When opiate abuse complicates pregnancy

Dr. Prasad is an assistant professor, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wexner Medical Center, The Ohio State University, Columbus. She reports no conflict of interest with respect to the content of this article.

When women learn that they are pregnant, they tend to stop drinking caffeine and alcohol, stop smoking, and even stop coloring their hair. Why, then, would any pregnant woman choose to continue to expose her unborn child to drugs?

Drug use rarely starts during pregnancy. More often, women enter pregnancy already abusing or dependent on drugs. The risks of such exposures to the fetus are well known. Incidence of neonatal abstinence syndrome (NAS), which is opiate withdrawal, rose 300% between 2000 and 2009.¹ Risks of prenatal opiate exposure are not limited to the fetus. The Centers for Disease Control and Prevention recently reported that deaths from opiate overdose among women have increased 400% since 1999 (compared to 265% among men).

This translates to about 18 women dying per day, and for every woman who dies, 30 are treated in emergency departments for painkiller misuse or abuse.² The stigma associated with drug abuse and limited resources available to physicians make tackling this problem difficult. Pregnancy, however, may be the point of entry to the healthcare system that allows us to initiate the process.

Screening for opiate abuse

Ob/gyns are well positioned to screen patients for substance abuse and dependence and offer intervention because of the impact that the problem has on women. Substance-abusing patients come from all socioeconomic strata, racial and ethnic groupings, and ages; therefore, screening methods targeted toward “high-risk” patients will invariably fail to identify all women in need of services.^3,4

Despite the adverse outcomes associated with exposure to tobacco, alcohol, and illicit drugs, only approximately 20% of ob/gyns effectively screen patients for illicit drug use.⁵ Barriers to screening include physician embarrassment with posing appropriate questions, fear that patients will change practitioners if they are offended by the questions, and uncertainty about where to turn when a woman screens positive.

Many general instruments exist for screening pregnant women for substance abuse. The 4Ps Plus, for example, is a 5-question screening instrument that has been validated for use in identifying substance abuse in pregnancy with a sensitivity of 87% and specificity of 76%.⁶ Questions include:

• Did your parents have trouble with drugs?

• Does your partner have a problem with drugs or alcohol?

• Have you ever drunk beer, wine, or liquor in the month before you knew you were pregnant? How many cigarettes did you smoke?

• In the month before you knew you were pregnant how much beer/wine/liquor did you drink?⁶

Another such instrument is the CAGE-AID screening questionnaire (below).⁷

A single “yes” response renders 79% sensitivity and 77% specificity for identifying drug abuse.⁷ Again, the detection of drug abuse is considered to be clinically important. Although single-item screening has not been validated specifically in pregnancy, physicians may consider simply asking, “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” In the primary-care setting a positive response to this single question is 100% sensitive and 74% specific for a drug use disorder.⁸

Biochemical screening can be used as an adjunct to such self-report screening tools. Samples that can be tested include urine, blood, hair, saliva, and sweat. Urine is the most accessible and simple, but assessment of substance abuse by biochemical screening alone is not without limitations. Negative tests do not rule out substance abuse and positive tests do not identify how much drug is used. The American College of Obstetricians and Gynecologists (ACOG) does not endorse biochemical screening as a sole method of detecting substance abuse during pregnancy.⁹ If performed, full consent should first be obtained.

The neonate can be screened for in utero drug exposure by testing meconium and urine. Universal meconium screening (reflective of drug exposure in the weeks prior to delivery) is a strategy sometimes applied in locations where opiate abuse is highly prevalent. As with maternal screening, ethical issues surrounding the population that is tested (eg, universal or targeted) and disclosure of results must be carefully evaluated.⁹

The most effective approach to screening for substance abuse during pregnancy may be through a series of nonjudgmental questions. ACOG recommends that all pregnant women be questioned thoroughly regarding substance abuse. Universal, structured self-reported screening for substance abuse will make ob/gyns more comfortable with this discussion, reduce interviewer bias, and reduce the stigma associated with substance use and abuse.

In addition, it allows for brief intervention, which may have an important effect on pregnancies ex posed to substance abuse.⁹

Brief intervention

Evidence for the effectiveness of brief interventions such as SBIRT (Screening, Brief Intervention, and Referral to Treatment) in reducing risky drug use is not as robust as has been demonstrated in reducing risky alcohol consumption, but it is accumulating and promising.¹⁰ The point of brief intervention is to seize the moment when substance abuse is identified, and in a time-limited, structured, goal-directed way, reduce the risk of harm from continued use of substances. Examples of brief interventions include asking clients to try nonuse to see if they can stop on their own, encouraging interventions directed toward attending a self-help group such as Alcoholics Anonymous or Narcotics Anonymous, and engaging in efforts to help pregnant patients stop using.¹¹

The 6 elements critical for effective brief interventions can be recalled by the acronym FRAMES:

Feedback about personal risk or impairment;

Responsibility for change placed on the participant;

Advice given by the provider;

Menus of alternative or self-help treatment options offered to the participant;

Empathetic counseling style; and

Self-efficacy or optimistic empowerment.¹¹

The goal of intervention for pregnant women found to be substance dependent is to recommend the optimal behavior change and level of care. In the setting of opiate abuse, opiate maintenance along with counseling and self-help are appropriate.

Opioid abuse and its effects

A wide variety of opiates are abused including heroin, methadone, and oxycodone. Abuse of any of these agents carries risks of adverse pregnancy outcomes. Opiates can be inhaled, injected, snorted, ingested, or used subcutaneously (“skin popping”). The term “speed-balling” refers to combined use of opiates and cocaine. Oxycodone derivatives intended for sustained release contain 20 times the normal amount of active ingredient. When crushed, the slow-release polymer is destroyed and the product can then be swallowed, snorted, or injected, with results similar to the heroin high.¹² Urine toxicology will identify opiate metabolites (morphine, codeine, methadone) for 1 to 3 days after use, but screening should occur with maternal consent and education.¹³

In 2010, an estimated 140,000 people began using heroin.¹⁴ Pregnant women are uniquely vulnerable to the impact of opiate abuse: opiates are exceedingly addictive, trading sex for drugs is common, heroin use is strongly associated with the behaviors of a male partner, women tend to initiate use earlier in life than men, and their transition from use to abuse is more rapid.¹⁴

Opiates exert their effect by binding to the mu-opioid and kappa-opioid receptors found in the limbic and limbic-related areas of the brain. Like most drugs of abuse, the addictive response is mediated by dopamine. After binding to opiate receptors a signal is sent to dopamine terminals to release dopamine. Dopamine then binds dopamine receptors, stimulates the postsynaptic cell, and results in a positive emotional response.

Opiate pathways play a role in reward and reinforcement, modulation of response to pain and stress, and homeostatic regulation. While mu-opioid receptors produce analgesia, euphoria, and miosis, and reinforce the reward behavior, kappa-opioid receptors produce the subjective sensation of dysphoria, spinal analgesia, sedation, and miosis.¹² Opiates are highly addictive, and once used, the likelihood of transition to abuse is significant. Recovery success rates are not encouraging: 71% of users relapse within 6 weeks of nonmedication rehabilitation efforts.¹⁵

Opioid maintenance with methadone

In an ideal world abstinence from drugs and medications would be a goal. At present, however, opioid detoxification’s role in pregnancy is minimal. Detoxification via opiate taper in pregnancy does not appear to have obvious adverse effects, but miscarriage, preterm birth, meconium passage, stillbirth, and elevated epinephrine and norepinephrine levels are found in case reports.^16-18 The major reason not to attempt detoxification is that it is generally unsuccessful, with relapse rates of 50% or more.¹⁹ If attempted, it is best to wait until the end of the first trimester because limited data suggest that miscarriage rates may be higher in the first trimester.¹⁹

If attempting detoxification late in the third trimester, antenatal surveillance should be undertaken. Only a single study has compared various detoxification regimens in pregnancy to a methadone maintenance (MM) comparison group.²⁰ The 5 participant groups in that study were those receiving 3-day methadone-assisted withdrawal (MAW) alone (n=67), 3-day MAW followed by MM (n=8), 7-day MAW alone (n=28), 7-day MAW followed by MM (n=20), and a continuous MM sample (n=52). On average, patients in the 3 MM groups remained in treatment longer, attended more obstetric visits, and delivered at the program hospital more often than the patients in the 2 MAW-alone groups. The researchers concluded that MM should be considered as primary treatment for opioid-dependent pregnant women.²⁰

Fortunately, treatment is available for opiate maintenance, both to decrease the impact of high-risk activities and to improve neonatal outcomes. The classic opiate maintenance drug is methadone, a full mu-opioid agonist and weak N-methyl-D-aspartate (NMDA) receptor antagonist, metabolized by the cytochrome P 450 system. It has many favorable qualities: high bioavailability, long half-life, low cost, convenient (daily) dosing, and slow onset to withdrawal syndrome. It has been used for more than 40 years to treat opiate addiction and has demonstrated benefits in deterring high-risk behaviors, incarceration, and spread of infectious disease.²¹

Methadone maintenance therapy for addiction occurs in US federally funded opiate maintenance programs. In this setting, patients are dosed daily and participate in counseling and drug screening per the regulations of the facility. Such MM programs are not widely available, and transportation issues and need for daily compliance may be barriers to participation.

In spite of potential challenges, the benefits of MM have been demonstrated in the pregnant population. Methadone maintenance has been associated with earlier and more-compliant prenatal care, improved nutrition and weight gain, fewer children in the foster system, and improved enrollment in substance abuse treatment and recovery programs. Pregnant women remain opiate dependent, but generally become more functional.²² The goal of treatment is to provide sufficient dosing to prevent drug cravings, eliminate illicit use, and keep additional opiates from creating euphoria.

The model of use of opiate maintenance in pregnancy is that of harm reduction, rather than elimination through abstinence. There is no ceiling of benefit to dosing methadone. Because it is a full mu-opioid agonist, increasing doses offer increasing benefit. The average MM dose needed to achieve clinical stability is between 80 and 120 mg daily.²³ A dose lower than 60 mg is believed to be insufficient to prevent drug-seeking behavior. Due to the physiology of pregnancy, split dosing is sometimes recommended.

Opioid maintenance with buprenorphine

In addition to methadone, buprenorphine has been gaining recognition as a treatment for opioid addiction during pregnancy. Buprenorphine is a synthetic opioid and partial mu-opioid agonist with a very high affinity for the mu-opioid receptor. It can therefore displace circulating opiates. It disassociates slowly from the receptor and is unlikely to be displaced by other competing opiates. A ceiling effect of buprenorphine benefit is believed to exist; dosing beyond 24 to 32 mg daily may not have any additional benefits. The autonomic withdrawal associated with buprenorphine is said to be less significant than with other opiates. Buprenorphine demonstrates favorable qualities similar to methadone, such as decreasing drug cravings with daily dosing, with the additional benefit of being prescribed by specifically certified physicians as opposed to federally funded clinics. This benefits patient autonomy and opiate maintenance.

In pregnancy, buprenorphine alone is favored over buprenorphine/naloxone because of lack of data regarding the combination product, and concerns that naloxone may produce maternal and subsequently fetal hormonal changes.^24,25 The naloxone component was added to limit the abuse potential of buprenorphine, because when the combination is taken sublingually naloxone is not bioavailable and does not accumulate to clinically significant concentrations. If buprenorphine/naloxone is injected or snorted, however, it will precipitate withdrawal in opioid-dependent individuals. We routinely use the combination in our clinics, and data are forthcoming regarding the relative safety of its use. Nevertheless, until more research is available use of buprenorphine alone remains standard for pregnant patients despite its high abuse potential.

Numerous comparisons of methadone and buprenorphine have been performed to assess their efficacy in the treatment of opioid dependence in pregnancy.²⁶ Because withdrawal symptoms associated with buprenorphine are purportedly less intense than with methadone, researchers sought to determine the impact of methadone versus buprenorphine on NAS.²⁷ The 2010 MOTHER (Maternal Opioid Treatment: Human Experimental Research) study found that buprenorphine was associated with significantly lower doses of morphine for treatment of NAS, shorter duration of treatment, and shorter hospital stay than methadone.²⁷ This report has had a significant impact on the treatment of opiate dependence in pregnancy, and use of buprenorphine for the treatment of opiate maintenance in pregnancy is increasing.

Neonatal aspects

A recent literature review of comparisons of methadone and buprenorphine supports 3 conclusions. First, buprenorphine produces a less-severe NAS than does methadone. Second, buprenorphine’s efficacy in the treatment of opioid dependence during pregnancy does not negate methadone’s utility in this regard, because no single treatment will likely be maximally effective for all patients. Finally, more research on the long-term effects of buprenorphine and methadone is needed.  

No obvious embryopathy has been attributed to opiate exposure, but NAS is a risk for all opiate-exposed babies. Seen in 40% to 90% of methadone-exposed babies and characterized by central nervous system irritability, respiratory distress, gastrointestinal dysfunction, and autonomic instability, NAS is treated most commonly with opiates (morphine/methadone), but phenobarbital can also be used.28 The decision to treat an infant is standardized by adherence to measurement instruments such as the Finnegan NAS measure.²⁹ The usual onset of NAS is in days 2 to 3 of life. Duration of therapy depends on neonatal response and ranges from days to weeks. depending upon response to treatment.

Debate is ongoing on the role that methadone dose plays in the development of NAS. Several authors have reported that higher doses of methadone have no impact on the severity of NAS.^30-33 Conversely, others have published that dose does matter.^34-36 The most comprehensive literature review, using 29 reports, concluded that “Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy.”³⁷ Thus, providers should be focused on treating the pregnant patient with a methadone dose that is most effective in preventing her use of other opioids. “Effective” implies that the mother is free of illicit drugs, so elimination of drug cravings is a key component of therapy. The difficulty of dosing methadone during pregnancy is that pregnancy-associated somatic complaints (musculoskeletal pains, nausea, sleeplessness, anxiety, irritability) can mimic suboptimal dosing. In addition, the physiology of pregnancy, with associated decreased absorption, rapid elimination, and higher clearance of drug, may mandate higher doses at the end.

Breastfeeding

Advice regarding breastfeeding and opioid intake needs to take into consideration whether the mother is abusing an opioid and is not otherwise receiving opioid-agonist pharmacotherapy treatment or is in opioid-agonist treatment with methadone or buprenorphine. Women who abuse heroin or prescription opioids and nurse run the risk of exposing their infants to levels of opioids high enough to cause tremors, restlessness, vomiting, poor feeding, and even addiction. The general advice in that case should be to avoid breastfeeding. In contrast, women who are in opioid-agonist treatment with methadone or buprenorphine should be encouraged to breastfeed because research has clearly demonstrated that methadone and buprenorphine concentrations in breast milk are low. For doses of methadone 50 to 105 mg daily, the neonatal dose is less than 0.2 mg per day, unlikely to have any clinical effect.³⁸ Therefore, breastfeeding should be recommended for agonist-maintained women unless contraindicated by existing medical conditions (eg, HIV). Cessation of breastfeeding is not likely to precipitate withdrawal because mothers do not generally abruptly stop nursing their infants.

Summary

Opiate abuse in pregnancy is highly prevalent, and if we pursue appropriate screening, cases will be identified that require brief intervention and referral to treatment. Leveraging community resources will empower us to more aggressively treat the problem.

Acknowledgment: The author wishes to acknowledge Hendree Jones, PhD, for her continued guidance and mentorship in the care of substance-abusing pregnant women.

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