The management of pregnancy and delivery of a woman on opiate-substitution therapy with buprenorphine requires a coordinated team approach by social services, addiction medicine, obstetrics, and pediatrics. Her obstetrical care is further complicated by the unique pharmacology of buprenorphine and the issues of pain management. Obstetrical providers should be familiar with the complex issues surrounding the optimal care of these women.
An estimated 2.25 million people in the United States are dependent on or abusing opiates. Women have a higher rate than men for addiction to prescription pain relievers. Substance abuse admissions for the treatment of prescription opiate addiction have increased nearly 4-fold since 1998. Among women aged 15-44 years, 10.6% used illicit drugs in the past month based on 2008-2009 self-reported survey data. Among women 15-25 years old, the use was higher, 7.1-15.8%. The rate was considerably lower in those who were pregnant (4.5%), but a substantial and very likely increasing number of women continue to use drugs in the peripartum period.
The general management of opiate dependency inside or outside pregnancy is grounded on psychosocial treatment including: self-help and 12 step groups, individual and group substance abuse counseling, and psychotherapy. To minimize or eliminate exposure to infectious diseases, reduce the risk of accidental overdose, and support a therapeutic environment conducive to recovery, opiate detoxification followed by abstinence or opiate-substitution maintenance is recommended. In the United States, methadone and buprenorphine are the only opiate-substitution medications approved for the treatment of opiate addiction. Both also have been used for medically supervised opiate withdrawal and detoxification, but results are disappointing because long-term abstinence is low. For the majority of opiate-addicted women, opiate-substitution programs combined with psychosocial treatment offer the best chance of stabilization of their addiction and opportunity for a sustainable recovery.
Opiate-substitution programs provide methadone through designated licensed clinics or buprenorphine through specifically trained and federally waivered physicians. Increasing demand for the treatment of opiate addiction has driven the buprenorphine/naloxone combination (Suboxone; Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA) to the 41st most prescribed drug in the United States in 2009, a year in which annual sales increased 68.1% to 5.7 million prescriptions. Prescriptions of buprenorphine monotherapy (Subutex [Reckitt Benckiser Pharmaceuticals, Inc.] and generic), used primarily for the treatment of pregnant women, numbered approximately one-third million in 2009.
During pregnancy, methadone (category B) is the recommended substitution treatment for opiate addiction and is considered the standard of care. If methadone treatment is refused or unavailable, then opiate-substitution management with buprenorphine may be considered after informed consent is obtained and the risk of inadequate experience in pregnancy is clearly documented. The literature that reports buprenorphine maintenance in pregnancy is limited but growing, and buprenorphine has recently been advocated as a first-line therapy.
There are 6 studies that report comparisons between buprenorphine and methadone-treated pregnant women and their infants. Compared with methadone, buprenorphine-treated pregnant women had similar cesarean section rates, maternal weight gain, and number of prenatal visits. Medical complications were lower in buprenorphine-treated women, and overdoses were less frequent than with methadone. Retention rates until delivery were variable. Rates of neonatal abstinence syndrome were the same as or lower in the buprenorphine group and hospitalizations shorter. Birthweights were similar or higher for infants in the buprenorphine group, whereas Apgar scores were not significantly different. Duration of newborn hospitalization was significantly shorter in the buprenorphine-treated group.
The available evidence supports the use of buprenorphine in the treatment of opioid-addicted pregnant women. It appears to be a suitable alternative to methadone in the maintenance of maternal addiction, with most researchers reporting a shorter and milder abstinence syndrome in the neonate.
Barriers to treatment
There are a number of barriers to the management of opiate abuse in pregnancy. The social stigma, guilt, and shame of ongoing drug addiction during pregnancy may pressure the woman into attempting to quit using opiates on her own or denying or hiding the problem until delivery. One fear is that seeking treatment for her opiate addiction will result in mandatory reporting and attract the attention of government social service and health authorities. Interventions, including the monitoring of herself, her partner, and the condition of her other children, are not always welcome. Poor self-esteem, a low level of education, and legal problems are common in opiate users and interfere with self-reporting and seeking assistance.
Economic barriers include the cost of missed employment to attend rehabilitation sessions in addition to child care and transportation expenses. Housing security is often tenuous and staying with friends or being homeless may place the women back into the drug subculture they are trying to escape.
The partner’s continued use of illicit drugs can be an insurmountable problem because the woman may be caught between the need for emotional and financial support with the continued temptation to relapse and the risk of social service intervention to remove a drug user from the household. Ongoing mental and physical abuse may complicate the relationship. Family dysfunction may include addicted future grandparents. There is also a higher prevalence of psychiatric disease and chronic medical illnesses in this population. Posttraumatic stress disorder because of prior sexual abuse is common among opiate users.
In some areas access to opiate-substitution therapy is limited by distance, waiting lists, or a shortage of licensed buprenorphine prescribers. Pregnant women can expect priority acceptance into most treatment programs. Opiate-addicted maternal-infant dyads should be delivered in a medical center with physicians and nurses experienced in their assessment and management. Treatment compliance and pregnancy outcomes are improved when addiction and obstetrical care are delivered at the same location.
Screening
Women are often reluctant to reveal their opiate use or addiction during the initial obstetrical intake screening visit. Providers may be unfamiliar with diagnostic and treatment options and hesitant to question the patient about drug use. An accepting open-ended interview may facilitate eliciting a history of a drug problem. Other risk factors for drug abuse are given in Table 1 . After patient consent has been obtained, routine urine toxicology and opiate confirmation testing is advisable for all women. A search of a state-supported database of controlled substance prescriptions may identify women who have received multiple opiate and/or controlled substance prescriptions that may be at risk.
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Cigarette smoking is very common among opiate addicted women (65-100%). Women may be motivated to quit when they learn that neonatal abstinence syndrome may be more severe and prolonged in infants born to mothers who smoke. Hepatitis B and C and human immunodeficiency virus (HIV) counseling and serology should be included in the routine prenatal laboratory testing and repeated in the third trimester if indicated.
Initiating treatment
Once screening is completed, women should be offered immediate and appropriate referral for substance abuse treatment. Most are already in the contemplation stage of behavior change and are readily motivated to take appropriate action. Detoxification from opiates is not generally recommended during pregnancy. Rather, opiate-substitution therapy using methadone or buprenorphine on a residential or outpatient basis combined with intensive group and individual counseling and social service support is recommended.
Where to refer a woman depends on community resources and individual patient preference. Methadone maintenance clinics require daily attendance to receive medication, often in a public setting, which allows contact with other drug abusers and an opportunity to engage in illicit activities.
Buprenorphine potentially offers greater privacy because it can be prescribed during a physician’s office visit and may be combined with routine obstetrical care and substance-abuse counseling. Buprenorphine in usual doses (8-16 mg daily) is as effective as methadone (60 mg) in preventing relapse but not as effective as high-dose methadone (120 mg), which is customarily used in treating addiction. Women with a long-standing addiction to high-dose intravenous opiates are at higher risk for relapse and should be considered for referral to a methadone clinic, whereas those abusing opiates orally or intranasally often are successful on buprenorphine. Release of information consent forms should be signed by the patient to authorize communication with all other medical, psychiatric, and social service providers. Mandated reporting to the state’s child protective agency is best accomplished with the mother’s agreement and presence during the actual contact.
Pharmacology of buprenorphine
Buprenorphine is a partial agonist for the mu-opioid receptor. Table 2 lists the buprenorphine preparations used in the treatment of opiate addiction. In clinical practice, buprenorphine is often combined with naloxone (Narcan; Endo Pharmaceuticals, Chadds Ford, PA), a mu-opioid antagonist, which is inactive when taken as prescribed (dissolved under the tongue). The addition of naloxone prevents misuse by intravenous injection. However, the consensus is that naloxone should be avoided during pregnancy.
| Drug name | Constituents | Notes |
|---|---|---|
| Suboxone |
| Sublingual tablets and film in child-resistant packet |
| Subutex | Buprenorphine 8 mg and 2 mg | Sublingual tablets |
| Buprenorphine | Buprenorphine 8 mg and 2 mg generic |
|
| Probuphine | Buprenorphine 80 mg |
|
Buprenorphine has a very high affinity but low intrinsic activity for the mu receptor and can precipitate withdrawal symptoms in opiate addicts by displacing morphine, methadone, and other opiates. Because of this high affinity (1000 times that of morphine), opiates cannot displace buprenorphine, and therefore, their euphoric effects are blocked. Buprenorphine has a slow dissociation from the mu-opioid receptor and can be given daily or even every other day, although every-other-day therapy is not advised in pregnancy. A typical daily dose of 10-16 mg occupies most mu receptors. Dosage requirements may increase moderately during pregnancy.
Buprenorphine produces typical opioid effects but is limited by a ceiling of 24-32 mg, which makes a lethal overdose from respiratory depression less likely in opiate-dependent individuals. This safety margin is lost when buprenorphine is combined with alcohol or benzodiazepines. In opiate-naïve subjects, 0.4 mg of buprenorphine every 6 hours is adequate for pain relief. The injectable preparation of buprenorphine (Buprenex; Reckitt Benckiser Pharmaceuticals Inc.) and the transdermal (Butrans; Purdue Pharma L.P., Stamford, CT) are indicated only for pain relief in the opiate-naïve patient and not approved for the treatment of opiate addiction. A depo-buprenorphine (Probuphine; Titan Pharmaceuticals, Inc., South San Francisco, CA) subcutaneous implant is under study.
Metabolism of buprenorphine is by CYP3A4-mediated N-dealkylation to norbuprenorphine, a metabolite with weak opioid potency. Both then undergo glucuronidation. Drugs that inhibit CYP3A4 such as protease inhibitors for HIV treatment and azole antifungals such are fluconazole will increase buprenorphine plasma levels. CYP3A4 inducers, including many seizure medications and rifampin, may decrease buprenorphine levels.
Prenatal care
Along with routine prenatal care, an expectant mother treated with buprenorphine requires additional coordination of services for optimal maternal-fetal management. Social services, community health nursing, substance abuse counseling, the obstetrical and pediatric providers, and the buprenorphine physician-prescriber must all be in regular communication. Opiate abusers are at high risk for obstetrical complications, and although opiate-replacement therapy reduces some of these risks, multiple-drug abuse is common early in rehabilitation and may continue throughout the pregnancy. As in other high-risk pregnancies, frequent visits are indicated. One small study with 12 patients reported decreased positive urine toxicology screens and increased birthweights in 6 women who received enhanced treatment with weekly prenatal care and rewards for negative urine screens. Guidelines for the prenatal care of buprenorphine-treated women are provided in Table 3 . Nonstress tests show increased fetal heart rate variability and more accelerations in the buprenorphine-treated fetus than in those whose mothers receive methadone.
| Intake screening: tuberculoses skin testing if appropriate | |
| Routine laboratory testing plus hepatitis B, C, and HIV | |
| Each visit: |
|
| 15-20 wks: | Ultrasound for abnormalities |
| 24-32 wks: |
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