B>Dexamethasone

Glucocorticoids have analgesic and antiemetic properties as well as anti-inflammatory effects. A

single preoperative dose of dexamethasone can reduce postoperative pain compared to placebo
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among patients undergoing general surgery with general anesthesia [47]. However,

dexamethasone use was associated with marginally higher blood glucose levels at 24 hours

postoperatively and thus, should be avoided in patients with insulin resistance [47]. In meta-

analyses which included studies of patients undergoing a variety of surgical procedures, a single-

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dose perioperative dexamethasone did not impair wound healing or increase the risk of infection

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[47, 48]. The addition of a single preoperative dose of dexamethasone has been shown to both

improve post-cesarean analgesia and decrease the incidence of nausea and vomiting [49]. Doses

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between 1.25 and 20 mg have been described; the optimal dose has not been determined [47].

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<B>Gabapentin AN
There has been growing interest in the use of gabapentin as either pre-emptive analgesia or to

supplement postoperative analgesia. Gabapentin has been shown to decrease opioid-associated

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vomiting and pruritus [50]. However, gabapentin has notable side-effects, including sedation
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(number needed to treat (NNH) = 8-35) and dizziness (NNH = 12) [50, 51]. In the setting of
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cesarean delivery, initial studies suggested that a single preoperative dose of gabapentin 600 mg

decreased post-cesarean delivery pain and increased maternal satisfaction [52]. Subsequent
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studies have not validated these findings [53, 54]. Gabapentin is a neurotropic drug with a high

umbilical vein-to-maternal vein ratio that limits preemptive use; breast milk transfer is a
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potential concern (Table 1) [55, 56]. Because strong evidence is lacking regarding a significant
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maternal analgesic effect, and concerns for maternal and neonatal side-effects, gabapentin is not

recommended as a routine post-cesarean analgesic. However, the benefit-risk ratio of

administering gabapentin may be favorable in patients with a history of chronic pain or

postoperative pain unrelieved by standard treatment protocols.

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<B>Ketamine

The efficacy of ketamine as a post-cesarean analgesic adjunct is uncertain. For patients

undergoing cesarean delivery with spinal anesthesia with intrathecal morphine and scheduled

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ketorolac, a single dose of ketamine 10 mg compared to saline, administered after delivery, did

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not offer any acute postoperative pain or opioid sparing benefit [57]. However, ketamine may

improve perioperative analgesia if intrathecal morphine is not provided [58-61] Side-effects of

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ketamine include hallucinations, visual effects, disturbing dreams, dizziness, and lightheadedness

[58]. A single intraoperative dose of ketamine 10 mg has been associated with lower pain scores

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2 weeks postpartum [57, 60], and the drug may have a role in patients with chronic pain or
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women at risk for developing persistent incisional pain after cesarean delivery.
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<A>LOCAL ANESTHETICS
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<B>Wound Infiltration
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The analgesic benefit of single-dose local anesthetic wound infiltration is limited in the setting of

neuraxial morphine with NSAIDs and acetaminophen. If single-dose local anesthetic wound
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infiltration is used, combined pre- and post-incisional wound infiltration provides superior

analgesia after cesarean delivery compared to each one alone [62]. Continuous wound infiltration
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via catheter-based techniques may be preferable to single-dose at time of surgery as the latter
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provides a relatively limited duration of analgesia [63-65]. Continuous wound instillation of

local anesthetic can reduce pain scores, opioid use, and opioid-related nausea and vomiting for

up to 48 hours postoperatively [63-65]. Subfascially cited catheters provided better analgesia

than subcutaneous or suprafascial placement [66]. If used, wound instillation should be

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considered part of a multimodal therapy because, in isolation, this regimen treats somatic, but not

visceral pain. A meta-analysis comparing wound infiltration to epidural analgesia for abdominal

surgery showed comparable pain scores at 24 and 48 hours, but the included trials were not

specific to cesarean delivery [67]. Continuous wound site local anesthetic instillation, compared

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with transversus abdominis plane (TAP) blocks, can provide similarly effective post-cesarean

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delivery analgesia [68-70].

A variety of different adjuncts (diclofenac, ketorolac, dexamethasone, magnesium

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sulfate) have been studied in combination with local anesthetics for wound instillation [9, 71-73].

Study results suggest these adjuvants administered at the site of injury may provide improved

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analgesia and reduce wound inflammation [9, 71-73]. However, safety data are required to
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determine if wound instillation of these drugs is preferable to systemic administration.
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<B>Transversus Abdominis Plane Blocks

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Studies indicate that transversus abdominis plane (TAP) blocks at the time of surgery can
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significantly improve postoperative pain and reduce opioid consumption for patients who

undergo general anesthesia, and for patients receiving neuraxial anesthesia without morphine
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[74, 75]. However TAP blocks offer minimal analgesic and opioid-sparing benefit after cesarean

delivery when intrathecal morphine is used [74, 75]. A potential indication for TAP blocks is to
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“rescue” severe postoperative incisional pain not responding to opioid therapy [76]. The typical
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duration of sensory blockade after a single-shot TAP block is 6 to 12 hours, with a mean

analgesic effect of 9.5 (IQR 8.5 to 11.9) hours [77]. For patients requiring a longer duration of

analgesia, a catheter-based technique may be preferable [78]. Clinicians should be aware that

TAP blocks are effective primarily for somatic incisional pain, not visceral or cramping pain.
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Current evidence suggests that adjuncts (sufentanil, fentanyl or clonidine) added to the local

anesthetics for TAP block do not provided significantly better quality analgesia than local

anesthetic alone [79-81]. TAP blocks should not be used as a substitute for using neuraxial

opioids for patients undergoing cesarean delivery with neuraxial anesthesia. Studies comparing

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TAP blocks to intrathecal morphine report inferior analgesia with more visceral pain in the TAP

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block groups [74, 75]. High local anesthetic blood concentrations have been reported after TAP

blocks [82], and several cases of local anesthetic systemic toxicity (LAST) have been reported

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following cesarean delivery [68, 83].

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<A>MANAGEMENT GOALS AND STRATEGIES AN
Based on current evidence, it is recommended that women undergoing cesarean delivery receive

neuraxial morphine (or equivalent long-acting opioid) with “round-the-clock” NSAIDs and
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acetaminophen for 2 to 3 days following surgery. Systemic opioids should only be prescribed as
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needed for significant pain not responding to opioid-sparing multimodal analgesics, i.e., NSAIDs
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and acetaminophen. Oral opioids, such as oxycodone, hydrocodone and tramadol are

recommended to treat moderate to severe breakthrough pain. Intravenous opioids should be

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reserved only for patients with extreme pain or who are intolerant of oral intake. Compared to

oral opioids, intravenous opioids do not provide superior analgesia but are associated with a
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greater incidence of opioid-related adverse-effects [84]. Codeine is not recommended as

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maternal and neonatal pharmacogenomic and metabolic variability can impact both efficacy and

side-effects [85].

Alternate clinical care pathways may be required for women with risk factors for severe

postoperative pain, such as general anesthesia, extended vertical skin incisions, and a known
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history of chronic pain [6]. Standard analgesic order sets may need to be modified for those not

responding to simple analgesics, or those requiring escalating doses of intravenous opioids to

manage their pain. For women identified to be at risk for severe postoperative pain, the following

analgesic options may be considered: postoperative patient-controlled epidural analgesia with

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local anesthetic and opioid, continuous local anesthetic wound instillation, continuous TAP

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block catheters, sub-anesthetic ketamine 10 to 15 mg intravenously and/or dexamethasone 4 to 8

mg intravenously after delivery of the baby. Potential analgesic options for severe breakthrough

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pain after surgery include a “rescue” TAP block [76], or gabapentin (600 mg initial oral dose and

300 mg every 8 h for ongoing severe pain responsive to gabapentin) [53, 54]. In the future, data

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from studies investigating patient-level and surgical-level factors associated with post-cesarean
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delivery pain may be used to develop individualized analgesic protocols as opposed to using a

“one-size fits all” approach.

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Unlike non-obstetric surgical procedures, in-utero fetal drug transfer must be considered
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for drugs administered prior to delivery, and transfer of drug to the nursing infant via breastmilk
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for drugs administered after delivery (Table 1). However, if maternal pain is well-managed after

surgery, successful breast-feeding and maternal-neonatal bonding may be facilitated [5]. The
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physiology and pharmacokinetics of drug transfer during breastfeeding are summarized in

several review articles [86-90]. Application of several principals minimize infant analgesic
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exposure via breastmilk:

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i) Opioid-sparing multimodal analgesia is preferable, as opioids are associated with

breast milk transfer and may cause neonatal sedation.

ii) Neuraxial opioids are preferred to intravenous, intramuscular or oral opioids.

iii) Clinicians should use the lowest effective analgesic dose when possible.
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iv) The drug concentration in breast milk parallels maternal blood levels.

v) Drugs with a short half-life, inactive metabolites and long record of safe use are

recommended.

vi) Lipophilic drugs are most likely to cross into the breast milk, while highly protein-

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bound drugs (e.g. NSAIDs, local anesthetics) have limited drug transfer.

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vii) Drugs with low oral bioavailability will have limited transfer to the breastfeeding

infant.

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viii) The amount of colostrum in first few days after delivery is small, so the amount of

drug transferred is relatively small.

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ix) Women should be informed about potential transfer of pain medications to the
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breastfeeding newborn.
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In conclusion, effective post-cesarean delivery analgesia while minimizing maternal and

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neonatal systemic opioid exposure is a key priority in the management of women undergoing
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cesarean delivery. Pre-emptive analgesic use is limited by fetal drug transfer. Post-operative

analgesics have the potential for transfer to the breastfeeding neonate. Multimodal analgesic
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approaches are recommended, comprising of neuraxial morphine in conjunction with non-opioid

adjuncts such as scheduled fixed-interval NSAIDs and acetaminophen, with oral or intravenous
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opioids reserved for moderate or severe breakthrough pain.

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PRACTICE POINTS:

• Providing effective pain relief to mothers after cesarean delivery should be a key priority

for obstetric and anesthesia providers.

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• Multimodal analgesic regimens should be considered for managing pain and reducing

opioid requirements after cesarean delivery.

• Long-acting neuraxial opioids (such as morphine) are recommended for optimizing

analgesia..

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• “Round-the-clock” nonopioid oral drugs such as NSAIDs and acetaminophen are

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strongly recommended.

• Additional analgesic and opioid-sparing options such as continuous wound instillation of

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local anesthetics, TAP blocks, dexamethasone, gabapentin and ketamine should be used as

appropriate in women at risk for severe postoperative pain or when postoperative pain is not well

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controlled. AN
RESEARCH AGENDA:
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• Further research is warranted to evaluate factors associated with protracted pain, ongoing
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opioid use and delayed functional recovery following cesarean delivery.

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• The analgesic benefit of regional anesthetic interventions such as long-acting local

anesthetic preparations for wound infiltration or TAP blocks, wound administration of NSAIDs
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and other drugs traditionally administered via systemic route, as well as the role of quadratus

lumborum blocks after cesarean delivery need to be determined.

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• Individualized analgesic protocols offer the prospect of tailoring analgesic regimens to

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specific patient and obstetric characteristics and preferences. Future studies are needed to

determine whether these approaches can improve analgesia compared to a “one-size fits all”

approach.
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CONFLICT OF INTEREST STATEMENT

Conflict of interest: none

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FIGURE LEGENDS

Figure 1: Survival curve of time to first opioid use during the first 48 hours after cesarean

delivery. The As-Needed Group (grey line) was given oral combination acetaminophen-opioid

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analgesics as needed for breakthrough postoperative pain. The Scheduled Group (black line)

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received 650 mg acetaminophen every 6 hours for 48 hours postoperatively and oral oxycodone

as needed for breakthrough postoperative pain. The curves are significantly different (log-rank

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test, P = 0.001).

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Reprinted from International Journal of Obstetric Anesthesia, Vol 24 /3, A.R. Valentine, B.

Carvalho, T.A. Lazo, E.T. Riley, Scheduled acetaminophen with as-needed opioids compared to
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as-needed acetaminophen plus opioids for post-cesarean pain management / pgs. 210-216,

Copyright August 2015, with permission from Elsevier.

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Table 1: Breastmilk Transfer Potential for Commonly Used Analgesics after Cesarean

Delivery as Measured by the Relative Infant Doses

Analgesic Relative Infant Dose (%)

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Opioids

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Morphine 5.8-10.7

Fentanyl 0.9-3

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Oxycodone 1.5-8

Hydrocodone 1.6-3.7

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Tramadol 2.4-2.9 AN
Non-opioid Analgesics

Ibuprofen 0.1-0.7
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Ketorolac 0.2-0.4
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Celecoxib 0.3
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Acetaminophen 1.3-6.4

Dexamethasone No data
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Gabapentin 1.3-6.5

The relative infant dose (RID) is expressed as a percentage and is weight-adjusted for the infant,
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normalizing that amount of drug to which the neonate is exposed relative to the mother’s dose. A
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RID greater than 10% is concerning in terms of infant exposure [87].

Data extracted from various sources [55, 56, 86-93].

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