Treatment of Adolescent Opioid Dependence: Title and subTitle BreakNo Quick Fix

The prevalence of adolescent opioid use and dependence is increasing. The epidemiology of opioid use among youth in the 21st century raises concern over the potential far-reaching impact of prescription opioid and heroin use on the current generation of adolescents. In 2007, 232 000 adolescents reported misuse of just one of the many forms of prescription opioids, sustained-release oxycodone.¹ During the same year, heroin, the opioid that is most often associated with “illicit” use, was used by 24 000 adolescents.¹ The prevalence of hydrocodone use is reported to be 3% among 8th graders, 7% in 10th graders, and 10% in 12th graders.² Most adolescent users report chewing, swallowing, or insufflating (snorting) opioids, although injection use is reported by 45% of users.³

Most users are male and white and live in both rural and urban areas.⁴ Ten percent of the 74 325 treatment admissions in 2006 for nonheroin opioids were patients younger than 20 years. This percentage increases to 31% if one includes those who are 20 to 24 years old. Forty-three percent of all admitted patients initiated their opioid use before they were 20 years old.⁵ These levels of opioid use, and the young age at onset, portend an increasing population of young adults at risk for the adverse consequences associated with opioid dependence, an often chronic and relapsing medical condition.

Untreated opioid dependence is associated with significant morbidity, social consequences, and mortality.⁶ Seventy-seven percent of opioid injection drug users are infected with hepatitis C virus within a year of initiating that practice,⁷ and 18% to 23% of human immunodeficiency virus (HIV) infections result from injection drug use.⁸ Overdose deaths are increasing and are the leading cause of death among opioid-dependent patients.⁹ These grim statistics likely escape the adolescents who experiment with prescription opioids, perceiving them as a safe alternative to illicit drugs.

Adolescents who experiment with opioids, like their adult counterparts, often do not understand the neurobiologic changes that accompany the transition from episodic opioid use to abuse and dependence. All substances of abuse interact with the brain's dopamine-based reward system.¹⁰ Ongoing exposure to opioids leads to important changes in cellular receptors, intracellular function, and protein transcription and translation, leading to the clinical phenomena that characterize addiction—physical dependence, craving, and loss of control over drug use.¹¹

The adolescent brain is particularly susceptible to the effects of drugs of abuse—leading to the observation that for many, substance abuse is a condition acquired in youth.¹² The brain circuits that are involved with inhibition, emotion, and judgment develop during adolescence. The dynamic interaction between developing neurotransmitter systems and drugs of abuse can impair the ability of adolescents to make sound decisions regarding substance use and limits their appreciation of the consequences of their behavior.¹³ Impaired decision making can lead to experimentation and subsequent opioid dependence.

Treatments for opioid dependence include medications, counseling, and the combination of the 2 methods. Naltrexone, methadone, buprenorphine, and the buprenorphine-naloxone combination are all approved medications for the treatment of opioid dependence. An expert panel convened by the National Institutes of Health (NIH) and an international systematic review and meta-analysis concluded that opioid agonist treatment, in the form of methadone or either of the buprenorphine preparations, is the most effective treatment for opioid dependence.^{14 - 15} The World Health Organization has recently added these compounds to its Model List of Essential Medicines.¹⁶

The Drug Addiction Treatment Act of 2000 was passed by Congress in response to concerns regarding limited access to opioid agonist medications and allows physicians to prescribe approved schedule III narcotic medications for the treatment of opioid dependence. In 2002, the Food and Drug Administration (FDA) approved buprenorphine and buprenorphine-naloxone as the first schedule III medications in this category. This approval paved the way for opioid agonist treatment via prescriptions written by office-based physicians and dispensed at pharmacies. To date, more than 16 000 physicians have received the necessary training to prescribe this medication, and an estimated 500 000 patients have received this form of treatment.¹⁷ A federal evaluation published in 2006 concluded that buprenorphine had successfully expanded access to agonist treatment without evidence of significant adverse public health effects.¹⁸

The relevance of methadone and buprenorphine treatment to adolescents is not clear because the data on which to make recommendations are limited.¹⁹ There is appropriate concern about providing these medications to young individuals despite the substantial risks of opioid dependence. This concern stems from the fact that these medications prolong a state of opioid physical dependence and therefore may limit an adolescent's chance for obtaining abstinence without an opioid-based medication. As a result, opioid-dependent adolescents often receive nonpharmacologic treatments following medication taper (detoxification). In the United States, methadone treatment is allowed for those younger than 18 years only if they have relapsed to drug use following 2 attempts at medication taper or short-term rehabilitation.⁴ Buprenorphine and buprenorphine-naloxone treatments are approved for use by the FDA but not in pediatric patients, citing a lack of data on efficacy and safety in those younger than 16 years.

The study by Woody and colleagues in this issue of JAMA²⁰ reports the results of an NIH-funded multisite randomized clinical trial of 2-week vs 12-week buprenorphine-naloxone treatment of opioid-dependent patients aged 15 to 21 years (mean age, 19 years), in which both groups had their medication tapered at the end of their respective treatments. Nearly half reported injection use, and one-fifth had evidence of hepatitis C infection. The median duration of their opioid use was 1 year. The primary finding is that the 12-week treatment with buprenorphine-naloxone was associated with greater treatment retention and decreased illicit opioid use—but only during the period that medication was provided. The study used a multisite design, appropriate eligibility criteria, rigorous methods, and cogent outcomes and provided long-term follow-up.

However, the study has several limitations. The investigators did not offer naltrexone to patients following buprenorphine-naloxone taper. This option might have allowed more patients to maintain abstinence following completion of buprenorphine-naloxone treatment.²¹ The medication was dispensed from offices and not provided by prescription as is the standard practice for adults. This procedure may have led to greater medication adherence than would occur in clinical practice in this young patient population. Counseling was offered only twice per week, and most patients who dropped out of the study did so because of lack of adherence to counseling. Moreover, the trial was too small to make strong conclusions regarding the safety of buprenorphine-naloxone in this population.

Despite these concerns, it is apparent that adolescent opioid-dependent patients have greater abstinence while receiving buprenorphine-naloxone. The most important finding of this study is the rate of relapse in both treatment groups following the medication taper. Past-week opioid use did not differ by treatment condition at 12 weeks or 12 months and was reported by 38% to 55% and 53% to 72% of participants, respectively. This finding is of concern given the young age of the participants and their relatively short duration of opioid use. The implication is that adolescent opioid-dependent patients, like their adult counterparts, will likely need long-term, rather than short-term, opioid agonist treatment.

Trials in adults that have compared brief methadone and buprenorphine tapers with long-term treatment (6 months to 1 year) have consistently demonstrated better outcomes with long-term treatment. Abstinence rates and retention in treatment are uniformly improved with provision of medication over longer periods of time.^{22 - 24} These trials, conducted in adults with longer durations of opioid dependence (eg, 5-10 years), were not previously thought to be generalizable to adolescents. The unique finding of the study by Woody et al,²⁰ that young opioid-dependent patients with relatively short durations of opioid use have high rates of relapse when provided with either brief or longer tapers of agonist medications, is sobering.

The results of this trial should prompt clinicians to use caution when tapering buprenorphine-naloxone in adolescent patients who receive this medication. Supportive counseling; close monitoring for relapse; and, in some cases, naltrexone should be offered following buprenorphine tapers. From a research perspective, additional efforts are needed to provide a stronger evidence base from which to make recommendations for adolescents who use opioids. There is limited research on prevention of opioid experimentation and effective strategies to identify experimentation and intercede to disrupt the transition from opioid use to abuse and dependence. No information is available regarding the efficacy of treatment with medications such as methadone or buprenorphine-naloxone compared with nonagonist approaches (eg, naltrexone) or nonpharmacologic approaches such as short-term rehabilitation or partial hospitalization programs.

The high rate of relapse seen with both medication taper protocols in the current trial involving opioid-dependent adolescents, combined with the adverse social, legal, and infectious consequences of opioid dependence—and the risk for overdose with relapse—makes the need for rigorous evidence in this area urgent. These findings are another important reminder that there are no quick fixes for opioid dependence.