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CHAPTER OUTLINE
As adolescents are the age group at highest risk of initiating substance use, substance use disorders (SUDs) are often considered developmental disorders (1). According to the school-based Monitoring the Future study (2), almost half (49.9%) of all 12th graders have tried an illicit drug in their lifetime. Cannabis is the most prevalent illicit psychoactive substance used by adolescents in the United States, with 45% of 12th graders reporting marijuana use. About 70% of youth in this age group have used alcohol, and over 51% have been drunk. Approximately 40% of this group has used cigarettes, 5.5% have tried cocaine, 1.4% report heroin use, and about 13% have used narcotics in their lifetime. Similar trends of substance use among youth have been reflected in data from non–school-based surveys, including the National Household Survey on Drug Use and Health.
Of considerable concern, some evidence suggests that the rewarding effects of substances may be greater in teens than adults (3). Substance use among youth has been shown to result in a wide array of social, medical, and psychological consequences. Using substances at an early age is associated with an increased likelihood of substance abuse (4). Early substance use is also associated with risky sexual behavior, alcohol-related accidents, and poorer academic outcomes (5,6). Additionally, substance exposure during adolescence may have lasting neurophysiologic and behavioral effects (7–10).
These patterns underscore the need for effective treatments of adolescent SUDs. To date, several types of psychosocial/behavioral treatments have been shown to be efficacious in the treatment of youth with SUD, while pharmacotherapy research has been studied only to a limited degree among youth. Youth may have differential responses to both the beneficial and potentially harmful effects of pharmacotherapies. As a result, systematic evaluations of the safety, tolerability, and effectiveness of various pharmacotherapies for the treatment of adolescent SUDs are needed to fully understand their clinical utility among youth.
In this chapter, we review the state of scientific research evaluating various pharmacotherapies for the treatment of adolescent SUDs. We also discuss the critical role of psychosocial treatment, especially in combination with medications for adolescent SUDs. We additionally refer the reader to Chapters 105 and 106 in this textbook, as well as other reviews of adolescent substance abuse treatment (e.g., (11,12)) for a broader review of this topic. We then discuss clinical considerations in the combined behavioral– pharmacologic treatment of adolescent SUDs, including issues related to withdrawal/detoxification and overdose management. We additionally comment on future directions related to this area of research with youth and conclude with a clinical case example and multiple choice questions.
EMPIRICAL SUPPORT FOR PHARMACOTHERAPIES IN THE TREATMENT OF ADOLESCENT WITH SUDs
Similar to adults, medications for SUDs for youth are chosen based on their mechanism of actions, that is, medications that (a) are aversive (produce an unpleasant response), (b) produce an agonist or partial agonist effect (that may substitute for some of the psychoactive effects of the substance of abuse), (c) function as antagonists (or blockers of a psychoactive effect of a substance of abuse), and (d) relieve withdrawal or craving. Below, we provide a summary of the scientific research evaluating various pharmacotherapies in the treatment of a variety of SUDs, including nicotine, alcohol, marijuana/cannabis, opioids, stimulants, and other substances. This review builds on and extends earlier reviews of this topic, for example, (13–15).
Nicotine
Nicotine use among teens remains a significant problem, and the majority of smokers began smoking as adolescents (16). In addition to long-term negative effects, smoking during adolescence is associated with a number of immediate health effects including poorer fitness, substance abuse, mental health disorders, and conduct disorder (17).
Some evidence suggests that the intensity and nature of smoking behavior among teens may vary from that of their adult counterparts. Specifically, adolescent smokers tend to smoke fewer cigarettes and less frequently than adult smokers. However, recent research suggests that teens who only smoke intermittently still resemble daily smokers in many ways, including their motivation to quit, attitudes toward smoking, and their quit history (18). Additionally, nicotine addiction develops rapidly in youth, with approximately 25% of adolescent smokers displaying signs of addiction within a month of smoking (19).
Adolescent smokers often report attempting to quit on their own; however, quit rates among teens who try to quit on their own are extremely low (estimated at about 4% to 6% annually). The scientific literature on effective strategies for smoking cessation among adolescents is much smaller than the literature on effective strategies for smoking cessation among adults. And the portion of this literature reporting on the efficacy or effectiveness of pharmacotherapy for adolescent smoking cessation is particularly small. Several medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of smoking cessation among adults. These include several types of nicotine replacement medications (e.g., nicotine gum, inhaler, lozenges, nasal spray and patch) as well as bupropion (Zyban) (a nicotine receptor antagonist and norepinephrine and dopamine reuptake inhibitor) and varenicline (Chantix) (a nicotinic receptor partial agonist). None of these medications have been approved for individuals under the age of 18 years (20).
A number of studies have indicated that several pharmacotherapies may be safe and tolerable among adolescent smokers. Overall, and as reviewed below, long-term quit rates with these pharmacotherapies have not been demonstrated, but several studies have produced reductions in numbers of cigarettes smoked (19).
Nicotine Replacement Therapy
To our knowledge, four randomized controlled trials have evaluated the efficacy of nicotine replacement therapy (NRT) with adolescent smokers. NRT medications exert their effects as agonists or partial agonists and promote reduction in craving and withdrawal symptoms. Hanson et al. (21) randomly assigned adolescent smokers to receive either the nicotine patch (with doses and titration schedules based on level of smoking) or placebo. Participants also received behavioral treatment. The nicotine patch did not produce different smoking abstinence rates but resulted in reduced craving and withdrawal symptoms compared to placebo. No youth dropped out as a result of adverse events.
A second randomized trial evaluated nicotine patches (n = 49) versus placebo (n = 49) with regular adolescent smokers (22). Overall, adherence rates and abstinence rates were low, and the authors concluded that nicotine patches did not appear to have much clinical utility for this population of youth. A third trial, conducted by Moolchan et al. (23), compared nicotine gum (n = 46) versus nicotine patch (n = 34) versus placebo gum/patch (n = 40) in nicotine-dependent adolescents, with dosing based on weight. Overall compliance rates were greater for the patch compared to the gum, but abstinence rates did not differ across groups. Finally, a fourth small study (24) compared weekly group-based counseling alone (n = 17) versus weekly group-based counseling plus nicotine nasal spray (n = 23). Overall, compliance with use of the nasal spray was low, and abstinence outcomes did not differ across groups.
Bupropion
Bupropion exerts its effect as a nicotine receptor antagonist and norepinephrine and dopamine reuptake inhibitor. Bupropion has a black box warning, required by the FDA, highlighting the risk of mental health changes when taking this medication (e.g., depressed mood, thoughts of suicide) and instructing clinicians to monitor changes in mood and behavior after prescribing this substance. Thus, the potential therapeutic benefit of this substance must be weighed against this potential risk.
In one open-label pilot study, sustained-release bupropion (150 mg b.i.d.) appeared to be safe and potentially clinically useful in reducing number of cigarettes smoked in a small sample of adolescent smokers (25). A double-blind, controlled trial (26) compared 150 mg/d of bupropion versus placebo and found higher rates of self-reported smoking abstinence among youth who received bupropion. Another controlled trial (27) evaluated different doses of sustained-release bupropion (150 mg/d vs. 300 mg/d vs. placebo) among adolescent smokers and found some promise for the highest dose of bupropion in reducing smoking among youth (although rates were lower than outcomes typically observed when adult smokers are provided with comparable treatment).
Another study evaluated the relative effectiveness of nicotine patch plus bupropion versus nicotine patch alone in adolescent smokers (28). Both groups demonstrated modest reductions in number of cigarettes smoked, but outcomes were not better for those who received the combined pharmacotherapy relative to those who received nicotine patch alone.
Finally, a recent study examined the combined efficacy of bupropion sustained release (SR) along with a contingency management (CM) behavioral intervention (in which youth received cash incentives contingent on evidence of smoking abstinence) (29). In this four-arm trial, youth received (a) bupropion SR plus CM, (b) bupropion SR only, (c) CM only, or (d) placebo with no CM. The combination of medication plus CM produced greater smoking abstinence rates compared to the no-intervention condition. The combined behavioral–pharmacologic treatment also produced better outcomes compared to either active intervention alone at various timepoints during treatment. Most participants experienced an adverse event, and the number of participants who experienced at least one adverse event did not differ across groups, although adverse events were slightly more common overall among those who received active bupropion.
Varenicline
Varenicline exerts its effects as a partial agonist and, like bupropion, is subject to a black box warning to monitor changes in mental health after starting patients on varenicline. One study, which evaluated the pharmacokinetics, safety, and tolerability of various doses of varenicline (Chantix) in teen smokers (with dosing based on weight), suggested it was generally well tolerated among this sample (30). Steady-state medication exposure among youth weighing greater than 55 kg was similar to that observed in adults, and doses were lower in lower body weight youth to accommodate varenicline’s pharmacokinetics. More than half of participants in the high-dose and low-dose group, including those in the higher body weight category as well as the lower body weight category, experienced adverse events. Most adverse events were considered mild and generally consisted of dizziness, nausea, vomiting, and headache and included some psychiatric adverse events (e.g., abnormal dreams). No participant discontinued use of varenicline due to adverse events.
To our knowledge, only one study has evaluated the effectiveness of varenicline in adolescent smokers. In this study by Gray et al. (31), treatment-seeking older teens (ages 15 to 20) received either varenicline (n = 15) or bupropion XL (n = 14) in a double-blind, randomized trial. Both medications were associated with marked reductions in cigarettes per day. Although there were no serious adverse events in either condition, two participants discontinued their use of bupropion XL as a result of adverse effects (none discontinued in the varenicline condition because of adverse events).
A number of guidelines for treating nicotine dependence in adolescents are available for clinicians. The U.S. Department of Health and Human Services (32) and the American Academy of Pediatrics (33) recommend that counseling be first offered to youth patients, and because there is insufficient evidence for medications for nicotine-dependent adolescents, medications are to be offered to youth smokers on a case by case basis.
Alcohol
Use of alcohol is normative during adolescence, with the majority of teens having tried alcohol before completing high school (2). Although most adolescents who use alcohol during adolescence do not go on to become alcohol dependent as adults, alcohol use during adolescence is associated with an array of psychosocial and biomedical consequences, ranging from negative impacts on academic achievement and relationships within the family to biomedical consequences including neurobiologic changes. Additionally, the severity and chronicity of adolescent alcohol use disorders are predictive of alcohol use disorders during adulthood, further underscoring the importance of interventions targeting adolescent alcohol use disorders (34).
As summarized below, several medications have been evaluated in the treatment of alcohol use disorders among adolescents. For a recent, more detailed review of the state of scientific research evaluating pharmacotherapies for the treatment of alcohol use disorders among adolescents, see an excellent recently published review published by Clark (34).
Disulfiram
A small placebo-controlled study (35) (conducted with adolescents with alcohol use disorders) compared the relative effectiveness of placebo versus disulfiram (Antabuse), a medication that blocks the processing of alcohol in the body and causes an unpleasant reaction when one consumes alcohol (thus having an aversive mechanism of action). This double-blind study demonstrated that youth who received disulfiram had a lower relapse rate. A similar beneficial effect in favor of disulfiram was observed in a separate study comparing disulfiram versus the μ opioid antagonist naltrexone with adolescents with alcohol use disorders (n = 58) (36). If used in the treatment of alcohol use disorders, disulfiram is recommended for use only with individuals who are committed to abstinence, and treatment with this medication requires careful medical supervision due to risks of hepatotoxicity associated with disulfiram and potentially lethal risks of combining disulfiram and alcohol (34).
Naltrexone
Naltrexone is an FDA-approved medication for the treatment of alcohol use disorders in adults that exerts its effects as an antagonist and by decreasing craving. Naltrexone has also been evaluated in an open-label trial conducted with a small sample (n = 5) of alcohol-dependent teens (37). In this 6-week trial, youth who received naltrexone showed significant reductions in number of drinks per day and in alcohol craving.
Ondansetron
Ondansetron as a serotonin antagonist is hypothesized to reducing dopamine release in response to alcohol consumption. Only one, small, open-label study has been conducted evaluating the 5-HT3 receptor antagonist, ondansetron (intended to reduce alcohol craving), with alcohol-dependent adolescents (38,39). In this 8-week study, youth provided with ondansetron (4 μg/kg twice daily) showed significant reductions in drinks per day and increases in number of days abstinent. The investigators who conducted this study reported that this apparent reduction in drinking behavior was mediated via reduction in craving for alcohol (39).
Other medications that have shown some promise in reducing alcohol use among adults with alcohol use disorder, including topiramate and baclofen, have not been systematically studied with adolescents, and thus their clinical utility with teens is not yet known.
Marijuana/Cannabis
Cannabis remains the most commonly used illicit substance worldwide (40) and is the most commonly used illicit substance of abuse among youth (2). Cannabis use among adolescents is associated with greater likelihood and persistence of use in adulthood, and use of cannabis before the age of 17 is particularly associated with a markedly increased risk for SUDs in adulthood (41). As with many other substances of abuse, marijuana use among teens is associated with lower academic performance, lower levels of educational and occupational achievement, and comorbid psychopathology. Additionally, marijuana use among adolescents has been associated with poorer cognitive functioning (42).
To date, no medications have been FDA approved for the treatment of cannabis dependence even for adults (43). Current evaluations of pharmacotherapies for cannabis dependence are generally examining three main approaches for treatment, which include treatment with agonists, antagonists, and medications that target the modulation of neurotransmitter systems (43).
A recent double-blind, randomized controlled trial evaluated the efficacy of N-acetylcysteine (NAC), a glutamate-modulating agent sold as a dietary supplement (over the counter) in the United States, in cannabis-dependent youth (44). NAC restores normal regulation of glutamate release (reverses the down-regulation of the cysteine–glutamate exchanger that is associated with chronic drug exposure). Youth participants received either 1,200 mg NAC or placebo twice daily along with a multicomponent psychosocial intervention. Results indicated that NAC was well tolerated and showed some promise in reducing cannabis use (as evidenced via greater reductions in negative urine cannabinoid results compared to the comparison condition). This finding was striking in that it is reportedly the first demonstration of any pharmacotherapy evaluated in a controlled trial to successfully impact a primary outcome of cannabis use cessation.
Opioids
Recreational use of prescription opioids (use without a prescription) among adolescents is a significant and growing public health concern. Prescription opioids are the second most commonly abused class of drugs among both adolescents and young adults in the United States (2). The increased recreational use of opioids among youth has paralleled the increasing availability and prescribing of opioid analgesics in the United States, and youth typically cite the availability and easy access to prescription opioids as a main reason for their recreational use of them (45).
The strikingly high prevalence of nonmedical use of prescription opioids among adolescents has been referred to as an “emerging epidemic” in the United States (46).
As reviewed in this section, several pharmacotherapies have been evaluated in the treatment of opioid use disorders among adolescents, including the partial μ opioid agonist buprenorphine, the antagonist naltrexone (both in the daily oral formulation as well as the extended-release formulation), as well as the μ opioid agonist methadone.
Buprenorphine
The partial μ opioid agonist, buprenorphine, has been studied in a number of rigorous experimental trials with opioid-dependent youth and has shown considerable promise as a pharmacotherapy for a youth population. Buprenorphine’s mechanism action is as a partial agonist and in the reduction of craving and withdrawal symptoms. One double-blind, randomized controlled trial demonstrated that buprenorphine (Subutex) produced markedly better opioid abstinence and treatment retention rates compared to clonidine (an alpha-2 adrenergic agonist), although both medications appeared safe and well tolerated in this youth sample (47). Additionally, a longer period of stabilization on buprenorphine (Suboxone, a 4:1 combination of buprenorphine to naloxone) has been shown to produce better treatment outcomes compared to shorter withdrawal regimes (48,49) and to be more cost-effective (50). This medication has also been shown to improve psychosocial functioning (51) and to be safe and efficacious in the treatment of both adolescents dependent on heroin as well as those dependent on prescription opioids (52). Youth with more advanced illness, those who received added ancillary treatments to buprenorphine, and those who were successful in the first 2 weeks and completed 12 weeks of treatment have been shown to particularly benefit from buprenorphine treatment (53). Buprenorphine has been reported by the FDA to be safe for the treatment of eligible youth as young as 16 years of age. And unlike methadone, which requires treatment in a specialty addiction treatment program, buprenorphine treatment can be accessed in a wide array of health care settings (including primary care).
Naltrexone
Oral naltrexone, an opioid antagonist (blocker of opioid effects), has also shown some promise in preventing relapse to opioid use among youth who are no longer dependent on opioids (47
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