**8. Special topics in pregnancy**

[67–69]. Contraindications to RFA are like those associated with other neuraxial procedures. Complications include increased pain, muscle spasms, numbness or paresthesias, infection, bleeding, superficial burns, damage to surrounding tissues, side effects of local anesthetics as well as fetal exposure to radiation. As a general rule, ultrasound and magnetic resonance imaging are the preferred imaging methods during pregnancy. Ionizing radiation (e.g., fluoroscopy) in large doses can have varying effects to the fetus via pregnancy loss, malformation, growth disturbances and mutagenic and carcinogenic effects depending on the stage of gestation. The most sensitive period of gestation to radiation occurs during organogenesis (weeks 2–8) [70]. The recommended maximum dose of radiation for the duration of pregnancy varies by source, but has been sighted as low as 500 mrem (or 0.5 Rads). For comparison, a pregnant interventional radiologist can expect an average dose of 30 mrem during a 40-week pregnancy if wearing double lead [71]. Radiation is not an absolute contraindication to RFA in the pregnant patient, and if clinically indicated RFA via fluoroscopy can be considered. Benefit–risk ratio of RFA is an important first step and if in doubt, a radiologist could be consulted. Since the average exposure of radiation during a fluoroscopic-guided RFA is not well defined in the literature, various methods should be employed to minimize the risk of exposure to the fetus. Some of these techniques include shielding the abdomen and pelvic region with lead, minimizing fluoroscopic exposure time, proper placement of the fluoroscope to maximize distance from the X-ray source, limit magnifications, narrowing of the fluoroscopic window (known as tight collimation) and proper gestational timing of the procedure [70]. Given the limited evidence of RFA, the lack of quality evidence of RFA during pregnancy, and the potential for radiation exposure to the fetus, RFAs should only be considered after failure of conservative

Transcutaneous electrical nerve stimulation (TENS) is a technique of delivering low level of constant electrical impulses of variable frequencies, intensities and pulse waveforms to the epidermal surface with aim of inhibition of spinal cord interneurons and descending pain pathways [62, 72]. The indications for TENs are various, and examples include lower back pain and myofascial pain. Onset of pain relief takes on average 20–30 min in 75% of patients and 1 h in 95% of patients. The duration of pain relief varies among patients and conditions, but appears to be short term, decreasing over past several months of use [73]. During labor, TENS has demonstrated a benefit in acute pain relief, decreased analgesic use, and patient satisfaction [61, 74]. In contrast, two systemic analyses and a Cochrane review have not shown a significant reduction in pain [62, 75]. Technical errors from electrodes placement and timing could lead to interference with fetal heart monitoring and possible premature labor. All can easily be corrected by proper timing, proper anatomical placement of the devices, and removing the TENs if necessary [61]. Overall, the benefit of TENS for the treatment of chronic pain during pregnancy is not well studied in the literature. The general consensus is that the device's benefits outweigh its risks. TENS is easy to use and accessible over the counter. It provides a cost-effective, noninvasive, and potential pharmacologic sparing effect in pregnant patients and may be considered as an adjuvant for the safe treatment of chronic pain during

treatments and an informed discussion with the patient.

**7.2. Transcutaneous electrical nerve stimulation**

86 Pain Management in Special Circumstances

pregnancy.

#### **8.1. Opioid use disorder in pregnancy**

Opioid use during pregnancy has increased worldwide in recent years. In the United States, the prevalence of opioid abuse or dependence among pregnant women has increased from 1.7 per 1000 delivery admissions in 1998 to 3.9 per 1000 delivery admissions in 2011. The rate of unintended pregnancy has been reported as high as 86% in women with opioid use disorder, exposing the fetus right from conception [76]. Increase in opioid-related morbidity has been directly linked with the high prevalence of opioid prescription, which reaches 27–39% among pregnant women [77]. Opioid use disorder (OUD) is a pattern of opioid intake associated with significant clinical impairment and distress. OUD is diagnosed, as described in (**Table 4**) by the *Diagnostic and Statistical Manual of Mental Disorders, 5th Edition* (DSM-5), by at least **two** criteria within a **12-month** period [78].

Treatment of pregnant women with OUD has been shown to improve maternal and fetal outcome by decreasing the risk of relapse, maternal withdrawal symptoms, drug-seeking behaviors, and repeated cycles of intoxications [79, 80]. It also enhances the adherence to prenatal care. Opioid dependence in pregnancy is directly linked to placental insufficiency, fetal growth restriction, fetal death, abortions, premature delivery, preeclampsia, abruptio placentae, premature rupture of membranes, and postpartum hemorrhage. However, clear causality could not be established in the studied populations because of confounders in from of polydrug abuse, opioid withdrawal symptoms or coexisting maternal conditions [81]. Medical, nutritional, financial, psychological and socio-economical rampant in this patient population and should be taken into consideration when formulating a treatment plan.

Opioid use disorder (**OUD**)—DSM-5 Diagnosis by at least **2** criteria over **12** months.


**Table 4.** DSM-5 diagnostic criteria for OUD.

Methadone is still the standard treatment for the opioid dependence in many institutions due to its proven safety profile and established efficacy. Recently, the American College of Obstetrics and Gynecology (ACOG) has recommended buprenorphine as the first line therapy in OUD [82]. The interest is growing for buprenorphine after retrospective reports for its benefit of lower rates, lesser severity of NAS, lower morphine doses used for NAS, and a shorter stay in NICU [83]. Buprenorphine has a ceiling effect with expected low risk for overdose compared with methadone. The efficacy of buprenorphine as a substitution therapy has been debated because it was found that the patients on buprenorphine have less compliance rate and more reversion to other opioid drug abuse; however, those reports were biased and have different patient characteristics [34]. Both buprenorphine and methadone are considered safe with no significant harm and have shown good outcomes in OUD treatment [35].

Long-term neurodevelopmental sequelae such as attention deficit disorders (ADD) and disruptive behavior have been reported in NAS. Therefore, long-term psychiatric follow-up is warranted [89]. Inpatient monitoring for 4–7 days for neonates with known in utero exposure

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Non-pharmacological management is the initial approach for NAS. It entails keeping the neonate in calm, soothing environment with minimal stimulation, repeated maternal contact, and frequent hypercaloric meals [90]. Pharmacologic treatment is usually needed. This constitutes oral morphine as the first line agent and either clonidine or phenobarbital as the second line agent [85]. Once withdrawal symptoms are stable for 48 h, pharmacological weaning can be started. Breastfeeding is recommended in general even for mothers on methadone or buprenorphine treatment, as long as no other contraindications are present (e.g., HIV, illicit

Chronic pain management in pregnancy is challenging. A multidisciplinary team approach and multimodal pain protocols are highly recommended. Optimum management includes a detailed review of the patient's comorbidities and considerations for behavioral and other socioeconomic factors that could affect chronic pain conditions. The safest approach is by following a goal-directed strategy that minimizes or optimizes opioid usage. Opioid sparing strategies include early alternative pain therapies such as exercise, physical therapy, behavioral changes, and non-opioid analgesics. Lifestyle and behavioral changes start with open, effective, and compassionate communication with the patient. The initial and follow-up visits should include patient education on different pharmacological options and alternative nonpharmacological modalities. Patients should be encouraged to take an active role in their own treatment plan. Acetaminophen is usually the first line drug for mild to moderate pain in any stage of pregnancy. Although ibuprofen is the non-steroidal anti-inflammatory drug (NSAID) of choice, it is contraindicated after 28 weeks of gestation as it could cause premature closure of the ductus arteriosus and impair fetal kidney function. Only in severe acute musculoskeletal pain, opioids should be used. Caution should be taken as peripartum administration is associated with neonatal respiratory depression. Additionally, a long-term therapy, particularly in late pregnancy, is associated with adaptation disorders and neonatal withdrawal symptoms. Once the opioids are indicated in a reproductive age woman, the benefits and risks of opioid use should be discussed. However, concerns about NAS or opioid abuse should not be a barrier for optimal pain management in pregnancy as long as a cautious and balanced approach is followed. Opioid prescriptions should be initiated with a drug monitoring program that could help to identify opioid use disorder or drug misuse. Concurrent opioid and benzodiazepines use should be avoided whenever possible. Opioid overdose is associated with high maternal and fetal mortality and morbidity. In case of overdose, substance abuse disorder, or higher opioid dosages (≥50 MME/day), naloxone should be prescribed. To avoid relapse, which is associated with very high morbidity in pregnant women with opioid use disorder, an opioid agonist (buprenorphine or methadone) is the recommended first line therapy in combination with behavioral therapy. Antiepileptic drugs are contraindicated during pregnancy as they carry a teratogenic risk; however, well-studied antidepressants, such

to opioids is recommended by the American Association of Pediatrics (AAP) [88].

drug use) [82].

**9. Recommendations summary**

#### **8.2. Neonatal abstinence syndrome**

As a shadow of opioid crisis and high prevalence of maternal opioid exposure, the incidence of NAS has increased worldwide. In the USA, a 400% increase in the incidence of NAS were reported and 5.8 up to 30 per 1000 hospital births in 2012, compared with 1.2 in 2000 [84, 85]. In 2012, one NAS-affected infant was born every 25 min in the United States [85].

**Neonatal abstinence syndrome (NAS)** is a neonatal drug withdrawal syndrome that occurs after opioids exposure in utero. The opioid is the main culprit for the withdrawal; however, other substances have also been reported, including alcohol, benzodiazepines, nicotine, and psychiatric medications such as antidepressants or antipsychotics [86]. The source of the opioid could be from clinician-approved use of prescription opioids for pain relief, or abuse of prescription opioids or illicit use (e.g., heroin); or medication-assisted treatment (MAT) of opioid use disorder.

In utero, fetal exposure to opioids during pregnancy is associated with a 60–80% risk of NAS [87]. However, the onset and severity are multifactorial and variable. They depend on gestational age, birth weight, maternal opioid dosage, concomitant use of other psychoactive medications and pharmacogenomics. NAS usually manifests within 2–3 days after birth with clinical signs of withdrawal as summarized in **Table 5** [88].

Multiple brain volumetric studies have reported a small volume of cortex, deep midbrain, brainstem, and thin cerebellar cortex in infants with in utero polydrug exposure including opiates [86].


**Table 5.** Summary of neonatal abstinence syndrome (NAS).

Long-term neurodevelopmental sequelae such as attention deficit disorders (ADD) and disruptive behavior have been reported in NAS. Therefore, long-term psychiatric follow-up is warranted [89]. Inpatient monitoring for 4–7 days for neonates with known in utero exposure to opioids is recommended by the American Association of Pediatrics (AAP) [88].

Non-pharmacological management is the initial approach for NAS. It entails keeping the neonate in calm, soothing environment with minimal stimulation, repeated maternal contact, and frequent hypercaloric meals [90]. Pharmacologic treatment is usually needed. This constitutes oral morphine as the first line agent and either clonidine or phenobarbital as the second line agent [85]. Once withdrawal symptoms are stable for 48 h, pharmacological weaning can be started. Breastfeeding is recommended in general even for mothers on methadone or buprenorphine treatment, as long as no other contraindications are present (e.g., HIV, illicit drug use) [82].

## **9. Recommendations summary**

**Autonomic nervous system activation**

**8.2. Neonatal abstinence syndrome**

88 Pain Management in Special Circumstances

**Table 5.** Summary of neonatal abstinence syndrome (NAS).

clinical signs of withdrawal as summarized in **Table 5** [88].

**Central nervous system irritability** High-pitched continuous crying Irritability—decreased sleep Tremors—muscle hypertonicity

**Cardiovascular dysfunction** Tachycardia—hypertension Hypotension in case of collapse

Seizures

Methadone is still the standard treatment for the opioid dependence in many institutions due to its proven safety profile and established efficacy. Recently, the American College of Obstetrics and Gynecology (ACOG) has recommended buprenorphine as the first line therapy in OUD [82]. The interest is growing for buprenorphine after retrospective reports for its benefit of lower rates, lesser severity of NAS, lower morphine doses used for NAS, and a shorter stay in NICU [83]. Buprenorphine has a ceiling effect with expected low risk for overdose compared with methadone. The efficacy of buprenorphine as a substitution therapy has been debated because it was found that the patients on buprenorphine have less compliance rate and more reversion to other opioid drug abuse; however, those reports were biased and have different patient characteristics [34]. Both buprenorphine and methadone are considered

safe with no significant harm and have shown good outcomes in OUD treatment [35].

In 2012, one NAS-affected infant was born every 25 min in the United States [85].

As a shadow of opioid crisis and high prevalence of maternal opioid exposure, the incidence of NAS has increased worldwide. In the USA, a 400% increase in the incidence of NAS were reported and 5.8 up to 30 per 1000 hospital births in 2012, compared with 1.2 in 2000 [84, 85].

**Neonatal abstinence syndrome (NAS)** is a neonatal drug withdrawal syndrome that occurs after opioids exposure in utero. The opioid is the main culprit for the withdrawal; however, other substances have also been reported, including alcohol, benzodiazepines, nicotine, and psychiatric medications such as antidepressants or antipsychotics [86]. The source of the opioid could be from clinician-approved use of prescription opioids for pain relief, or abuse of prescription opioids or illicit use (e.g., heroin); or medication-assisted treatment (MAT) of

In utero, fetal exposure to opioids during pregnancy is associated with a 60–80% risk of NAS [87]. However, the onset and severity are multifactorial and variable. They depend on gestational age, birth weight, maternal opioid dosage, concomitant use of other psychoactive medications and pharmacogenomics. NAS usually manifests within 2–3 days after birth with

Multiple brain volumetric studies have reported a small volume of cortex, deep midbrain, brainstem, and thin cerebellar cortex in infants with in utero polydrug exposure including opiates [86].

Fever—sweating

 Temperature dysregulation Increased respiratory rate Nasal stuffiness, sneezing

opioid use disorder.

**Gastrointestinal dysfunction** Feeding difficulties Vomiting—loose diarrhea

Chronic pain management in pregnancy is challenging. A multidisciplinary team approach and multimodal pain protocols are highly recommended. Optimum management includes a detailed review of the patient's comorbidities and considerations for behavioral and other socioeconomic factors that could affect chronic pain conditions. The safest approach is by following a goal-directed strategy that minimizes or optimizes opioid usage. Opioid sparing strategies include early alternative pain therapies such as exercise, physical therapy, behavioral changes, and non-opioid analgesics. Lifestyle and behavioral changes start with open, effective, and compassionate communication with the patient. The initial and follow-up visits should include patient education on different pharmacological options and alternative nonpharmacological modalities. Patients should be encouraged to take an active role in their own treatment plan. Acetaminophen is usually the first line drug for mild to moderate pain in any stage of pregnancy. Although ibuprofen is the non-steroidal anti-inflammatory drug (NSAID) of choice, it is contraindicated after 28 weeks of gestation as it could cause premature closure of the ductus arteriosus and impair fetal kidney function. Only in severe acute musculoskeletal pain, opioids should be used. Caution should be taken as peripartum administration is associated with neonatal respiratory depression. Additionally, a long-term therapy, particularly in late pregnancy, is associated with adaptation disorders and neonatal withdrawal symptoms. Once the opioids are indicated in a reproductive age woman, the benefits and risks of opioid use should be discussed. However, concerns about NAS or opioid abuse should not be a barrier for optimal pain management in pregnancy as long as a cautious and balanced approach is followed. Opioid prescriptions should be initiated with a drug monitoring program that could help to identify opioid use disorder or drug misuse. Concurrent opioid and benzodiazepines use should be avoided whenever possible. Opioid overdose is associated with high maternal and fetal mortality and morbidity. In case of overdose, substance abuse disorder, or higher opioid dosages (≥50 MME/day), naloxone should be prescribed. To avoid relapse, which is associated with very high morbidity in pregnant women with opioid use disorder, an opioid agonist (buprenorphine or methadone) is the recommended first line therapy in combination with behavioral therapy. Antiepileptic drugs are contraindicated during pregnancy as they carry a teratogenic risk; however, well-studied antidepressants, such as sertraline and amitriptyline can be used for chronic pain with the appropriate indications. Sumatriptan is safe to use in pregnant patients with migraine.

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