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Review Articles

Anesthetic management of the parturient with opioid addiction

Ring, Laurence E. MD; Landau, Ruth MD

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International Anesthesiology Clinics: Summer 2021 - Volume 59 - Issue 3 - p 28-39
doi: 10.1097/AIA.0000000000000323
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Managing the parturient with an opioid use disorder (OUD)

Provision of optimal analgesia during labor and delivery is a challenge that anesthesiologists face every day, with an estimated 385,000 babies born daily worldwide.1 In parturients with an OUD, this challenge is further amplified by the complex biopsychosocial construct of opioid addiction, opioid tolerance, and the inevitable pharmacological interactions between a woman’s chronic opioid intake (illicit opioids, methadone, buprenorphine, or naltrexone) and analgesic medication that will be administered by the anesthesiologist during the childbirth experience. Obstetric and perinatal outcomes, including adequate pain management, avoidance of withdrawal for both mothers and neonates, and nonescalation or minimal escalation of opioid requirement at discharge, require a multidisciplinary approach that ideally includes the obstetric anesthesia team from the antenatal period, during labor and delivery, and throughout the in-hospital postpartum period.

Approaches to preventing persistent opioid use after delivery will not be reviewed here, although this topic is of equally crucial importance, because opioid-naive women exposed to opioids during pregnancy or postpartum are at significant risk, with reported rates for persistent opioid use ranging from 1:300 women and up to 4%,2–5 although reported rates may be highly variable depending on the definition used.6

In this review article, we will provide evidence-based approaches when available and share our experience in managing labor analgesia and cesarean delivery anesthesia in pregnant women with an OUD, from admission to the labor and delivery unit until hospital discharge.

The opioid epidemic in the United States

With increased lay and scientific attention, the opioid abuse epidemic in the United States has witnessed some signs of abatement; however, there are still considerable improvements to be made. A total of 70,630 drug overdose deaths occurred in the United States in 2019, of which one half involved synthetic opioids, corresponding to a 4.3% increase from the 2018 rate.7 According to the most recent report by the Substance Abuse and Mental Health Services Administration, 3.7% of the population aged 12 years and older (about 10 million people) misused opioids in 2019, with the far majority of this misuse being of prescription opioids, with 1.6 million people qualifying for the clinical diagnosis of OUD.8

The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition,9 defines OUD as a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least 2 of the following 11 items, occurring within a 12-month period.

  • Taking larger amounts of opioids or taking opioids over a longer period than was intended.
  • Experiencing a persistent desire for the opioid or engaging in unsuccessful efforts to cut down or control opioid use.
  • Spending a great deal of time in activities necessary to obtain, use, or recover from the effects of the opioid.
  • Craving, or a strong desire or urge to use opioids.
  • Using opioids in a manner that results in a failure to fulfill major role obligations at work, school, or home.
  • Continuing to use opioids despite experiencing persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
  • Giving up or reducing important social, occupational, or recreational activities because of opioid use.
  • Continuing to use opioids in situations in which it is physically hazardous.
  • Continuing to use opioids despite knowledge of having persistent or recurrent physical or psychological problems that are likely to have been caused or exacerbated by the substance.
  • Tolerance, as defined by either a need for markedly increased amounts of opioids to achieve intoxications or the desired effect, or a markedly diminished effect with continued use of the same amount of an opioid.
  • Withdrawal, as manifested by either the characteristic opioid withdrawal syndrome, or taking opioids to relieve or avoid withdrawal symptoms.

It was recently reported that the diagnosis of OUD may be identified using information available in the electronic health record, even when diagnostic codes do not reflect this diagnosis,10 which may be highly relevant when screening women during pregnancy.

Opioid prescriptions in women and OUD in pregnancy

Evidence from early in the opioid epidemic suggested that women are more likely than men to be prescribed opioids and several studies have found that women may be more at risk than men for the misuse of prescription opioids and the development of OUD. In fact, women, especially women of child-bearing age, have been found to report higher unfavorable global pain status, which likely correlates with higher number of interactions with the medical system, increased rates of opioid prescriptions, and higher rates of prescription escalation.11 Unlike men, who report increased likelihood of obtaining opioids through dealers, women report obtaining opioids from prescriptions, friends, or family.12

When examining databases of medical care in the United States covering the years 2000-2014, 4.4% of publicly insured women and 1.1% of privately insured women were dispensed 2 or more opioid prescriptions during the first trimester of pregnancy,13 with a low incidence of congenital malformations in the offspring (although a small increase in oral clefts was identified).14 Since then, temporal trends in opioid misuse in the obstetric population, resulting in maternal deaths, have been reported in the United States, with tremendous regional variations.15–19 The reported incidence of polysubstance use among pregnant women with OUD, defined as at least 1 co-occurring diagnosis of other substance use, including alcohol, amphetamine, cannabis, cocaine, sedative, or tobacco, has also shown an alarming increase in the last decade, particularly in rural compared with urban counties in the United States.20,21

The American College of Obstetrics and Gynecology (ACOG) 2017 Committee Opinion on “Opioid use and OUD in pregnancy”22,23 highlights the importance of the “Screening, Brief Intervention and Referral to Treatment” (SBIRT) approach24 to identify, reduce, and prevent problematic use of alcohol or other substance dependence. It also emphasizes the importance of opioid agonist/antagonist pharmacotherapy (methadone, buprenorphine), rather than medically supervised detoxification25,26 or naltrexone. Recent surveys conducted by ACOG identified that 80% of obstetricians are routinely screening their women for substance use, 33% always or usually advise medication-assisted therapy (MAT) and 61% use shared decision-making when managing pregnant women with OUD.27–29 The clinical, ethical, and research imperatives of the opioid epidemic as discussed in a Joint Workshop of the Society for Maternal-Fetal Medicine, ACOG, and American Society of Addiction Medicine, with representation from the Society for Obstetric Anesthesia and Perinatology, were summarized in a white paper.30

MATs in the pregnant woman with OUD

Medically supervised opioid withdrawal or detoxification in pregnant women with OUD is possible and has been suggested as an important strategy to decrease fetal exposure and opioid-associated fetal brain stress,31–38 but needs to account for the possibility of maternal relapse and fetal withdrawals, which may result in fetal demise.39 Rather, because it significantly reduces the risk of both relapse and withdrawal, MAT is the preferred treatment modality for pregnant women with OUD. Induction of MAT as early in pregnancy as possible, closely supervised by an addiction specialist, should be a treatment goal for women with OUD.40

Recent emphasis on racial and ethnic disparities in maternal healthcare identified that non-Hispanic black and Hispanic women are less likely to receive MAT for OUD during pregnancy compared with non-Hispanic white women.41,42 Geographically, barriers to MAT have been reported in rural areas, especially in Appalachian states.43

MAT is characterized by daily treatment with either methadone, buprenorphine, occasionally buprenorphine with naloxone,44,45 or naltrexone.46 Because the mechanisms of action, pharmacokinetics, and pharmacodynamics of each of these are different, the approach to labor analgesia, cesarean delivery anesthesia, and postpartum analgesia might be affected.

Methadone

Methadone is a mu-opioid receptor full agonist, and through that mechanism, can mitigate withdrawal symptoms and opioid craving. Methadone use is less rewarding than opioids of abuse and the action of methadone attenuates the action of coadministered opioids.47 Under United States law, women on methadone therapy, which is dosed once daily, must receive the methadone at an appropriately licensed facility under directly supervised conditions. This, along with matters of payment and insurance, represents a major impediment to methadone treatment in some women who lack employment, transportation, or proximity to a methadone clinic.48 Treatment with methadone during pregnancy has been shown to markedly reduce the rate of relapse (92%) and reduce the rate of neonatal opioid withdrawal syndrome (NOWS) by more than half (29% in the treated group versus 60% to 80% in neonates of untreated women).49 Previously, it was believed that the likelihood of NOWS does not correlate with maternal methadone dose at delivery, but recent data suggest otherwise.50 Maternal and neonatal genetic and epigenetic factors may further affect the risk of NOWS in methadone-treated women.51,52

Women on methadone replacement presenting for labor and delivery should continue to receive their methadone treatment. Significant metabolic changes in the peripartum period can result in the need for changes in methadone dose (escalation) and dose frequency to maintain maternal/fetal stability; increased dosing will need to be reversed postpartum.53,54

Buprenorphine

Buprenorphine is a synthetic opioid unique in its mechanism of action. As a partial agonist at the mu-opioid receptor and antagonist at the kappa and delta opioid receptors, buprenorphine has a strong affinity for the mu-receptor and a long half-life, allowing it to displace and interrupt the actions of other opioids, potentially precipitating symptoms of withdrawal at induction of treatment.55 This represents a significant drawback, and has resulted in women abandoning clinical trials and programs.56,57 However, unlike methadone, buprenorphine may be prescribed in an in-office setting and women may be treated without the need for directly observed ingestion. Using a theoretical cohort of over 22,400 pregnant women, which is an estimation of pregnancies affected by OUD per year in the United States, recent modeling suggests that buprenorphine should be considered the most cost-effective treatment option for OUD in pregnancy as it is associated with improved neonatal outcomes compared with methadone despite the risk of treatment discontinuation.58 Buprenorphine seems to show a plateau effect on respiratory depression, such that, beyond a certain dose, the risk of respiratory depression does not increase.59

Similar to methadone, parturients may require increasing dose and dose frequency of buprenorphine at term,60,61 although this may vary greatly at an individual level,62 which is attributed to pharmacogenetic effects.63

Naltrexone

Naltrexone differs from either of the approaches listed above in its mechanism of action and mode of administration. Naltrexone is a nonselective opioid receptor antagonist that may be administered orally but may also be administered in a long-acting injectable or implantable form. This approach may be more practical, but the prerequisite to be abstinent from short-acting opioids for 5 to 7 days and long-acting opioids for 7 to 10 days before initiation of treatment can be problematic. Consequently, naltrexone is usually considered a MAT approach for women who are opioid abstinent and wish to remain so.

Compared with either methadone or buprenorphine, naltrexone pharmacotherapy presents at least 2 unique challenges in pregnant patients. First, owing to its mechanism of action, opioid-based analgesia is difficult to achieve in patients receiving naltrexone. The usual approach to patients on naltrexone therapy is to have the patient cease naltrexone 2 to 3 days before a surgical procedure. This is not practical for many pregnant women anticipating labor and delivery, nor would this be feasible without excellent planning in women receiving depot or implantable dosing. Second, long-term use of naltrexone may lead to the development of significant hyperalgesia, which is undesirable considering the pain of childbirth.

Practical experience and scientific investigation into the risks and benefits of naltrexone use during pregnancy are particularly meager. At this time, there is no human evidence for naltrexone being associated with fetal developmental defects or malformations. Animal studies provided mixed results; rabbit pups were found to demonstrate no birth defects after exposure to naltrexone doses several hundred times normal human dosing. However, rat pups gestated under similar circumstances were reported to have reduced pain sensitivity, possibly representing abnormal development of the endogenous opioid system.64 Some studies have suggested that with careful planning, naltrexone may be superior to buprenorphine or methadone in pregnancy.65 Comparing 6 mother-infant dyads exposed to naltrexone with 13 buprenorphine-exposed dyads, none of the naltrexone-treated mothers suffered from relapse (compared with 23% in the buprenorphine group) and none of the infants in the naltrexone group (compared with 92% in the buprenorphine group) suffered from NOWS.66 In a large prospective study, no newborns of the 87 mothers treated with naltrexone until delivery showed signs of NOWS, no maternal relapse occurred during the 7-day “no-treatment” window anticipating naltrexone induction, and birth defects in the naltrexone group were no more prevalent than those seen in the methadone or buprenorphine groups.67

Antenatal management of the pregnant woman with OUD

Successfully managing childbirth, with the significant paroxysms of severe pain during labor and the complicated pain of the postsurgical period of a woman with OUD, should begin well before the parturient is admitted to the labor and delivery unit. Childbirth is unpredictable; pain during the process is not, and it is likely that the parturient with OUD has anxiety over this fact.

In interviews of pregnant or recently pregnant women with OUD, patients harbored deep feelings of shame and guilt related to their disease, with most describing experiences of external stigma.68 An antenatal consultation with the obstetric anesthesia team, ideally done well before admission for labor and delivery in the late second or third trimester, should consist of a review of the patient’s medical and prescription history. A thorough history and physical examination can provide insight into a parturient’s risk of withdrawal, tolerance, and opioid-induced hyperalgesia (OIH), allowing for the creation of a personally tailored, pain management plan well before labor and delivery. This gives time for adequate preparation on the patient’s and provider’s part. One common concern of patients that should be addressed during the anesthesia consultation is opioid tolerance, the phenomenon by which individuals taking opioids begin to require increasing amounts of opioids to achieve the desired clinical benefit; this may occur quickly, after only a few days of opioid intake.69 Reassuring women who are using chronic opioids that they will continue to receive their usual opioids, in addition to what they will require for management of labor pain, is key.

Chronic conditions, including depression, anxiety, and fibromyalgia, may play a role in the experience of pain during pregnancy, labor, delivery, and postpartum; it is critical that the anesthesiologist understands the effects of these diseases and how they may contribute to the birthing experience. Sickle cell disease is another chronic disease associated with chronic opioid use,70 and a 4-fold increase in opioid-related disorders,71 that will influence analgesia requirements at the time of delivery and postpartum.

Women with OUD might be deemed to be “drug-seeking” when, in fact, they are experiencing: (1) opioid tolerance, (2) pain exceeding what might be expected in similar circumstances in women with no OUD, (3) drug-drug interactions (particularly if maintained with partial opioid receptor agonist/antagonist therapy), or (4) opioid withdrawal. If a parturient with OUD is maintained with MAT, continuation of treatment is an important discussion. Shared decision-making is important when discussing analgesic options, for example, women who are recovering from OUD and in a period of abstinence may request opioid-free analgesia.

OIH is another concern for patients with OUD, defined by painful stimuli leading to pain out of proportion than that expected; OIH may be encountered when women with OUD react in unexpected ways to blood draws or intravenous (IV) line placements. Recent advances in the understanding of the biological underpinnings of the phenomena include increased activation of central N-methyl-D-aspartate (NMDA) receptors and the elaboration of spinal excitatory neuropeptides.72 Acknowledgment of OIH may occur, and discussing all options with women, including the coadministration of nonopioid analgesia (eg, alpha2-agonists adjuvants, anti-NMDA drugs, and neuraxial and regional blocks), will facilitate management of labor pain or cesarean delivery anesthesia.

Labor analgesia for the pregnant women with OUDs

With few exceptions noted below, no standard available labor analgesia modalities should be denied to women with OUD. Maintenance of buprenorphine or methadone upon arrival to the labor and delivery unit is paramount, and neuraxial labor analgesia remains the optimal approach for all patients, barring medical contraindications. Strategies for labor analgesia are presented in Figure 1.

Figure 1
Figure 1:
Different scenarios and peripartum pain management approaches for vaginal and cesarean deliveries. In all scenarios, maintenance therapy is continued during labor and delivery (not shown) and all approaches are intended to optimize analgesia while minimizing postpartum systemic (oral) opioid use and prescription at discharge. IV indicates intravenous; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; PF, preservative free; PIEB, programmed intermittent epidural analgesia.

The abstinent parturient recovering from OUD

Parturients recovering from OUD may have special concerns about maintaining their abstinence from opioids during labor and delivery, with particular anxiety over a risk of relapse if receiving opioids in the peripartum period. The risk of relapse is real and is likely directly correlated to multiple patient factors, including history of relapse, coexisting disease, outside stressors beyond the labor process, and social support system.73

Any available and mutually agreed upon analgesic modality can be offered to a parturient recovering from OUD. A multimodal opioid-sparing analgesic approach is recommended. Neuraxial analgesia, which can include local anesthetics, nonopioid adjuvants (alpha2-agonists), and low-dose short-acting opioids (fentanyl), should be the bedrock of this strategy and early neuraxial labor analgesia should be encouraged. There is currently no evidence for or against very low doses of intrathecal fentanyl or epidural analgesia solutions (0.0625% bupivacaine with fentanyl 2 mcg/mL) being associated with a relapse. Even so, some women may request a total opioid-free approach. For these women, consideration should be given to adding clonidine to the epidural infusion, as reported successfully in women maintained with buprenorphine,74 and/or for increasing the local anesthetic concentration (eg, bupivacaine 0.1%) in the epidural infusion. For women in whom placement of an epidural catheter is contraindicated, other approaches may be considered including inhaled nitrous oxide, IV patient-controlled analgesia with an ultra-short-acting opioid, or truncal blocks. Quadratus lumborum block has been specifically reported as being effective at treating labor pain in a patient with Hemophilia A, especially during the first stage of labor.75

The parturient with an untreated OUD

A primary concern in women with untreated OUD is the risk of opioid withdrawal, which may present as anxiety, piloerection, insomnia, cold or flu-like symptoms, myalgias, abdominal pain, fever, hypertension, hallucinations, and seizures.76 Some of these symptoms may mimic serious diseases of pregnancy, and obstetric and anesthesia providers should be trained to consider diagnoses of both opioid withdrawal and preeclampsia for symptomatic pregnant women with a history of OUD. Another barrier to diagnosing opioid withdrawal is that women may fear being truthful about the full extent of their opioid use. Their unwillingness to disclose this information may be attributed to social stigma or local laws, which may punish a pregnant woman for using opioids by forcing loss of custody of her newborn children or even jail time.77,78 Nursing-level providers should be trained in administering a validated tool to ascertain possible withdrawal in these women, for example, the clinical opioid withdrawal scale.79,80 Symptoms of withdrawal should be treated with a long-acting opioid and is likely best managed in consultation with a clinical addiction specialist.

As with parturients recovering from OUD, neuraxial labor analgesia with a local anesthetic and nonopioid and opioid adjuvants represents the optimal labor analgesia for parturients with untreated OUD. Because the local anesthetic in the solution works directly on transmission of pain though sodium channels, standard concentration and infusion strategies will work well for many parturients. However, increased concentrations may be considered in women with allodynia or hypersensitivity to painful stimuli. For women in whom neuraxial labor analgesia is contraindicated or refused, other modalities may be used, but likely come with more risks. The use of inhaled nitrous oxide during labor, for example, may cause hypoxemia when combined with opioids,81 and IV administered opioids for labor (remifentanil) are generally thought of as being less safe than neuraxial labor analgesia.82

The parturient on medication-assisted treatment for OUD

Similar to the principle that neuraxial labor analgesia is the optimal analgesic approach in opioid-naive parturients, women maintained with methadone, buprenorphine, or buprenorphine with naloxone should be offered and encouraged to receive early neuraxial labor analgesia. Parturients treated with methadone may be at risk for hyperalgesia, requiring increased amounts of neuraxial local anesthetics.83 It has been suggested that with methadone, but not with buprenorphine, analgesic use is increased after vaginal delivery.84

It is important to keep in mind that parturients with polysubstance use disorder may be self-medicating during labor, unbeknownst to the teams. The unusual need for benzodiazepine reversal in a patient with methadone-replacement therapy was highlighted in a case report describing altered mental status mistaken for local anesthetic systemic toxicity, when in fact the patient was self-medicating.85

Anesthesia for cesarean delivery in the parturient with OUD

Data for the most effective approach for cesarean delivery anesthesia and postcesarean delivery analgesia in women with OUD are sparse. Recommendations for cesarean delivery management in women with OUD are based on societies’ practice bulletins,23,86 studies,87 case series,74,83,88–93 case reports94,95 letters,96 and review articles summarizing expert opinions (Table 1).98,99 Recommendations exist in 2 key areas: multimodal, stepwise, opioid-sparing analgesia, and the choice of neuraxial over general anesthesia. A combination of neuraxial analgesia for 48 to 72 hours, along with nonopioid adjuvants and possibly abdominal wall blocks (with catheters or liposomal bupivacaine), may be considered for women with severe persistent pain after delivery (Fig. 1).

Table 1 - Studies reporting on postpartum pain management in women maintained with buprenorphine or methadone.
References Study Cohort Anesthesia Buprenorphine Methadone Comparison and main findings
Reno et al88 Case series (N=146)—Ohio State University (2011-2018) Buprenorphine vs. methadone CD (N=146) Spinal/CSE 74% Epidural 15% General 11% N=99 Oxycodone median daily dose 80.6 mg N=47 vs. 76.3 mg (P=0.694) Buprenorphine vs. methadone: No difference in pain scores and opioid use
Wendling et al96 Case-control study (N=73)—University of Florida (2014-2017) Buprenorphine vs. methadone CD (N=73 with MAT vs. N=2620 opioid-naive) Neuraxial 85% General 15% N=36 N=37 MAT vs. controls: Reported higher pain intensity (4.6 vs. 3.2) despite consuming more MEQs (54.0 vs. 29.4) and receiving more gabapentin, ketamine, and ketorolac than opioid-naive patients. No difference in LOS Buprenorphine vs. methadone: No difference in outcomes (postoperative MEQs: 51.7±55.9 vs. 56.3±47.5; P=0.1821)
Stanislaus et al94 Case report (N=1)—Ohio State University Epidural hydromorphone in a methadone case First delivery: CD (twins) Second delivery: CD CSE—spinal PFM (200 mcg) and PCEA (BUP 0.0625% and fentanyl 4 mcg/mL) for 18 h Epidural PFM (2 mg) and epidural hydromorphone infusion 140 mcg/h (PCEA 20 mcg q30min) for 40 h Methadone 85 mg-165 mg/d Methadone 190 mg/d Oxycodone 85 mg/d postoperatively with bupivacaine and fentanyl PCEA for 18 h Oxycodone 2.5 mg/d postoperatively with epidural hydromorphone 3.36 mg/d
Tith et al89 Case series (N=8)—University of Washington (2012-2013)—cases with polysubstance abuse maintained with buprenorphine CD (N=5) VD (N=3) (1) CD—spinal and CSE and General (2) CD—CSE and General (3) NSVD (D&C)—CSE (4) CD for IUFD—General (5) VBAC—CSE (6) CD—CSE (7) NSVD—CSE (8) CD—CSE Buprenorphine 8 mg—PCEA 24 h—oxycodone and IV hydromorphone Buprenorphine 8 mg—oxycodone IV PCA hydromorphone Buprenorphine 8 mg/naloxone—oxycodone and epidural blood patch Buprenorphine 24 mg—ketamine 8 mg/h and IV PCA fentanyl 48 h, oxycodone Buprenorphine 4 mg—oxycodone Buprenorphine 16 mg—PCEA and IV PCA hydromorphone, oxycodone Buprenorphine 16 mg—oxycodone Buprenorphine 2 mg BID—PCEA and IV PCA hydromorphone, oxycodone All cases were morbidly obese (BMI: 30-58) Iterative failures of neuraxial analgesia (general anesthesia required as rescue in 2 cases IV infusions/PCA: Ketamine, hydromorphone, fentanyl Benzodiazepine in 3 cases (clonidine, dexmedetomidine, gabapentin, abdominal wall blocks not used)
Hoyt et al74 Case series (N=14)—Cleveland Clinic (2012-2013) Epidural clonidine in buprenorphine cases CD (N=7) CSE (no PFM) VD (N=7) epidural (no fentanyl) BUP 0.0625% and clonidine 2 mcg/mL (N=2) BUP 0.1% and clonidine 1.2 mcg/mL (N=12) Buprenorphine 2-24 mg/daily (between 1 and 3/d) Effective labor and postcesarean analgesia with no neuraxial opioid (replaced by clonidine at 1.2/2 mcg/mL) with infusion for 24 h Hypotension with clonidine requiring vasopressor
Leighton et al90 Case series (N=4)—Washington University Thoracic epidural in buprenorphine cases CD (N=3) BTL (N=1) (1) CD—spinal and thoracic epidural (2) CD—CSE (L2-L3) (3) CD—spinal PFM (100 mcg) (4) BTL—spinal sufentanil (10 mcg) Buprenorphine 8 mg/naloxone 2 mg bid—PCEA 48 h, NSAIDs Buprenorphine 4 mg TID—PCEA 48 h, NSAIDs Buprenorphine 4 mg every other day—IV PCA hydromorphone 48 h, NSAIDs Buprenorphine 4 mg—NSAIDs Thoracic epidural provided effective analgesia T10-T11: BUP 0.0625% 4 mL/h, PCEA 2 mL q30min L2-L3: BUP 0.0625% 10 mL/h, PCEA 2 mL q15min
Vilkins et al91 Retrospective cohort study (N=273)—Boston Medical Center (2006-2014) Buprenorphine vs. methadone CD (N=273) Spinal/CSE Epidural General N=88 (mean: 16.1±7.8 mg) Intraoperative MED 5.2±13.7 mg Postoperative MED 85.1±73.0 mg N=185 (mean: 93.7±2.6 mg) Intraoperative MED 3.5±6.6 mg Postoperative MED 97.7±65.6 mg Buprenorphine vs. methadone: No detectable differences in any pain outcome
Gupta et al93 Case series (N=19)—Wayne State University (2007-2011) Buprenorphine for MAT CD (N=9) VD (N=10) 8/19 epidural fentanyl 3/19 spinal PFM (250 mcg) Buprenorphine 13 mg Spinal PFM (N=3) vs. not (N=3) The total IV hydromorphone dose was higher, but not statistically significantly in women who received spinal PFM (52±60.81 vs. 19.07±16.25; P=0.43)
Hoflich et al87 RCT (N=40) from the MOTHER study and matched opioid-naive controls (N=80)—University of Vienna Buprenorphine/methadone vs. controls CD (N=19) VD (N=21) VD: Epidural (no fentanyl) CD: Spinal (no PFM or fentanyl) NSAIDs and tramadol postoperatively Buprenorphine 6-28 mg (N=21) Methadone 20-130 mg (N=19) Buprenorphine vs. methadone: Not compared In VD: Higher epidural rate in MAT (38%) vs. controls (14%), same opioid use postpartum In CD: MAT patients received less opioids than controls, but more NSAIDs
Wasiluk et al95 Case report (N=1)—University of Florida Dexmedetomidine infusion in a methadone case CD (N=1) Spinal PFM (200 mcg) Methadone 80 mg/d IV morphine (10 mg) and ketorolac (30 mg), hydromorphone (2 mg) with no effect Dexmedetomidine from 0.2-0.7 mcg/kg/h (20 h)—effective Percocet next day
Meyer et al92 Case-control study (N=63)—University of Vermont (2003-2008) Buprenorphine for MAT CD (N=19) VD (N=44) Neuraxial labor analgesia Neuraxial for CD 7/63 received long-acting neuraxial opioid Buprenorphine 13.7±6.2 mg Controls vs. buprenorphine VD: Same neuraxial labor analgesia rate (82% vs. 88%; P=0.58) Pain scores higher in the buprenorphine group, with no difference in the amount or frequency of opioid use [control 13/44 (29.5%) vs. buprenorphine 11/44 (25%); P=0.45] Oxycodone equivalent (mg/24 h): 5.4±10.4 vs. 11.8±24.8 (P=0.10) CD: The buprenorphine group had higher postoperative pain scores and had a 47% increase in opioid use Long-acting spinal opioid (morphine or meperidine) at the discretion of the anesthesiologist (N=6 buprenorphine group) Oxycodone equivalent (mg/24 h): 60.9±13.1 vs. 89.3±38.0 (P=0.004)
Jones et al84 Secondary analysis, RCT (N=18)—Johns Hopkins Buprenorphine vs. methadone VD (N=18) Buprenorphine Methadone Buprenorphine vs. methadone: Oxycodone more likely to be received in the first postpartum day and then decreasingly used over time, with both buprenorphine and methadone Ibuprofen use over time decreased in buprenorphine cases but increased in methadone cases (while both showed similar average pain scores) Suggests that with methadone, but not buprenorphine, analgesic use is increased to maintain low pain ratings
Meyer et al83 Case-control study (N=68)—University of Vermont (1999-2006) Methadone for MAT CD (N=33) VD (N=35) 9/33 received long-acting neuraxial Methadone dose 60 mg (45, 115) Controls vs. methadone VD: Same neuraxial labor analgesia rate (91.2% vs. 88.9%; P=0.68) Pain scores higher in the methadone group, with no difference in opioid use (control P=0.33) Oxycodone equivalent (mg/24 h): 6.8±12.47 vs. 12.7±32.1 (P=0.33) CD: The methadone group had higher postoperative pain scores and had a 70% increase in opioid use Long-acting spinal opioid (morphine or meperidine) at the discretion of the anesthesiologist (N=9 methadone group) Oxycodone equivalent (mg/24 h): 54.0±18.6 vs. 91.6±51.8 (P=0.001)
Jones et al97 Case report (N=2) Buprenorphine vs. methadone Intrapartum CD (N=2) Epidural (no epidural opioid) Buprenorphine 18 mg Methadone 80 mg Buprenorphine case vs. methadone case: IV PCA morphine Both used the maximum daily dose of IV morphine (180 mg) For the buprenorphine case, with maximum daily oxycodone dose (60 mg and acetaminophen 6 g), pain well managed without NSAIDs For the methadone case, despite the same oxycodone and acetaminophen, pain was moderate to severe and ibuprofen (600 mg q8h) was prescribed
bid indicates twice daily; BMI, body mass index; BTL, bilateral tubal ligation; BUP, bupivacaine; CD, cesarean delivery; CSE, combined spinal epidural; D&C, dilatation and curettage; IUFD, intrauterine fetal demise; IV, intravenous; MAT, medication-assisted therapy; MED, morphine equivalent dose; NSAID, nonsteroidal anti-inflammatory drug; NSVD, normal spontaneous vaginal delivery; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; PMF, preservative-free morphine; RCT, randomized-controlled trial; tid, 3 times a day; VBAC, vaginal birth after cesarean; VD, vaginal delivery.

Stepwise multimodal opioid-sparing analgesia

No randomized-controlled trial has specifically examined the benefits of stepwise, multimodal opioid-sparing analgesia in women with OUD undergoing cesarean delivery, but the minimal side-effect profile and the proven benefits of these agents in women without OUD provide a strong argument for their use in the opioid-addicted population.100–102 Gabapentin may provide preemptive analgesia, although benefits in healthy opioid-naive women undergoing cesarean delivery have not been overwhelming.103–107 In addition, gabapentin has not been specifically evaluated in pregnant women with chronic pain or opioid tolerance. The sedative effects of gabapentin may be a concern in women with polysubstance abuse and should be administered with caution in a monitored environment.

Anesthesia for cesarean delivery

The superiority of neuraxial over general anesthesia in women undergoing cesarean delivery is a basic truism in the practice of obstetrical anesthesia and this also applies to women with OUD. Among the benefits of neuraxial anesthesia from an experiential standpoint are: (1) increased maternal satisfaction, (2) increased maternal-infant bonding, (3) decreased acute and chronic pain, (4) decreased risk of postpartum depression,108 and an overall reduction in maternal complications.109

Neuraxial anesthesia for cesarean delivery will provide a dense sensorimotor block, and in the case of a planned cesarean without previous labor, the spinal anesthetic will provide preemptive analgesia. The neuraxial approach also allows the administration of long-acting opioids (preservative-free morphine), which will achieve between 18 and 24 hours of postpartum analgesia. With respect to long-acting neuraxial opioids in women undergoing MAT, there is no evidence to argue against the administration of neuraxial opioids, although in some series, it appears to have been avoided/omitted.74,90,97 There are numerous publications reporting on the use of long-acting neuraxial opioids (preservative-free morphine),83,88,89,92 and one study on the continuous administration of epidural hydromorphone for postcesarean analgesia.94 In one small series, it was proposed that neuraxial opioids administered to women maintained with buprenorphine undergoing intrapartum cesarean delivery after a failed trial of labor may be associated with more rescue analgesia doses.93

Taken together, the available literature, including several recent reviews,110–112 supports the use of neuraxial opioids in the immediate postcesarean delivery period in patients maintained with buprenorphine.

Postcesarean analgesia

The most challenging period will be the first 2 to 4 days after cesarean delivery once the neuraxial opioid has worn off, leading toward hospital discharge. The goals of care should include the following:

  • Maintenance of methadone or buprenorphine, with doses possibly divided into 2, 3, or even 4 equal doses throughout the day,61 reducing the dose only with excessive sedation,113 and cautious monitoring postpartum.53,54
  • A stepwise multimodal opioid-sparing analgesia approach, which, as mentioned above, is the mainstay for enhanced optimized recovery in all women undergoing cesarean delivery,102 through a combination of scheduled acetaminophen and nonsteroidal anti-inflammatory drugs, usually oral ibuprofen.101 In addition, adjuvants acting synergistically to interrupt the pain transmission process at various levels,114 may be used.
  • A shared decision-making, patient-driven model, with realistic analgesic goals, and appropriate patient-reported outcome measures for this patient population where anxiety and pain will not be well tolerated.115–117

Intravenous or oral opioids

Systemic opioids have been considered the usual “rescue” strategy for postoperative breakthrough pain, particularly in the United States; however, special consideration should be given to propose opioid-balanced or even opioid-free strategies to this specific population. Opioids have been safely used in women with OUD, including those on methadone and buprenorphine, although approaches should differ between groups and the lowest possible dose and the shortest time of administration are keys. Opioids should be reserved for breakthrough pain, and other modalities for an opioid-balanced (even opioid-free) approach are probably preferable. Case series in the postpartum setting report the use of hydromorphone patient-controlled analgesia, particularly for women maintained with buprenorphine, as high mu-opioid receptor affinity is important in competitively displacing buprenorphine from the mu-receptors. A wide range of doses required for acceptable analgesia, skewing toward high doses, should be expected.88–90

Neuraxial and systemic alpha2-agonist adjuvants

Epidural clonidine has been extensively studied as an adjuvant during labor epidural analgesia, as a bolus for breakthrough pain,118,119 or added to the local anesthetic infusion.120–125 It has been used for postcesarean analgesia in women with OUD, added to a continuous infusion of low-concentration bupivacaine (1.2 to 2 mcg/mL clonidine in 0.0625% or 0.1% bupivacaine) in lieu of fentanyl, with remarkable analgesic success.74

Spinal clonidine as an adjuvant for cesarean delivery anesthesia has also been extensively studied, and provides prolonged analgesia, anxiolysis, sedation, and an antishivering effect.126–133

Dexmedetomidine may be administered as an IV infusion or neuraxial, although there are no robust studies describing its effect for postcesarean analgesia. Dexmedetomidine may have an effect of myometrial contraction, raising concerns against its use in laboring women where it could reduce fetoplacental perfusion.134,135 Low-dose IV dexmedetomidine was recently shown to reduce spinal-induced shivering, which may be particularly uncomfortable during cesarean delivery.136 Dexmedetomidine infusion (0.2 to 0.7 mcg/kg/h) was reported for postcesarean analgesia in women on methadone (80 mg/d), who, after receiving preservative-free morphine (200 mcg), experienced severe acute pain; the infusion was maintained for 20 hours.95

Intravenous ketamine

NMDA-receptor activation is the proposed mechanism resulting in OIH in patients with OUD, and may be involved in opioid withdrawal, and137 ketamine, a competitive NMDA-receptor antagonist, may be beneficial in this setting.72,138 Importantly, concurrent use of buprenorphine, methadone, or naltrexone does not appear to interact with the antidepressant effect of ketamine.139

Evidence of successful use of ketamine for postpartum analgesia is sparse, but has been reported in the setting of 2 pregnant women with sickle cell disease,140 for burn surgery during pregnancy,141 and after a cesarean delivery in a woman maintained with buprenorphine, where ketamine 2 mcg/kg/min was used for 12 hours.89 In addition, cesarean delivery cases were included in 2 systematic reviews, both showing a reduction in postoperative opioid use and pain severity in patients receiving ketamine.142,143

Neuraxial postcesarean analgesia

Peripartum epidural analgesia is effective and safe in OUD patients, and can combine low-concentration local anesthetics (bupivacaine 0.0625%) with adjuvants (ie, fentanyl and/or clonidine). In a small report, 2 women maintained with buprenorphine received lumbar and low thoracic epidural after cesarean delivery,90 although in both cases, it was decided to omit neuraxial opioids. Epidural clonidine has been successfully used in women maintained with buprenorphine,74 and epidural hydromorphone was extremely effective in a patient using high doses of methadone, for her second cesarean delivery.94 Although not published, spinal clonidine (0.5 to 1 mcg/kg) and repeated doses of epidural preservative-free morphine (3 mg) are our current practice in opioid-tolerant patients, which provides prolonged and effective analgesia, without limiting women’s ability to mobilize and ambulate.144

Abdominal wall blocks

In general, regional techniques are often proposed for postcesarean analgesia to improve postpartum recovery. By minimizing opioid use, these blocks can facilitate earlier discharge as part of enhanced recovery protocols.145 Transversus abdominis plane or quadratus lumborum blocks may be performed if neuraxial analgesia is not possible or if rescue analgesia is needed.146–148 Extending the duration of a regional block with the use of liposomal bupivacaine may be offered,149–152 even though this approach has not been evaluated in women with OUD.

Future directions

With recent efforts to reduce unnecessary opioid consumption in the peripartum period, to prevent persistent opioid use, and finally, to curb the opioid epidemic, stepwise multimodal opioid-sparing analgesia has become the gold standard in opioid-naive patients, and the same should apply to women with OUD. Creating a repository of cases where neuraxial opioids have been provided along with neuraxial or systemic nonopioid adjuvants should allow us to better identify which strategies might work best in combination with methadone or buprenorphine. The Centers for Disease Control and Prevention (CDC) initiated the “MATernaL and Infant NetworK to Understand Outcomes Associated with Treatment of Opioid Use Disorder during Pregnancy (MAT-LINK)” in 2020, with an agenda to monitor over 2000 mothers and their infants for up to 2 years after delivery, capturing data from diverse geographical sites, addressing key questions that will inform the management and treatment of pregnant women with OUD.153 Meanwhile, a case-by-case approach that includes shared decision-making should improve women’s experience while maintaining their safety.

Conclusions

Providing peripartum analgesia, and whenever needed anesthesia, to pregnant women with OUD remains complex and requires striking an optimal balance between adequate opioid-balanced analgesia (sometimes opioid-free) and excessive sedative-analgesic combinations that will require prolonged monitoring and reversal of action if respiratory compromise occurs. In general, women with chronic pain, opioid tolerance, polysubstance abuse, and those maintained with buprenorphine or methadone have been excluded from postcesarean delivery studies, deemed ineligible due to the expected variability in pain experience and response to analgesic drugs. In our review of the available literature that has specifically examined postpartum pain and analgesic approaches in women with MAT, our search identified only 14 papers, which is too limited a sample to allow the drawing of conclusions about best clinical approaches.

Descriptions of postpartum pain and analgesic consumption have shown that women maintained with either methadone or buprenorphine will experience significantly more pain compared with opioid-naive women, and robust multimodal analgesia is required, ideally with opioid-sparing approaches (neuraxial opioids and nonopioid adjuvants, acetaminophen, and ibuprofen) and possibly abdominal wall blocks, although clinical studies assessing the best strategies in this specific population are lacking. It is of crucial importance to maintain the usual daily dose of methadone or buprenorphine (which may have increased during the third trimester), and not omit any dose upon admission to the labor and delivery unit.

Conflict of interest disclosure

The authors declare that they have nothing to disclose.

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