**4. Summary of non-labor pain management algorithm**

A structured, multimodal approach is the essence of management of NLP. It is essential to set realistic goals based on functional status rather than chasing a pain score of zero. The impact of setting realistic goals of pain management has been shown to produce more patient satisfaction, better psychological well-being, higher quality of life and reduced anxiety [26, 27]. On the other hand, a patient feeling her pain is poorly controlled leads to more disability, increased pain intensity, anxiety, and depression [28, 29].

**Non-pharmacological** therapies are very valuable as they augment pain relief and minimize the utilization of drugs. These benefits are welcomed by pregnant women who often have concerns about medications and their side effects. Activity modifications, physical exercise, and a physiotherapy program have been shown to be effective in pain reduction in comparison with standard care. The additive benefit of combining different approaches such as adding acupuncture to stabilization exercises, has been proven in different studies. Pelvic belt bracing has been shown to improve SIJ stability by decreasing joint laxity and sagittal rotation by 19% [30].

## **5. Summary of pharmacological management**

#### **5.1. Teratogenicity and toxicity**

Agents that are toxic and cause birth defects are known as teratogens [31]. During fetal development, teratogens impart their effect mostly during the time of organogenesis which begins in the third week of gestation. The severity of malformation depends on many factors, including type of teratogenic agent, dose and duration of exposure, time period of gestation, and


**Table 3.** FDA classification for safety of medications in pregnancy.

maternal and fetal health prior to the exposure. Teratogenicity can be caused by fetal cell death leading to spontaneous abortion, impaired cellular functions, or placental toxicity [31].

The US Food and Drug Administration (FDA) classification for safety of medications in pregnancy is shown in "**Table 3**" [32].

#### **5.2. Opioid medications**

**3.4. Neuropathic pain**

80 Pain Management in Special Circumstances

of the thigh.

by 19% [30].

**5.1. Teratogenicity and toxicity**

Causes of neuropathic pain in pregnancy include carpal tunnel syndrome, meralgia paresthetica, low intercostal nerve compression, and the pain of a previous cesarean section wound scar. Physiological water retention, obesity, and diabetes are contributory factors for neuropathic pain. Pregnancy-related carpal tunnel syndrome (PRCTS) is as prevalent as 43%, as confirmed by nerve conduction studies [24]. It manifests as pain and numbness in the distribution of the median nerve with progressive worsening at night. CTS usually subsides by conservative treatment and night splints. Physical therapy, infiltration of local anesthetic, and slow-release steroids could be added. Surgical decompression is rarely required and is reserved only for severe cases with motor neuropathy [25]. Differential diagnosis includes De-Quervain tendinopathy which presents with pain, swelling, and tenderness along the radial aspect of the wrist. Meralgia paresthetica is mononeuropathy of the lateral femoral cutaneous nerve (LFCN) which presents as tingling and numbness in the anterolateral aspect

A structured, multimodal approach is the essence of management of NLP. It is essential to set realistic goals based on functional status rather than chasing a pain score of zero. The impact of setting realistic goals of pain management has been shown to produce more patient satisfaction, better psychological well-being, higher quality of life and reduced anxiety [26, 27]. On the other hand, a patient feeling her pain is poorly controlled leads to more dis-

**Non-pharmacological** therapies are very valuable as they augment pain relief and minimize the utilization of drugs. These benefits are welcomed by pregnant women who often have concerns about medications and their side effects. Activity modifications, physical exercise, and a physiotherapy program have been shown to be effective in pain reduction in comparison with standard care. The additive benefit of combining different approaches such as adding acupuncture to stabilization exercises, has been proven in different studies. Pelvic belt bracing has been shown to improve SIJ stability by decreasing joint laxity and sagittal rotation

Agents that are toxic and cause birth defects are known as teratogens [31]. During fetal development, teratogens impart their effect mostly during the time of organogenesis which begins in the third week of gestation. The severity of malformation depends on many factors, including type of teratogenic agent, dose and duration of exposure, time period of gestation, and

**4. Summary of non-labor pain management algorithm**

ability, increased pain intensity, anxiety, and depression [28, 29].

**5. Summary of pharmacological management**

Codeine, hydrocodone, oxycodone, and propoxyphene are currently among the most commonly prescribed opioid agents in the United States [33]. Opioid medications should not be considered as a homogenous class of medications regarding its maternal and fetal effects, as some subclass are safer than the others. Evidence is still inconclusive regarding the relationship of opioid with poor fetal growth, preterm birth, and birth defects as most of the studies were biased with a lot of confounders. The general recommendation is that opioid usage should be avoided or minimized during pregnancy and should never be considered as a first line option. Usage during early pregnancy could be associated with neural tube defects and heart defects, and during late pregnancy, with neonatal abstinence syndrome (NAS) and neonatal respiratory distress syndrome. All opioid medications are classified as Class C (uncertain safety, no human studies; animal studies show an adverse effect).

Fentanyl patches seem to be safe, but there is still a risk of withdrawal. Methadone is associated with neonatal morbidity, such as preterm birth (<32 weeks of gestation), low birth weight, decreased head circumference, jaundice, thrombocytosis, arrhythmia, and admission to the neonatal intensive care unit [34, 35]. Codeine is classified as category C by the FDA [36]. It is neither teratogenic nor associated with congenital malformation. However, there have been reports of postpartum hemorrhage if it was taken near the end of pregnancy. Moreover, it could be rapidly metabolized into morphine, by CYP450 enzymes leading to a significant risk of fetal opioid toxicity during lactation [37]. Tramadol is classified as a category C medication. It has a risk of withdrawal with high maternal dosing [32]. It is not recommended to discontinue it during breastfeeding as only trace amounts cross into the breast milk.

The morphine equivalent daily dosage (MEDD) is a mean of calculating the daily cumulative intake of any opioid-related drugs. The aim is to reduce the risk of overdose, especially in chronic opioid use. Evidence has shown that there is no single dosage threshold below which overdose risk could be avoided, but opioid dosages of <50 MEDD/day (mg/day) would likely reduce the risk of fatal overdose.

#### **5.3. Non-opioid analgesic medications**

#### *5.3.1. Acetaminophen (paracetamol)*

Acetaminophen is widely used as an analgesic. In the USA, 65–70% of women used acetaminophen during pregnancy [38]. It has no known maternal adverse outcomes or fetal congenital defects as confirmed by analysis of registries [39]. Despite the reports about increased risk of attention deficit hyperactive disorder (ADHD) in children if used for over 6 weeks, the evidence was inconclusive according to the latest FDA warning [40].

*5.4.1. Antidepressants*

*5.4.2. Benzodiazepines*

*5.4.3. Antiepileptic agents*

Patients with chronic pain commonly experience depression. Selective serotonin receptor inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are widely used as antidepressants and also as adjuvant therapy for chronic pain. SSRIs have been the most commonly studied antidepressants in pregnancy and include Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. There is little information about other SSRIs. Majority of studies report that SSRIs are not teratogenic; however, some consider them as low-risk teratogens as due to there has been associated increase, albeit minimal, in cardiac congenital anomalies in the form of small ventricular defects that spontaneously close in childhood [43, 44]. The use of SSRIs minimally increases the risk of antepartum and postpartum hemorrhage. There has been no increase in the risk of spontaneous abortions, perinatal deaths, or hypertensive disorders of pregnancy. Peripartum fetal exposure is not believed to be associated with postpartum withdrawal or toxicity symptoms in the neonate. Case reports that had reported an association were confounded by other psychotropic medications [45]. Among SSRIs, sertraline has

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TCAs are believed to be generally nonteratogenic except Clomipramine as reported by most studies. All drugs in this class could increase the risk of spontaneous abortion, hypertensive disorders of pregnancy, postpartum hemorrhage and transient fetal withdrawal symptoms [47]. There is still limited information and less usage of antidepressants drugs other than SSRIs, such as Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) and atypical

A majority of studies report benzodiazepines to be nonteratogenic. Even the few conflicting reports showed that the incidence of minor anomalies such as cleft palate is only minimally increased compared with the general population. Perinatal usage increases the risk of low birth weight, preterm labor and spontaneous abortion. Moreover, peripartum exposure is

Antiepileptic drugs are now commonly used in pain management, particularly for the treatment of neuropathic pain such as, trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, post-stroke pain, phantom limb pain and pain after spinal cord injuries. Majority of studies have reported significant fetal morbidity due to in-utero exposure that including major anomalies like neural tube defects, congenital heart abnormalities, and urinary tract defects, skeletal abnormalities, cleft palate and impaired cognitive and motor development [49, 50]. Pregabalin, which is very commonly prescribed for chronic neuropathic pain, has a better safety profile than other antiepileptics. However, it is still associated with a higher risk

the safest profile as its low levels in blood and breast milk [46].

antidepressants like Mirtazapine and Buspirone.

associated with withdrawal and toxicity symptoms [48].

for malformation than in the general population [51].

#### *5.3.2. Non-steroidal anti-inflammatory agents*

Non-steroidal anti-inflammatory agents (NSAIDs) such as Ibuprofen, Naproxen, Diclofenac, and Celecoxib are very commonly prescribed for analgesia. It was reported that 18–25 and 4% of the USA pregnant women are exposed to over-the-counter (OTC) Ibuprofen, and Naproxen respectively [38]. In the third trimester, NSAIDs are linked with premature closure of the ductus arteriosus and development of pulmonary hypertension in a fetus. At high doses, NSAIDs decrease renal perfusion in fetus and lead to oligohydramnios. Despite NSAIDs being Category B drugs before the third trimester, it is generally recommended to be avoided as in the first trimester there is risk of miscarriage and in the third trimester there is a risk of oligohydramnios and ill effect on fetal circulation. Furthermore, NSAIDs are associated with a delay in onset of labor and increase in duration.

#### *5.3.3. Aspirin*

Aspirin is not commonly used to treat pain or fever in pregnancy. It is associated with neonatal hemorrhage, IUGR, gastroschisis and perinatal death. Similar to NSAIDs, they delay onset of labor and increase labor duration. An increased risk of bleeding during delivery has also been reported. Low-dose Aspirin (81 mg) is considered safe and is commonly given with heparin in conditions with recurrent miscarriage and in women with antiphospholipid syndrome [41].

#### **5.4. Psychotropic medications**

Psychotropic drugs are medications that affect mood, cognitive function or any other mental process [42]. These include antidepressants, benzodiazepines, antiepileptic agents and antipsychotics. Most of the safety profiles and recommendations for using these drugs are based on retrospective observational studies in pregnant patients with underlying psychiatric or mood disorders (such as bipolar or depression or anxiety) and are thus liable to bias and confounding. Some medications are well known to cause significant congenital malformations, such as Valproate, Carbamazepine, Lithium, and Lamotrigine. Therefore, they must be avoided in pregnancy. Most of other drugs are debated in their fetal outcome. In general, the risk-benefit ratio should be weighed, and the lowest dose should be applied.

#### *5.4.1. Antidepressants*

**5.3. Non-opioid analgesic medications**

*5.3.2. Non-steroidal anti-inflammatory agents*

a delay in onset of labor and increase in duration.

*5.3.3. Aspirin*

syndrome [41].

**5.4. Psychotropic medications**

Acetaminophen is widely used as an analgesic. In the USA, 65–70% of women used acetaminophen during pregnancy [38]. It has no known maternal adverse outcomes or fetal congenital defects as confirmed by analysis of registries [39]. Despite the reports about increased risk of attention deficit hyperactive disorder (ADHD) in children if used for over 6 weeks, the

Non-steroidal anti-inflammatory agents (NSAIDs) such as Ibuprofen, Naproxen, Diclofenac, and Celecoxib are very commonly prescribed for analgesia. It was reported that 18–25 and 4% of the USA pregnant women are exposed to over-the-counter (OTC) Ibuprofen, and Naproxen respectively [38]. In the third trimester, NSAIDs are linked with premature closure of the ductus arteriosus and development of pulmonary hypertension in a fetus. At high doses, NSAIDs decrease renal perfusion in fetus and lead to oligohydramnios. Despite NSAIDs being Category B drugs before the third trimester, it is generally recommended to be avoided as in the first trimester there is risk of miscarriage and in the third trimester there is a risk of oligohydramnios and ill effect on fetal circulation. Furthermore, NSAIDs are associated with

Aspirin is not commonly used to treat pain or fever in pregnancy. It is associated with neonatal hemorrhage, IUGR, gastroschisis and perinatal death. Similar to NSAIDs, they delay onset of labor and increase labor duration. An increased risk of bleeding during delivery has also been reported. Low-dose Aspirin (81 mg) is considered safe and is commonly given with heparin in conditions with recurrent miscarriage and in women with antiphospholipid

Psychotropic drugs are medications that affect mood, cognitive function or any other mental process [42]. These include antidepressants, benzodiazepines, antiepileptic agents and antipsychotics. Most of the safety profiles and recommendations for using these drugs are based on retrospective observational studies in pregnant patients with underlying psychiatric or mood disorders (such as bipolar or depression or anxiety) and are thus liable to bias and confounding. Some medications are well known to cause significant congenital malformations, such as Valproate, Carbamazepine, Lithium, and Lamotrigine. Therefore, they must be avoided in pregnancy. Most of other drugs are debated in their fetal outcome. In general, the

risk-benefit ratio should be weighed, and the lowest dose should be applied.

evidence was inconclusive according to the latest FDA warning [40].

*5.3.1. Acetaminophen (paracetamol)*

82 Pain Management in Special Circumstances

Patients with chronic pain commonly experience depression. Selective serotonin receptor inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are widely used as antidepressants and also as adjuvant therapy for chronic pain. SSRIs have been the most commonly studied antidepressants in pregnancy and include Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. There is little information about other SSRIs. Majority of studies report that SSRIs are not teratogenic; however, some consider them as low-risk teratogens as due to there has been associated increase, albeit minimal, in cardiac congenital anomalies in the form of small ventricular defects that spontaneously close in childhood [43, 44]. The use of SSRIs minimally increases the risk of antepartum and postpartum hemorrhage. There has been no increase in the risk of spontaneous abortions, perinatal deaths, or hypertensive disorders of pregnancy. Peripartum fetal exposure is not believed to be associated with postpartum withdrawal or toxicity symptoms in the neonate. Case reports that had reported an association were confounded by other psychotropic medications [45]. Among SSRIs, sertraline has the safest profile as its low levels in blood and breast milk [46].

TCAs are believed to be generally nonteratogenic except Clomipramine as reported by most studies. All drugs in this class could increase the risk of spontaneous abortion, hypertensive disorders of pregnancy, postpartum hemorrhage and transient fetal withdrawal symptoms [47]. There is still limited information and less usage of antidepressants drugs other than SSRIs, such as Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) and atypical antidepressants like Mirtazapine and Buspirone.

#### *5.4.2. Benzodiazepines*

A majority of studies report benzodiazepines to be nonteratogenic. Even the few conflicting reports showed that the incidence of minor anomalies such as cleft palate is only minimally increased compared with the general population. Perinatal usage increases the risk of low birth weight, preterm labor and spontaneous abortion. Moreover, peripartum exposure is associated with withdrawal and toxicity symptoms [48].

#### *5.4.3. Antiepileptic agents*

Antiepileptic drugs are now commonly used in pain management, particularly for the treatment of neuropathic pain such as, trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, post-stroke pain, phantom limb pain and pain after spinal cord injuries. Majority of studies have reported significant fetal morbidity due to in-utero exposure that including major anomalies like neural tube defects, congenital heart abnormalities, and urinary tract defects, skeletal abnormalities, cleft palate and impaired cognitive and motor development [49, 50]. Pregabalin, which is very commonly prescribed for chronic neuropathic pain, has a better safety profile than other antiepileptics. However, it is still associated with a higher risk for malformation than in the general population [51].

#### *5.4.4. Antipsychotic agents*

In recent times, Olanzapine, the atypical antipsychotic, has been gaining popularity in chronic pain management. A majority of studies report Olanzapine as nonteratogenic and not associated with spontaneous abortions or major congenital malformations. Nevertheless, it has been associated with an increase in birth weight [52].

pregnancy. In addition, meta-analyses have suggested that any superiority of acupuncture over sham acupuncture is not clinically significant [61, 62]. The literature does not suggest any absolute contraindications to acupuncture, but relative contraindications are similar to other needling techniques used for the treatment of pain. The incidence of serious adverse risks is rare (estimated to be 0.05 per 10,000 treatments) and is generally associated with poorly trained or unlicensed acupuncturists. The two most common adverse risks reported in one study were needling pain (3.3%) and hematoma (3.2%). Other risks include bruising, syncope, exacerbation of symptoms, paresthesia, infection, retained needle, and damage to surrounding tissues [63]. Two studies have commented on the adverse effects of acupuncture during pregnancy, and both suggest that, provided the practitioner avoid locations associated with the cervix and uterus, acupuncture is safe for both the mother and the fetus [64]. Despite the lack of evidence for the efficacy of acupuncture, the overall consensus is that acupuncture's benefits outweigh its risks, and that a trial of acupuncture can be considered in interested

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Botulinum toxin has been reported safe during the first trimester of pregnancy [65]. Although research for the use of Botox as a treatment for several chronic pain syndromes (e.g., myofascial pain, neuropathic pain) is promising, the only FDA-approved indications of Botox (serological types A and B) related to the treatment of chronic pain conditions are spasticity and chronic migraine. Evidence suggests that Botox is effective in providing pain relief for several months as a result of its long half-life [66]. Animal studies have shown some fetal damage, but the risk is uncertain in humans due to lack of sufficient evidence. Botox is classified by the FDA as a pregnancy category C drug. The current recommendation by the FDA is that Botox should be "*administered during pregnancy only if the potential benefits justifies the potential risk to the fetus.*" In addition, other more conservative treatments should be exhausted first. If Botox is considered, the risk and benefits should be acknowledged by the patient prior

Radiofrequency ablation (RFA) is a process of nerve destruction via radiofrequency-generated heat by insertion of a catheter or electrode close to the target nerve under fluoroscopic guidance, confirming the correct location through sensory and motor testing, and applying a preset temperature for a fixed time period. This aims for neuromodulation of pain pathway by disruption of the transmission of nerve impulses from the pain generators to the central nervous system. The most common application of RFA is for the treatment of facet joint pain. Other applications include discogenic pain, radicular pain, and sacroiliac pain. Generally, a diagnostic and therapeutic block with local anesthetic with or without steroid is required to proceed with RFA. Current evidence suggests that RFA treatment has a modest, short-term benefit at best, with no long-term pain improvement, as supported by a recent meta-analysis

patients when the availability of other safe treatment options is limited.

**6.3. Botulinum toxin**

to proceeding.

**7. Interventions for pain management**

**7.1. Radiofrequency ablation**

#### **6. Non-pharmacological management**

#### **6.1. Physical therapy**

Physical therapy has been one of the cornerstones of chronic pain treatment, replacing the original approach of rest. Activities are aimed at restoring flexibility, strength, and endurance, as well as reducing the severity of chronic pain through modulation of the biochemical processes within the body [30, 53]. Numerous physical therapy programs exist (e.g., aerobic, yoga, tai chi, strength, pilates, flexibility, and range of motion), and each one differs in frequency, intensity, and design. Despite the high utilization of physical therapy and several studies that have demonstrated its benefits in chronic pain, the effectiveness of physical therapy is unclear and current high-quality evidence to support such claims are lacking [53–56]. Absolute contraindications are myocardial infarction, ongoing unstable angina, and severe aortic stenosis [56]. Adverse effects of physical therapy are rare with musculoskeletal injury being the most common. Other potential adverse events include pain exacerbations, soreness, rhabdomyolysis, dehydration, hypo- and hyperthermia, and cardiac and respiratory events [57]. Importantly, neither the AHA nor the systemic reviews site pregnancy as an absolute or relative contraindication to physical therapy. Currently, the consensus is that the potential benefits of physical activity in pain relief, and improved quality of life outweigh its risks. For maximum effectiveness and minimum adverse effects, the evidence suggests that supervised and structured program schedules are superior to self-supervised and varying program schedules [53]. Moreover, adding a specifically tailored training to a standard physical exercise has less disability and more functional recovery at 2 years postpartum in comparison with physical exercise alone [58].

#### **6.2. Acupuncture**

Acupuncture is a technique where needles or other modalities are used to stimulate predetermined locations throughout the body to promote the flow of 'Qi' and rebalance the body's energy. Although the practice originated in China thousands of years ago, the specific mechanism of action has yet to be uncovered. Current theories suggest that acupuncture boosts the body's intrinsic neuropeptide pathways, including endogenous opioids. However, these effects appear to be short term and do not explain the longer term benefits of acupuncture [59]. Due to the heterogeneity of acupuncture techniques, outcomes are hard to study and compare. A few studies have shown benefits, including several randomized controlled trials which demonstrated acupuncture to be an effective alternative to pharmacologic treatment [60]. However, these studies focused on labor-related pain and not chronic pain during pregnancy. In addition, meta-analyses have suggested that any superiority of acupuncture over sham acupuncture is not clinically significant [61, 62]. The literature does not suggest any absolute contraindications to acupuncture, but relative contraindications are similar to other needling techniques used for the treatment of pain. The incidence of serious adverse risks is rare (estimated to be 0.05 per 10,000 treatments) and is generally associated with poorly trained or unlicensed acupuncturists. The two most common adverse risks reported in one study were needling pain (3.3%) and hematoma (3.2%). Other risks include bruising, syncope, exacerbation of symptoms, paresthesia, infection, retained needle, and damage to surrounding tissues [63]. Two studies have commented on the adverse effects of acupuncture during pregnancy, and both suggest that, provided the practitioner avoid locations associated with the cervix and uterus, acupuncture is safe for both the mother and the fetus [64]. Despite the lack of evidence for the efficacy of acupuncture, the overall consensus is that acupuncture's benefits outweigh its risks, and that a trial of acupuncture can be considered in interested patients when the availability of other safe treatment options is limited.

#### **6.3. Botulinum toxin**

*5.4.4. Antipsychotic agents*

84 Pain Management in Special Circumstances

**6.1. Physical therapy**

been associated with an increase in birth weight [52].

**6. Non-pharmacological management**

comparison with physical exercise alone [58].

**6.2. Acupuncture**

In recent times, Olanzapine, the atypical antipsychotic, has been gaining popularity in chronic pain management. A majority of studies report Olanzapine as nonteratogenic and not associated with spontaneous abortions or major congenital malformations. Nevertheless, it has

Physical therapy has been one of the cornerstones of chronic pain treatment, replacing the original approach of rest. Activities are aimed at restoring flexibility, strength, and endurance, as well as reducing the severity of chronic pain through modulation of the biochemical processes within the body [30, 53]. Numerous physical therapy programs exist (e.g., aerobic, yoga, tai chi, strength, pilates, flexibility, and range of motion), and each one differs in frequency, intensity, and design. Despite the high utilization of physical therapy and several studies that have demonstrated its benefits in chronic pain, the effectiveness of physical therapy is unclear and current high-quality evidence to support such claims are lacking [53–56]. Absolute contraindications are myocardial infarction, ongoing unstable angina, and severe aortic stenosis [56]. Adverse effects of physical therapy are rare with musculoskeletal injury being the most common. Other potential adverse events include pain exacerbations, soreness, rhabdomyolysis, dehydration, hypo- and hyperthermia, and cardiac and respiratory events [57]. Importantly, neither the AHA nor the systemic reviews site pregnancy as an absolute or relative contraindication to physical therapy. Currently, the consensus is that the potential benefits of physical activity in pain relief, and improved quality of life outweigh its risks. For maximum effectiveness and minimum adverse effects, the evidence suggests that supervised and structured program schedules are superior to self-supervised and varying program schedules [53]. Moreover, adding a specifically tailored training to a standard physical exercise has less disability and more functional recovery at 2 years postpartum in

Acupuncture is a technique where needles or other modalities are used to stimulate predetermined locations throughout the body to promote the flow of 'Qi' and rebalance the body's energy. Although the practice originated in China thousands of years ago, the specific mechanism of action has yet to be uncovered. Current theories suggest that acupuncture boosts the body's intrinsic neuropeptide pathways, including endogenous opioids. However, these effects appear to be short term and do not explain the longer term benefits of acupuncture [59]. Due to the heterogeneity of acupuncture techniques, outcomes are hard to study and compare. A few studies have shown benefits, including several randomized controlled trials which demonstrated acupuncture to be an effective alternative to pharmacologic treatment [60]. However, these studies focused on labor-related pain and not chronic pain during Botulinum toxin has been reported safe during the first trimester of pregnancy [65]. Although research for the use of Botox as a treatment for several chronic pain syndromes (e.g., myofascial pain, neuropathic pain) is promising, the only FDA-approved indications of Botox (serological types A and B) related to the treatment of chronic pain conditions are spasticity and chronic migraine. Evidence suggests that Botox is effective in providing pain relief for several months as a result of its long half-life [66]. Animal studies have shown some fetal damage, but the risk is uncertain in humans due to lack of sufficient evidence. Botox is classified by the FDA as a pregnancy category C drug. The current recommendation by the FDA is that Botox should be "*administered during pregnancy only if the potential benefits justifies the potential risk to the fetus.*" In addition, other more conservative treatments should be exhausted first. If Botox is considered, the risk and benefits should be acknowledged by the patient prior to proceeding.

#### **7. Interventions for pain management**

#### **7.1. Radiofrequency ablation**

Radiofrequency ablation (RFA) is a process of nerve destruction via radiofrequency-generated heat by insertion of a catheter or electrode close to the target nerve under fluoroscopic guidance, confirming the correct location through sensory and motor testing, and applying a preset temperature for a fixed time period. This aims for neuromodulation of pain pathway by disruption of the transmission of nerve impulses from the pain generators to the central nervous system. The most common application of RFA is for the treatment of facet joint pain. Other applications include discogenic pain, radicular pain, and sacroiliac pain. Generally, a diagnostic and therapeutic block with local anesthetic with or without steroid is required to proceed with RFA. Current evidence suggests that RFA treatment has a modest, short-term benefit at best, with no long-term pain improvement, as supported by a recent meta-analysis [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 treatments and an informed discussion with the patient.

**8. Special topics in pregnancy**

**8.1. Opioid use disorder in pregnancy**

criteria within a **12-month** period [78].

• **Craving**, "strong desire or urge" to use opioids

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

plan.

• **Tolerance** • **Withdrawal**

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**

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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

Opioid use disorder (**OUD**)—DSM-5 Diagnosis by at least **2** criteria over **12** months. • **Opioids intake** in larger amounts or over a longer period than was intended

• A persistent **desire** or unsuccessful efforts to cut down or control opioid use • A great deal of **time** is spent to obtain, use or recover from the opioid • **Failure** to fulfill **major role** obligations at work, school, or home • **Recurrent opioid use** in physically hazardous situations • **Reduction in important** social, or recreational activities.

despite the opioid related social or interpersonal problems

• **Continued opioid** use despite the opioid related physical or psychological problem **Continued opioid** use

#### **7.2. Transcutaneous electrical nerve stimulation**

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 pregnancy.
