Effects of Buprenorphine in Pregnancy

Data on the pharmacokinetics of buprenorphine in pregnant women and neonates are extremely limited (Johnson et al. 2003a ; Marquet et al. 1997). Likewise, data are limited regarding the clinical use of buprenorphine for the maintenance treatment of opioid addiction in pregnant women. The literature in this area generally consists of case reports and a small number of prospective studies; there have been no controlled clinical trials. In case reports from European and Australian sources on the use of buprenorphine in opioid‐addicted pregnant women, doses have ranged from 0.4 to 24 mg per day. In these limited reports, pregnancies have generally progressed normally, with low rates of prematurity or other problems. Maternal clinical laboratory data in these reports generally have been within normal limits; or were deemed either clinically nonsignificant at levels expected during pregnancy, when outside normal limits, or were due to factors other than the medication. For a complete review of the published literature on the use of buprenorphine in the treatment of opioid addiction in pregnant women, see (Johnson et al. 2003a ).

Infants of Mothers Treated With Buprenorphine

Buprenorphine and its metabolite norbuprenorphine have been found in high concentrations in the blood, urine, and meconium of the neonates of women maintained on buprenorphine (Johnson et al. 2003a ; Marquet et al. 1997).

The published literature includes information on at least 309 infants born to women maintained on buprenorphine treatment. Although not systematically studied, a neonatal abstinence syndrome (NAS) has been reported in 191 of these 309 infants, with approximately one‐half of those with NAS requiring treatment. In more than 40 percent of the cases, however, evaluation of the abstinence syndrome was confounded by other drug use by the mothers. Overall, although no randomized controlled trials have been reported, the NAS associated with buprenorphine has been reported to be less intense than that observed with methadone.

One prospective open‐label study (Fischer et al. 2000) found signs of NAS in 7 of 15 neonates exposed to buprenorphine in utero. Of these 15 neonates, 3 had moderate signs of NAS that required treatment, 4 had mild signs of NAS that required no treatment, and 8 had no signs of NAS. A second prospective open‐label study (Johnson et al. 2003a ) reported NAS in 3 of 3 neonates; however, none required treatment with medications.

NAS from buprenorphine generally appears within the first 2 days of life, peaks within 3 or 4 days, and lasts for 5 to 7 days. Few infants were reported to have had a withdrawal syndrome for 6 to 10 weeks.

Similar to the treatment of NAS following exposure to methadone, several different medications (including chlorpromazine, phenobarbital, benzodiazepine, paregoric elixir, and morphine drops) have been used successfully to treat the NAS associated with buprenorphine. The American Academy of Pediatrics recommends tincture of opium as the medication of choice for treatment of neonatal opioid withdrawal symptoms (American Academy of Pediatrics Committee on Drugs 1998).

Breast Feeding While on Buprenorphine Treatment

The limited human pharmacokinetic data show that buprenorphine passes into the breast milk of lactating women at a plasma‐to‐milk ratio of approximately 1. As a result, and because of the poor oral bioavailability of buprenorphine, the nursing infant will be exposed to only 1/5–1/10 of the total amount of buprenorphine available.

The literature includes reports on approximately 40 to 50 women who were maintained on buprenorphine and who breastfed after delivery (Johnson et al. 2003a ; Lejeune et al. 2001; Loustauneau et al. 2002; Marquet et al. 1997). These reports indicate that buprenorphine present in breast milk does not appear to suppress NAS. Additionally, NAS has not been observed after the cessation of breastfeeding by women who were maintained on buprenorphine (Loustauneau et al. 2002).

Although the Subutex® and Suboxone® package inserts state that breastfeeding is not advised in mothers treated with these medications, it is the consensus of the panel that any effects of these medications on the breastfed infant would be minimal and that breastfeeding is not contraindicated. However, given the limited literature in this subject area, physicians are advised to use their professional judgment in their recommendations.

The Buprenorphine/Naloxone Combination in Pregnancy

The panel notes that there is a question whether the buprenorphine/naloxone combination is or is not recommended for use in pregnancy. Naloxone is labeled by FDA as a Pregnancy Category B drug. The FDA Pregnancy Labeling Task Force assigns a human prescription drug to Pregnancy Category B (1) if animal reproduction studies have failed to demonstrate a risk to the fetus and (2) if there are no adequate and well‐controlled studies in pregnant women. Despite the fact that naloxone is classified as a Pregnancy Category B drug, it should be used with caution in pregnant women who are addicted to opioids. Because both mother and fetus will be dependent on the opioids used by the mother, administration of naloxone could precipitate withdrawal in both.

If it is determined that buprenorphine is the only acceptable option for the treatment of a pregnant woman, and she understands the issues and risks, then she should be treated with buprenorphine monotherapy so as not to risk fetal exposure to naloxone. It should be noted that use of buprenorphine monotherapy, because of its greater potential for abuse, necessitates more frequent monitoring of patients and of their medication supplies. To prevent abuse and diversion of the buprenorphine monotherapy formulation, quantities of take‐home supplies and quantities provided via prescription should be smaller compared to treatment with the buprenorphine/naloxone combination formulation.

Summary

Buprenorphine is classified by FDA as a Pregnancy Category C drug. Data from controlled studies on the use of buprenorphine in pregnant women are needed. The available evidence does not show any causal adverse effects on pregnancy or neonatal outcomes from buprenorphine treatment, but this evidence is from case series not from controlled studies. Methadone is currently the standard of care in the United States for the treatment of heroin addiction in pregnant women. Pregnant women presenting for treatment of opioid addiction should be referred to specialized services in methadone maintenance treatment programs. If such specialized services are refused by a patient or are unavailable in the community, maintenance treatment with the buprenorphine monotherapy formulation may be considered as an alternative. In such circumstances, it should be clearly documented in the medical record that the patient has refused methadone maintenance treatment, or that such services were unavailable; that she was informed of the risks of using buprenorphine, a medication that has not been thoroughly studied in pregnancy; and that she understands those risks.

Parental Consent

Parental consent is a critical issue for physicians who treat adolescents addicted to opioids. In general, adult patients with “decisional capacity” have the unquestioned right to decide which treatments they will accept or refuse, even if refusal might result in death. The situation for adolescents is somewhat different, however. Adolescents do not have the legal status of adults unless they are legally “emancipated minors.” Adolescents’ rights to consent to or to refuse medical treatment differ from those of adults. Rules differ from State to State regarding whether an adolescent may obtain substance use disorder treatment without parental consent. Some State statutes governing consent and parental notification specify consideration of a number of fact‐based variables, including the adolescent’s age and stage of cognitive, emotional, and social development, as well as issues concerning payment for treatment and rules for emancipated minors.

More than one‐half of the States permit individuals younger than 18 years of age to consent to substance use disorder treatment without parental consent. In States that do require parental consent, providers may admit adolescents to treatment when parental consent is obtained. In States requiring parental notification, treatment may be provided to an adolescent when the adolescent is willing to have the program communicate with a parent. Histories of neglect or abuse may be revealed during the care of adolescent patients, and physicians must be aware of reporting requirements in their State. Mandatory child abuse reporting takes precedence over Federal addiction treatment confidentiality regulations, according to Title 42, Part 2 of the Code of Federal Relations (42 C.F.R. Part 2).

Additional difficulties may arise when adolescents requesting treatment refuse to permit notification of a parent or guardian. With one very limited exception, the Federal confidentiality regulations prohibit physicians (or their designees) from communicating substance abuse treatment information to any third parties, including parents, without patient consent. The sole exception allows a “program director” (i.e., treating physician) to communicate “facts relevant to reducing a threat to the life or physical well‐being of the applicant or any other individual to the minor’s parent, guardian, or other person authorized under State law to act in the minor’s behalf,” when the program director believes that the adolescent, because of extreme youth or mental or physical condition, lacks the capacity to decide rationally whether to consent to the notification of his or her parent or guardian (42 C.F.R. Part 2, Subpart B, Section 2.14d 2001). The program director must believe the disclosure to a parent or guardian is necessary to cope with a substantial threat to the life or physical well‐being of the adolescent applicant or someone else. In some cases, communication with State child protection agencies or judicial authorities may be an acceptable alternative, or the required course of action, if the physician believes neglect or abuse has already occurred.

Treatment Setting

The more intensive a proposed treatment is, the more risk a program assumes in admitting adolescents without parental consent. Outpatient programs may have a better justification for admitting adolescents without parental consent than do intensive outpatient or residential programs.

Summary

Buprenorphine can be a useful option for the treatment of adolescents who have opioid addiction problems. The treatment of addiction in adolescents is complicated by a number of medical, legal, and ethical considerations, however. Physicians intending to treat addiction in adolescents should be thoroughly familiar with the laws in their State regarding parental consent. Physicians who do not specialize in the treatment of opioid addiction or adolescent medicine should strongly consider consulting with, or referring adolescent addiction patients to, such specialists. Additionally, State child protection agencies can be a valuable resource when determining the proper disposition for adolescent patients.

Patients Being Treated for Pain Who Become Dependent on Opioids

Patients who need treatment for pain but not for addiction should be treated within the context of their regular medical or surgical setting. They should not be transferred to an opioid maintenance treatment program simply because they are being prescribed opioids and have become physically dependent on the opioids in the course of their medical treatment.

It can be difficult to distinguish between the legitimate desire to use opioids for pain relief and the desire to procure them for purposes of obtaining a high. This may be especially true in patients who have become physically dependent on opioids in the course of the treatment of a pain condition when that pain has been undertreated and inadequately relieved. Figure 5-1 presents some distinguishing features in the use of opioids by patients who are not addicted and who are using opioids for pain relief versus their use by patients who are addicted.

Patients Who Are Addicted to Opioids and Who Require Treatment for Pain

Behaviors associated with drug abuse frequently result in the development of acute and chronic pain conditions. These conditions may be caused by the toxic effects of the drug itself, as well as by trauma and infection. Patients receiving addiction treatment also may experience pain due to illness or injury unrelated to drug use. Physicians must manage this pain efficiently and appropriately. Opioids are among the most effective available options for managing pain, but they are often not prescribed to patients receiving treatment for addiction out of fear of “feeding the addiction” or of triggering relapse in currently abstinent patients. State laws governing the prescription of opioids to known substance abusers may place prescribing physicians at risk for prosecution unless the medical record clearly distinguishes between treatment of the addiction and treatment of the pain condition.

Treatment Approach. Little clinical experience is documented regarding the treatment of pain in patients receiving buprenorphine. Pain in patients receiving buprenorphine treatment initially should be treated with nonopioid analgesics when appropriate. Although buprenorphine itself has powerful analgesic properties, the once‐daily administration of buprenorphine, as used for the treatment of opioid addiction, often does not provide sufficiently sustained relief of pain. Additionally, the onset of action of analgesia with buprenorphine may not be adequate for the treatment of acute pain. In a study of the use of buprenorphine for acute analgesia (Nikoda et al. 1998), the high analgesic activity of buprenorphine was comparable to that of morphine, but the onset of action was found to be inadequate for urgent care.

Patients maintained on buprenorphine whose acute pain is not relieved by nonopioid medications should receive the usual aggressive pain management, which may include the use of short‐acting opioid pain relievers. While patients are taking opioid pain medications, the administration of buprenorphine generally should be discontinued. Note that, until buprenorphine clears the body, it may be difficult to achieve analgesia with short‐acting opioids in patients who have been maintained on buprenorphine, and higher doses of short‐acting opioids may be required. Noncombination opioid analgesics are generally preferred to avoid the risk of acetaminophen or salycilate toxicity when combination products are used at the doses that are likely to be required for pain control in patients who have been maintained on buprenorphine. Analgesic dose requirements should be expected to decrease as buprenorphine clears the body.

When restarting buprenorphine administration, physicians should refer to chapter 4 for induction procedures. To prevent the precipitation of withdrawal, buprenorphine should not be restarted until an appropriate period after the last dose of the opioid analgesic, depending on the half‐life of the opioid analgesic used.

Patients who are receiving opioids for chronic severe pain may not be good candidates for buprenorphine treatment because of the ceiling effect on buprenorphine’s analgesic properties. This rationale also would be applicable to terminally ill patients. In patients who are maintained on buprenorphine and require end‐of‐life opioid analgesia, buprenorphine administration should be discontinued, unless the buprenorphine provides adequate analgesia or the patient prefers buprenorphine for some other reason.

In patients who are opioid addicted and who have severe chronic pain, methadone several times per day or other “round the clock” (rather than as required) long‐acting, full‐agonist medications may be the best alternative for treatment. This form of treatment is often best undertaken in conjunction with an Opioid Treatment Program (OTP). However, if the physician is (1) otherwise qualified to treat the condition causing the pain and (2) careful to document that the primary purpose of the opioid pharmacotherapy is the management of that pain condition, then it may be acceptable to treat that patient in the office setting without further referral. As long as this type of patient remains compliant and is not abusing the pain medication or other drugs, there is no legal need for the patient to be treated in an OTP or with buprenorphine for the preexisting or concurrent addictive disorder. However, the Drug Enforcement Administration (DEA) frowns on the use of this as a rationale to treat the “pain of withdrawal” or spurious and ill‐defined pain conditions to justify unsanctioned opioid maintenance. Patients who are on chronic opioids for pain management and who have a history of drug abuse or addiction can be referred to a 12‐Step program or other self‐help group to help them maintain their level of recovery. Random drug screening also can reassure the physician that both physician and patient are staying within lawful bounds.

Because all pharmacological treatment with opioids is highly regulated, physicians who desire to use opioids to treat chronic pain in patients who are at risk for opioid addiction or relapse are advised to consult with a colleague knowledgeable in opioid maintenance pharmacology.

Opioid Addiction in Patients Under the Jurisdictions of Criminal Justice Systems

It is well documented that the crimes committed by most of the more than 1 million individuals incarcerated in the United States are related to the abuse of or addiction to drugs. Opioids are the preferred contraband drugs of choice in prisons and can be relatively easy to obtain in some institutions. Prison environments and inmate culture reinforce the addiction cycle and addiction lifestyle. Recidivism rates are higher in patients with a history of opioid addiction because they are typically reincarcerated after failing parole or drug‐testing requirements.

Assessment of Patients Who Are Opioid Addicted and Who Are Recently Released From Controlled Environments

Physicians should consider the following factors when assessing for addiction in patients recently released from controlled environments: length of incarceration; postrelease addiction patterns and cycles; addiction treatment history (drug‐free, outpatient, recovery, or therapeutic community); self‐help involvement (before, during, and since incarceration); and reported triggers of illegal drug use and addiction upon release. Physicians should evaluate for the presence of comorbid mental health issues or history of other drug or alcohol use that could complicate buprenorphine treatment. (See chapter 3 for further information.) If office‐based buprenorphine treatment is being considered, physicians should carefully assess the patient’s level of commitment to treatment and the likelihood of self control.

Assessing Psychosocial Issues

Attention to psychosocial issues is important in patients who are coming out of controlled environments. Issues that often affect the success of addiction treatment include

• Number and/or length of incarcerations
• Types of crimes committed (e.g., violent offenses, drug‐related)
• Gang affiliations
• Type and length of parole or probation (e.g., whether the patient will be given regular or random drug testing)
• The patient’s collateral contacts and reporting requirements
• Prior and current involvement of the patient’s social support system (e.g., the presence of opioid addiction problems or current use in family members)
• Recent changes in familial or marital relationships
• Whether permission from the criminal justice system is required for treatment with buprenorphine

Physicians should ask the patient whether he or she has a reasonable plan for a stable lifestyle (e.g., involvement in job, school, family) and whether the plan includes total abstinence from drug and alcohol use. If there is no plan, the physician should ask why not and offer to help the patient create one.

Final determination of a patient’s appropriateness for buprenorphine treatment will involve analysis of the subjective assessment and disclosed information, as well as a review of medical records to determine treatment compliance and cooperation. Physicians should assess a patient’s psychosocial needs and the compatibility of the patient with the potential limitations of an outpatient, office‐based environment.

Determining Appropriateness for Buprenorphine Treatment

A number of issues should be considered in determining the most appropriate treatment modality for patients with addiction who are recently released from controlled environments. If a methadone clinic alternative is available, the physician should determine the factors that may preclude referral. The existing doctor/patient relationship should be assessed, as well as eligibility for other assistance, and the presence of a solid support system. A physician’s limitations with regard to potentially intensive buprenorphine monitoring activities should be considered, as a treating physician may be called on to determine, verify, and explain a treatment regimen (e.g., to parole and probation officers); to document the patient’s compliance; and to interact with the legal system, employers, and others. Physicians should consider potential issues associated with detoxification in jail if a patient is reincarcerated. The cost of treatment needs to be considered, as well as whether the costs are covered by a patient’s health insurance. Additionally, potential risk issues need to be considered (e.g., diversion, overdose, criminal activity while in a limited, professional care setting, mixing with other patients).