Young, Jessica L. MD*; Lockhart, Ellen M. MD†; Baysinger, Curtis L. MD‡
Opioid dependence has become an epidemic in the United States with more than tripling of reported nonmedical use of prescripted narcotics and deaths between 1999 and 2010 (Fig. 1).1 The 2010 National Survey on Drug Use estimated that 4.4% of pregnant women had reported illicit drug use within the last 30 days1; another study reported that 2.6% of urine drug tests were positive for opioids among pregnant women tested at an urban United States hospital, and screened for opioid use.2 Owing to an increasing number of people treated with opiates for chronic pain, there has similarly been an increase in the number of women who have been pregnant while on opioid therapy for the management of chronic pain conditions. A recent study on the Tennessee Medicaid patient database showed an increase in opiate prescriptions in the first trimester of pregnancy from 8% in 2005 to 20% in 2009.3 The incidence of neonatal abstinence syndrome (NAS) caused by chronic exposure to opioids during pregnancy has increased markedly. Parturients who are on chronic opioid therapy, whether prescribed or illicit, pose a challenge to the obstetrician who manages their obstetric care and anesthesiologist who must manage their peripartum anesthesia and pain management needs.4
Management of the health care and psychosocial needs of opioid-dependent pregnant women is often challenging (Fig. 2). Risks of opioid dependence (OD) include miscarriage, preterm labor, preterm rupture of membranes, intrauterine growth restriction, intrauterine fetal demise, NAS, infectious disease, lack of prenatal care, malnutrition, abuse of other substances, and co-occurring psychiatric disorders (Table 1). For those who have developed physical dependence on opioids, withdrawal symptoms include nausea, vomiting, diarrhea, irritability, myalgias, abdominal pain, and chills. Withdrawal is taxing to maternal physiology and causes tachycardia, hypertension, decreased placental perfusion, and uterine contractions.5 Repeated episodes are thought to lead to poor fetal growth.6
Pregnant women with OD often abuse other substances as well. Cigarette smoking is 4 times greater than in the general pregnant population.7 Although it is not known how many pregnant women with OD also consume alcohol, one study on OD showed that 14% of OD women drank alcohol to intoxication in the 30 days before the study.8 Other drugs of abuse such as benzodiazepines, marijuana, amphetamines, and cocaine are used more frequently in this population. In a prospective randomized trial comparing methadone with buprenorphine administration (the MOTHER trial), 34% of subjects had used cocaine in the 30 days before enrollment in the study.9
Concurrent psychiatric disorders are common in OD. Identification and treatment may assist with the efficacy of treatment of addiction. A 2010 study on OD pregnant women reported that 64.6% endorsed symptoms of mental illness.10 Depression and anxiety are the disorders most frequently encountered in this population and an increased rate of both is associated with more severe addiction.11,12
The American College of Obstetricians and Gynecologists advocates routine screening of all women for substance abuse before and during pregnancy with a validated screening tool such as 4Ps plus (an acronym for parents, partner, past, and pregnancy) or CRAFFT (car, relaxation, alone, forget, friends, trouble).13 Universal urine toxicology testing is generally not recommended as a screening tool but should be used for further assessment of the woman who has a positive screen with the initial tool or has other risk factors. Informed consent should be obtained before urine drug testing and it is important to explain why the test is being ordered and how the results will be used. Failure to do so can result in distrust of the medical team causing the patient to disengage from care and may have legal implications. Substance abuse screening that is done with empathy and in a nonjudgmental manner can strengthen the therapeutic alliance between the physician and the patient.14 Women who are on opioids to treat chronic pain must be carefully screened for signs of psychological dependence or addiction. The evaluation of women diagnosed with OD in pregnancy, including suggested laboratories and imaging, is shown in Table 1.
Although there is a lack of data on teratogenicity of opioid exposure in the first trimester, the assumption has been that this class of medications is safe with regard to congenital anomalies. There have been some retrospective studies that suggest an association between codeine exposure in the first trimester and a variety of malformations including cardiac defects, cleft lip and palate, and pyloric stenosis.15 However, a report from Collaborative Perinatal Project, a large prospective study on perinatal outcomes, showed no association between opioid exposure and birth defects.16 In 2011, The National Birth Defects Prevention Study showed an association between first trimester opioid exposure and gastroschisis, cardiac defects, and spina bifida.7 These results have yet to be replicated and points to the need for future studies regarding opioid teratogenicity.
Detoxification of OD parturients is not recommended, as detoxification is difficult to accomplish without inducing withdrawal and increasing the rate of obstetric complications including miscarriage, preterm labor, and fetal demise. One study on detoxification in pregnancy reported that 29% of patients resumed using street drugs during their pregnancy. Of those successfully detoxed, 12% opted for methadone treatment at a later point in pregnancy. A quarter of the patients had significant enough withdrawal to precipitate active labor.17 Owing to an increase in the incidence of NAS, there is renewed interest in maternal detoxification for prevention of this outcome. A recent retrospective cohort study showed a 56% success rate of detoxification using a methadone taper with an average length of admission of 25 days.18
Owing to risk of relapse and concern for complications during detoxification, methadone maintenance therapy (MMT) for OD has been the standard of care for decades. Converting patients to MMT reduces opioid abuse behaviors and improves obstetric outcomes while improving some neonatal outcomes.17 Women have better adherence to prenatal care and are less likely to have children placed in foster care. There is also a significant decrease in the incidence of NAS from 75% to 50%.6 There are several disadvantages to MMT that make adherence to this treatment regimen burdensome. Methadone therapy can only be provided in the context of a licensed treatment facility and this requires daily visits to the center for dosing. For women who live in rural areas, the travel distance may be prohibitive. Many methadone treatment centers do not accept health insurance, thus making access to methadone financially impossible for some women.
Buprenorphine is an alternative to methadone maintenance and has been shown to have equivalent outcomes in pregnancy.19 Buprenorphine is an office-based treatment for OD and can be prescribed by any physician who has taken a training course and obtained a waiver for the prescription of buprenorphine. Thus, it does not require daily visits and prescriptions are often covered by health insurers. To begin buprenorphine, a patient must be in moderate withdrawal or have taken their short-acting opioid more than 6 hours previously. Buprenorphine has a high affinity for the mu-opioid receptor and a ceiling to its mu-agonist effect, and thus its administration can precipitate severe withdrawal in a patient who has taken heroin, methadone, or other long-acting opioids.20 Patients taking suboxone should be converted over to buprenorphine therapy if possible to avoid pre-delivery neonatal exposure to naloxone as endogenous opiates help regulate fetal circulatory responses during hypoxemia.13
If an OD patient presents without prenatal care, their current nonillicit opioids should be maintained to prevent withdrawal and provide an analgesic floor or converted to longer-acting opioid equivalents (Table 2). Illicit opioids should be converted to equivalent medium to longer duration narcotics. The conversion from one opioid to others may be difficult as published conversion tables vary in their equivalence recommendations. Recent systematic reviews of papers that have studied opioid conversion report that the recommended ratios found vary widely, the ratios may change if the conversion is reversed (ie, different if one converts from morphine to methadone vs. methadone to morphine), and tables of equianalgesic ratios vary between those found in physician educational materials and commercially prepared package inserts.21,22 Concurrent patient disease and drug therapy will alter drug equivalences as well.21,22 The analgesic equivalences listed in Table 2 should be viewed as guidelines for initial dosing and adjusted.
Intrapartum management of the OD patient is not substantially different than in the routine obstetric patient. Vaginal delivery is the preferred mode of delivery for these patients, as pain control during and after a cesarean section can be challenging.
Neonatal Abstinence Syndrome (NAS)
NAS is a manifestation of physical dependence and can appear after the discontinuation of transplacental opioids at birth (Fig. 2).23,24 NAS associated with maternal opioid use can result in prolonged and costly hospitalizations, and infants often require pharmacologic therapy.19,25 Symptoms are noted in approximately 50% to 80% of neonates after withdrawal of in utero opioid exposure.26–28 NAS is characterized by central nervous system irritability and gastrointestinal and autonomic nervous system dysfunction. Affected infants may display symptoms such as a high-pitched cry, feeding difficulties, tremors and hypertonia, sweating, fever, and tachypnea. If left untreated, NAS can result in seizures and death.25,28 Although these symptoms in isolation are nonspecific, taken as a whole they can indicate the severity of withdrawal and point to indications for treatment.
The American Academy of Pediatrics recommends the use of an assessment tool such as the Finnegan Neonatal Abstinence Severity Score, or one of the many modified versions of this scoring system, as well as maternal history and drug testing and testing of urine and meconium from the infant in diagnosing NAS.29 Decisions regarding treatment are based on a cumulative threshold score.29
The rate of diagnosis of NAS does not seem to be influenced by the dose of MMT.30,31 However, a large retrospective cohort study demonstrated that the severity and need for treatment of NAS is related to the amount of prescribed methadone.32 This project also demonstrated that preterm birth did not influence the odds of the infant receiving treatment for NAS and that breastfeeding for >72 hours was associated with reduced odds of requiring treatment for NAS.32 A retrospective review and risk stratification analysis of 232 infants demonstrated that the timing and mode of delivery and last maternal methadone dose were significant risk factors for the development of NAS requiring treatment.27
As buprenorphine has become a viable option for use in the pregnant population, the question of its effects on NAS versus those of methadone is an important one. The MOTHER trial, a randomized, double-blind, double-dummy, flexible-dosing controlled study demonstrated that buprenorphine-exposed neonates required significantly less morphine for the treatment of NAS during hospitalization compared with methadone-exposed neonates.19 A secondary analysis of these data confirmed that the profile of NAS differs in methadone-exposed versus buprenorphine-exposed neonates, with methadone-exposed neonates experiencing a more severe NAS.33 The long-term effects of NAS in mothers treated with buprenorphine are not as well defined, although initial reports suggest that they are at risk for neurobehavioral problems.34
In neonates who demonstrate escalating symptoms, pharmacologic intervention is required for 50% to 70% of infants with NAS. Two or more consecutive Finnegan Neonatal Abstinence Scoring Tool scores of 8 or 9 is a common indicator of need for intervention.35 Once symptoms resolve, treatment can be weaned over a period of days to weeks.24 The need for pharmacologic therapy is affected by many factors including genetics, other drug exposures, gestational age, breastfeeding, and maternal rooming-in.35 Methadone or morphine are most commonly used to treat NAS and clonidine administration offers another option.29 Barbiturates and benzodiazepines have been used but are not currently recommended.29 The use of naloxone is contraindicated as it may induce neonatal seizures.29
Peripartum Pain Management
OD parturients often pose a challenge to effective anesthetic and pain management during and after delivery (Fig. 2). Opioid tolerance (OT) and opioid-induced hyperalgesia (OIH),36 as evidenced by higher opioid requirements, concomitant illicit substance use, and manifestations of physical dependence pose challenging management issues.37 Patients who consume opioids over long periods of time demonstrate hypersensitivity to pain,38,39 as well as altered sensitivity to experimental pain stimuli such as cold pressor and electrical stimulation.36
OT and OIH complicate opioid use in OD patients. OT is thought to be due to opiate receptor desensitization,40 upregulation of cAMP pathways in the locus coeruleus,40 and a permanent increase in central NMDA receptor activity and downregulation of central glutamate receptors, particularly in the superficial laminae of the dorsal horn.41 OIH seems to result from increased NMDA receptor activity and an increase in spinal dynorphin concentrations.42 Although these 2 phenomena are different in that tolerance reflects desensitization of antinocipetive pathways and hyperalgesia represents sensitization of pronocioceptive pathways,42 distinguishing the 2 during clinical care does not assist in patient management. Upregulation of NMDA receptor activity supports the use of NMDA receptor antagonists such as ketamine and cyclo-oxygenase inhibitors, which act synergistically with NMDA receptor antagonists.43
Reports of peripartum pain management of OD parturients are limited to 3 retrospective cohort studies with a total of 253 patients maintained on buprenorphine or methadone44–46; 2 retrospective observational studies on 18 patients47 and 85 patients,48 respectively; and 2 case reports totaling 3 patients (Table 3).49,50 As a result, recommendations for pain management are based mostly on studies reported on non-OD women who present for labor and vaginal delivery and studies on nonpregnant OD patients who present for anesthesia and surgery. The applicability of such work to OD parturients may be limited as the effectiveness of these techniques have been based primarily on measuring changes in opioid consumption in non–opioid-dependent patients. The recent observational study by Cassidy and Cyna48 highlights the challenges that these patients present to anesthesiologists, noting that 74% of patients presented after cesarean delivery (CD) pain problems and that 26% required additional consultation for pain management above that required for labor, although the authors did not cite a control group for comparison.
Continuation of Baseline Opioids After Delivery
Baseline dosing of buprenorphine, methadone, or other daily opiate should be continued through the peripartum period.44,45,51,52 Opioid antagonists and mixed agonist-antagonists that block mu receptors are to be avoided as their use may precipitate withdrawal symptoms.52
Although once-daily dosing of methadone or buprenorphine is effective in preventing withdrawal, analgesic effects will be improved if the total daily dose is divided and administered in 6- to 8-hour intervals.53 Although small doses of these drugs in opioid-naive patients are sufficient to provide postsurgical pain relief,54,55 they will most likely be inadequate in postcesarean section patients who are OD.
General Versus Regional Anesthesia for CD
Studies specifically evaluating general and regional anesthesia for CD have not been reported in OD parturients. Neuraxial anesthesia is the anesthetic of choice for most OD women as it is in non-OD women, enabling use of neuraxial adjuncts that can enhance pain control after delivery. A greater reliance on regional techniques is advocated by most for postoperative analgesia, as local anesthetics should have the same efficacy as in non-OD patients.
Postcesarean Section Analgesia
The studies by Meyer et al,44,45 in which oral opioids were added to acetaminophen and ibuprofen analgesia in patients dependent on methadone and buprenorphine, reported pain scores that were higher than in matched controls (approximately 1.5 to 2 cm on a visual analog pain scale). Oxycodone equivalent consumption was 70% higher in patients on chronic methadone therapy compared with controls not on chronic opioid therapy. Although greater difficulty in pain control might be theoretically expected in patients on buprenorphine therapy compared with methadone therapy because of partial noncompetitive mu-receptor blockade, the 50% increase in opioid supplementation reported by Meyer et al44 was similar to that in patients on chronic methadone. The doses described in these 2 reviews are similar to the 30% to 100% increase noted in other OD postoperative surgical populations.41,56,57
The use of intravenous opioids increases the risk of respiratory depression in OD women as it does in non-OD women. Plasma concentrations of opioid associated with analgesia are approximately 30% of those associated with respiratory depression in non-OD patients.58 Whether this percentage is altered in OD women is unknown. Tolerance to respiratory depression cannot be inferred from tolerance to other common side effects such as pruritus, nausea, and vomiting. Some evidence suggests that the risk for respiratory depression may be higher in non-OD patients. One study noted that the rate of central sleep apnea during sleep studies was higher than in non-OD patients.59 Another study found that the incidence of moderate to severe postoperative sedation was 50% in OD patients compared with 19% in opioid-naive patients, despite visual analog pain scores that were 1 to 2 cm higher in the patients on chronic opioid therapy.60 Although the increased ventilatory drive associated with pregnancy may reduce susceptibility to opioid-induced respiratory depression, this possible protection has not been quantified. A prudent monitoring approach would be the of use more frequent checks for respiratory depression and sedation in OD patients using IV PCA narcotics post-cesarean delivery and less reliance on patient pain scores for opioid titration.
Transversus Abdominus Plane Blockade
Ultrasound-guided transversus abdominus plane blockade has been found to reduce opioid consumption after CD with general anesthesia and spinal anesthesia without opioid, and has been used when systemic opioid therapy failed to provide adequate analgesia.61,62 Ultrasound-guided transversus abdominus plane block is associated with little morbidity61 and, in the patient in whom the efficacy of neuraxial narcotics may be reduced,63 its routine use is attractive.
Other Peripheral Nerve Bocks
Iliohypogastric and ilioinguinal nerve blockade are associated with modest reductions in pain scores and significant reductions in opioid consumption in women who have64 and have not received intrathecal morphine.65 Peripheral nerve blockade using single dose and continuous wound infiltration with local anesthetics have shown variable results, with some studies showing reduction in pain scores and reductions in opioid consumption over the first 24 hours after delivery,66–68 and others showing no benefit when compared with the use of intravenous NSAIDs.69,70 Differences in catheter placement and more accurate catheter placement when ultrasound guidance is used have been proposed as explanations for the difference in outcome, with catheter placement below the transversalis fascia associated with better efficacy.71
Patient-controlled Epidural Analgesia (PCEA)
PCEA after CD is another alternative. Both reports by Meyer et al44,45 noted significant reductions in opiate consumption in the total 5 patients who received epidural analgesia after CD. In 2 of the patients on chronic buprenorphine therapy, PCEA was effective in treating pain when other techniques failed. However, in non-OD patients, use of local anesthetic is associated with an incidence of 20% to 36% of significant motor blockade72,73 and failed to show benefit over continuous wound infiltration alone in 1 study.71 The use of this technique might be recommended with a switch to other techniques if motor blockade occurs.
Neuraxial opioids do not prevent opiate withdrawal,41 and estimating an effective dose of neuraxial opioids is difficult in OD patients because of downregulation of opiate receptors.41,52,63
One study noted that the need for supplemental narcotics was similar in OD women after intrathecal administration of long-acting opioids versus those who did not receive them.45 Reports on postoperative OD patients with advanced cancer63,74 suggest that doses of 2 to 3 times used in opioid-naive patients may be effective, with little additional increase in risks for opiate-associated side effects. However, more vigilant monitoring for sedation and respiratory depression is warranted when opiates are administered by different routes.41
Adjunct Neuraxial Agents
Intrathecal clonidine in doses of 30 to 150 μg and epidural in doses of 75 to 150 μg prolongs pain relief for 4 hours but does not seem to offer substantial benefit over the use of intrathecal narcotics alone.51,75–77 An incidence of maternal sedation of 20% to 50% and an increased risk for hypotension51,75,76 as well as a United States Food and Drug Administration warning against its use in obstetric patients have discouraged its routine use.51 However, as an effective analgesic dose of narcotics is difficult to determine in OD parturients, neuraxial clonidine administration may offer benefit. An epidural solution to which 2 to 7.5 μg/mL of clonidine has been added administered by a patient-controlled technique may provide significant postoperative analgesia. Single-shot neuraxial use in doses of 30 to 150 μg may be considered, despite the increased risks of hypotension and maternal sedation.78–80
Expert opinion encourages the use of adjunct non-narcotic drugs as part of the effective management of acute postoperative pain in nonpregnant OD patients.41,60,81,82 The efficacy of nonsteroidal anti-inflammatory drugs, α2 agonists, acetaminophen, gabapentinoids, and ketamine have not been firmly established in OD parturients post-CD, but are effective in managing acute pain in nonsurgical OD patients and in postoperative OD patients.41 Most of these agents have acceptable safety profiles for use in the immediate peripartum period and can be used in breastfeeding mothers.13 Nonsteroidal anti-inflammatory drugs, such as ketorolac, potentiate the quality of pain relief from systemic or neuraxial opioids and decrease side effects in opioid-naive post-CD patients.83,84 Potential problems with maternal bleeding, platelet dysfunction, uterine atony, and gastrointestinal side effects have not been substantiated as clinically significant. NSAIDs are considered safe in breastfeeding women by the American Academy of Pediatrics.85
Acetaminophen seems to provide effective postoperative analgesia in surgical patients,86 but has shown variable effectiveness for CD pain relief when added to NSAID administration.87,88 Recent evaluations of intravenous acetaminophen for labor analgesia89 and for postoperative analgesia90 suggest that it would have good efficacy when administered by that route.
Gabapentin in doses of 300 to 1200 mg orally improves analgesia after other operative procedures,77 and is not associated with significant adverse fetal risk in pregnant patients who receive it chronically for seizure prophylaxis.91 A recent study in which 600 mg was administered orally before CD reduced pain on movement in non-OD women who also received intrathecal morphine.92 Severe sedation occurred in 19% of patients, but may be a desirable side effect in OD women after delivery.
Intravenous clonidine in doses of 0.1 to 0.2 μg/kg/h43,93 and clonidine patch use (0.1 mg/h)93 have been shown to improve analgesia and will reduce the risk of opiate withdrawal.43 One study examined the use of oral clonidine 0.4 μg/kg before CD and noted no difference in pain scores after delivery, but reported reductions in average morphine use from an average 25 to 15 mg over the first 24 hours.94 It noted no neonatal effects, but small numbers make conclusions on neonatal safety difficult.
Intravenous ketamine has been shown to be effective in reducing opioid use in opioid-tolerant patients,95 and reduced opioid consumption by one third in 1 study on opioid-naive patients using bolus doses of 0.25 to 0.5 mg/kg or continuous infusions 1 to 2 μg/kg/min.96 If the use of postdelivery opioids is high, bolus doses of 5 to 10 mg can be used for improved pain control.43 Its extensive safety record when used in obstetrics supports its use. However, a recent study showed that 10 mg of intravenous ketamine had no opiate-sparing benefit in parturients after spinal anesthesia for cesarean section.97
Summary and Recommendations
The increase in opioid prescription for chronic pain combined with illicit opioid use has been associated with an increase in the numbers of pregnant OD women. A coordinated and multidisciplinary approach involving obstetricians, anesthesiologists, and neonatologists is essential in improving outcomes of both the patient and the neonate, and in providing safe, effective peripartum care.
On the basis of our review, we offer the following specific recommendations.
- Opiate-abusing women who present for antepartum care should have either methadone or buprenorphine substituted for other opioids as this is associated with improved obstetric outcomes. Buprenorphine is associated with a reduction in NAS.
- Baseline opiate therapy should be maintained through and after parturition. Postdelivery breastfeeding is encouraged.
- OD women should be screened for the use of other illicit drugs and for infectious diseases that might alter obstetric and anesthetic management.
- Tolerance and hyperalgesia, use of other illicit substances, and concomitant psychosocial issues may complicate the pain management in OD patients.
- Tolerance to other intravenous opioid analgesic effects does not imply tolerance to respiratory depressant effects and additional monitoring should be considered.
- Neuraxial analgesia in OD patients is effective for labor vaginal delivery and cesarean section similar to non–opioid-dependent patients and has been effective for postdelivery analgesia in the small numbers of patients who were refractory to other treatments.
- Multimodal anesthesia, including the use of additional opioids, supplemental regional anesthesia techniques, neuraxial adjuvant therapy, and nonopioid analgesics can be beneficial and should be used.
- Prospective trials evaluating optimal pain management for labor and delivery are needed. The current recommendations for analgesia are based primarily on trials showing reductions in narcotic use in non-OD parturients undergoing labor and delivery or from work in nonpregnant OD patients undergoing surgical procedures.
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