Dr. Alexander Y. Walley: I am aware of the diagnosis in this case. This 29-year-old woman presented to her primary care clinic after she had symptoms consistent with opioid withdrawal syndrome, which had spontaneously resolved in less than 1 day. At the end of the visit, she requested injectable intramuscular naltrexone, and she later described a history that fulfilled criteria for severe opioid use disorder (Table 1).1 The patient reportedly used approximately $100 worth of nonprescribed oxycodone per day and thus was at high risk for use of heroin and illicitly manufactured fentanyl, which are more potent, widely accessible, and less expensive. However, according to the history and results of urine toxicology screening, her opioid use disorder was limited to use of illicit oxycodone. Although the patient requested naltrexone treatment, she did not complete the urine toxicology screening or return to the clinic for 6 months. I suspect that the patient had some ambivalence about treatment, which is common among patients with substance use disorder. Despite any ambivalence, the high mortality associated with opioid use disorder makes it imperative to find an effective treatment for this patient.
Treatment for Opioid Use Disorder
First-line treatment for this patient would be one of the three medications approved by the Food and Drug Administration (FDA) for the treatment of opioid use disorder: naltrexone, methadone, or buprenorphine. These medications lead to longer retention in treatment and decreased opioid use and opioid cravings. In a meta-analysis, methadone and buprenorphine were strongly associated with decreased rates of overdose and death from any cause.2 In choosing the best medication for this patient, it would be necessary to have an understanding of not only the treatment-program requirements for each medication but also the patient’s preferences and previous experience with these medications.
This patient indicated a preference for naltrexone (an opioid antagonist). Oral naltrexone is available in generic form and is administered once daily as a tablet. However, meta-analyses have shown that oral naltrexone is no more effective than placebo in lowering the rate of opioid use or increasing the rate of retention in treatment.3 Injectable intramuscular naltrexone is administered every 28 days by a health care provider and is effective in reducing opioid cravings and illicit opioid use. Prescribing naltrexone does not require special training or licensing, although prescribing injectable intramuscular naltrexone often requires prior authorization from an insurance company or collaboration with a specialty pharmacy.
The initiation of either injectable or oral naltrexone treatment precipitates withdrawal symptoms if the patient has not abstained from opioid use for several days before initiation. Of course, abstinence also causes withdrawal symptoms, which are a potent driver of continued substance use. Achieving the abstinence that is necessary to initiate naltrexone therapy is a major challenge; this explains the patient’s unsuccessful attempts at treatment with naltrexone. If she again attempts to undergo treatment with naltrexone, how can she and her provider work together to increase the likelihood that she will continue to take the medication? Before the initiation of naltrexone treatment, the patient’s withdrawal symptoms should be treated either in an inpatient detoxification unit or at home on an outpatient basis, with comfort medications, social support, and close follow-up.
In contrast with naltrexone, methadone (a full opioid agonist) is not associated with a risk of precipitated withdrawal, so abstinence before the initiation of methadone treatment is not necessary. However, because methadone has a relatively long and unpredictable half-life, the treatment must be initiated carefully. An initial low dose and slow approach helps to ensure that the patient is not oversedated during the first several weeks. As a treatment for pain, methadone can be prescribed and dispensed in a manner similar to any other opioid pain medication, but as a treatment for opioid use disorder, methadone can be administered to patients outside the hospital only through an opioid treatment program that is licensed and regulated at the federal and state levels.
If this patient were hospitalized for a reason other than addiction, she could be treated with methadone for opioid withdrawal, and if on discharge from the hospital she were linked to an opioid treatment program, she could be treated with methadone for opioid use disorder.4 Regulations for opioid treatment programs require patients to receive methadone daily at the clinic and to undergo weekly counseling, random toxicology testing, and medical and psychiatric assessment. Patients may earn “take home” doses after 60 days of documented abstinence and with perfect attendance of dosing and counseling appointments. Methadone treatment through an opioid treatment program is one potential option for this patient to consider.
Buprenorphine (a partial opioid agonist) can precipitate withdrawal if the patient has not abstained from opioid use for several hours before the first dose and has not begun to have withdrawal symptoms. Like naltrexone, buprenorphine can be prescribed in any clinical setting, although to prescribe buprenorphine in an outpatient setting, a waiver must be obtained from the Drug Enforcement Agency after completion of additional training (8 hours for physicians and 24 hours for nurse practitioners and physician assistants). Buprenorphine is typically combined with naloxone in a sublingual or buccal formulation to reduce the potential for injection or diversion. A long-acting injectable buprenorphine formulation was approved by the FDA in 2018.
This patient had some experience with use of buprenorphine that had been obtained by illicit means. I would ask the patient whether she had any withdrawal symptoms, sedation, or dysphoria when she took buprenorphine; whether it was helpful in reducing her oxycodone use; and how well she functioned while she took it. If buprenorphine had worked well for her, then I would ask why she requested naltrexone rather than buprenorphine during her primary care visit. As agonist treatments, buprenorphine and methadone are often stigmatized as “trading one drug for another.” This stigma undermines the clear evidence from multiple clinical trials that buprenorphine and methadone therapies can break the addiction cycle of compulsive use.
Risk for Relapse
Adherence to treatment is a major challenge for patients who receive any of these three medications. It is worth noting that patients who take methadone may have longer retention in treatment than those who take buprenorphine,5-7 and patients who take buprenorphine have longer retention than those who take naltrexone.7 In the first 4 weeks after discontinuation of these medications, there is a surge in overdose mortality,2 which is driven by the high likelihood of relapse coupled with reduced tolerance. Before the initiation of naltrexone, methadone, or buprenorphine treatment in this patient, it would be crucial to explain to her that she is at very high risk for relapse and overdose if she discontinues the medication.
Regardless of the treatment that is chosen, this patient will need a strategy to reduce the risk of overdose in the event of relapse. Key elements of an overdose risk-reduction plan include use of opioids in the presence of others who are equipped with naloxone and can respond if overdose occurs; avoidance of additional sedative substances, such as benzodiazepines and alcohol; and administration of the opioid at the lowest possible dose and slowly to test its potency. In accordance with guidance from the Department of Health and Human Services, a naloxone rescue kit should be prescribed to this patient so that she can be prepared to respond to any overdose that she witnesses and can ensure that naloxone is available to anyone who is with her if she relapses.8
Opportunities for Improving Care
This case shows several ways in which the care of patients with opioid use disorder can be improved. During the patient’s previous encounters with the health care system, there were missed opportunities to discuss and diagnose her opioid use disorder. Although the U.S. Preventive Services Task Force has found insufficient evidence to support universal screening for substance use disorder,9 screening was warranted in this patient on the basis of her history, which included multiple risk factors for substance use disorder, such as tobacco use disorder, underlying mood disorder, fatigue and daytime drowsiness, and motor vehicle accidents. Although overdose has replaced motor vehicle crashes as the leading cause of injury-related death in the United States, this case reminds us that a substantial proportion of motor vehicle crashes involve the use of substances — most commonly alcohol but increasingly other substances, such as marijuana and opioids.10
Effective screening can be accomplished with one question: “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?”11 In this patient, the answer to this question, followed by further exploration of the frequency of her substance use and the quantity that she used each time as well as exploration of the consequences of her use, could have allowed her providers to address her substance use disorder at an earlier stage. When the patient requested medication for opioid use disorder, she most likely had already met criteria for this diagnosis. However, it is useful to review the diagnostic criteria with the patient to confirm the diagnosis and its severity (Table 1). The criteria will continue to be useful for monitoring this patient. As her condition improves, the number of criteria she meets will decrease, indicating reduced severity.
This patient has at least two promising prognostic characteristics. First, she is seeking treatment and has sought treatment in the past. It is normal for patients with substance use disorder to have multiple episodes of attempted treatment and relapse, but over time, the relapse periods should shorten and the remission periods should lengthen. Second, she abstained from drug use for years after the birth of her daughter, which is a sign that she may be able to abstain in the future.
The patient is receiving care from primary care and mental health care providers. Who would best treat her opioid use disorder? Does she need specialty treatment? If she and her providers decide that methadone is the best option, then she will need to enroll in an opioid treatment program, which is typically separate from primary care and mental health care. If they choose naltrexone or buprenorphine, either treatment can be delivered effectively in the primary care or community mental health care setting. The patient should receive care in the setting in which she is least likely to discontinue treatment, thus minimizing her risk of relapse and overdose.