The public health effects of adolescent substance abuse disorders (SUD) reaches further than the immediate intoxicating effects. Medications play a limited role in the treatment of youth beyond addressing short-term symptoms but may improve longer-term outcomes for some patients. Given the potential devastating consequences of SUD, clinicians should become familiar with all available treatment options. This article reviews the pharmacotherapy for adolescent SUD to inform clinicians considering the use of this modality for selected groups of patients.
The public health effects of adolescent substance use disorders (SUD) reach beyond the immediate intoxicating effects of specific substances. SUD that begin in early adolescence are more difficult to treat, exhibit higher relapse rates, and have poorer outcomes. Furthermore, SUD are strongly associated with major causes of youth mortality such as suicide, homicide, and motor-vehicle accidents. National data from the Youth Risk Behavior Survey (YRBS) conducted by US Centers for Disease Control (CDC) as well as local agencies illustrate the extent of the problem: during the 30 days before the survey, 41.8% of the participating high school students had drunk alcohol, 20.8% used marijuana, 28.3% rode in a car or other vehicle driven by someone who had been drinking alcohol, and 19.5% smoked cigarettes. Moreover, during the 12 months before the survey, 2.1% of students had injected an illegal drug. Although these surveys do not make a distinction between drug use and abuse, they provide valuable information about early use patterns. Not all individuals who experiment with drugs and alcohol go on to develop SUD but early use is associated with increased risk for alcohol abuse and dependence, greater risk for alcohol-related injuries and violence, and increased risk for developing other drug disorders. A recent epidemiologic study of adolescents aged 13 to 17 years found that the lifetime prevalence for any substance disorder (based on Diagnostic and statistical manual of mental disorders fourth edition (text revision) [DSM-IV]) was 11.1%. Prevalence rates of 6.9% for alcohol dependence and 1.9% for illicit drug dependence were lower but these figures are nonetheless cause for concern. In general, legalized substances such as alcohol and tobacco are the most prevalent drugs of abuse among adolescents. This situation could be partially related to the perception that, because these drugs are legal, they may be less harmful. Among illicit drugs, marijuana is the most prevalent substance of abuse in adolescence. A worrisome trend is that prescription drugs are becoming increasingly abused. For instance, in the case of opioids, abuse of prescription narcotics has greatly surpassed the use of intravenous (IV) heroin. Other medications abused include stimulants and tranquilizers that adolescents obtain from classmates, friends, and family members who were prescribed these compounds for legitimate reasons.
Standard treatment of adolescent SUD consists of a multipronged approach that includes 12-step programs as well as other psychosocial modalities addressing individual and family issues. Although biologic agents are a regular component of adult treatment, these agents have not been generally favored in youth, probably because of concerns regarding the risk/benefit ratio of medications in this population, lack of US Food and Drug Administration (FDA) approval, few available published data in adolescence, and because, for most individuals, experimentation does not usually lead to SUD. Although medications currently play a limited role in the treatment of youth beyond addressing short-term symptoms (ie, withdrawal), they may improve longer-term outcomes for some patients. Given the potential devastating consequences of SUD, it is important to become familiar with all potential available treatment options. The present article reviews the existing literature on the pharmacotherapy for adolescent SUD to inform clinicians considering the use of this modality for selected groups of patients.
Diagnosing adolescents with substance abuse disorders
DSM-IV classifies substance-related diagnoses in 2 groups: (1) substance-induced disorders, including intoxication and withdrawal, which consist of physical and psychological symptoms that result from acute exposure to, or interruption of, a particular substance; and (2) disorders of substance use, which encompass abuse and dependence, and include chronic behavioral patterns with significant detrimental functional effects. Similarly to adults, adolescents are also slow to volunteer information about substance abuse problems, minimize the severity of symptoms, and resist seeking help and treatment. Therefore, providers frequently rely on indirect evidence to detect and identify substance abuse patterns. In order to gather collateral information, it is essential to establish a partnership with extended family members, with the caveat that, in many instances, parents of substance abusing adolescents are unaware or only partially aware of the activities that adolescents engage in during or after school. Warning signs of emerging drug abuse include physical findings such as weight loss, poor sleep, low energy, and deteriorating hygiene as well as changes in overall behavior patterns (ie, school truancy, disobeying house rules, fighting with parents, demands for financial allowances). Although none of these signs alone can prove the onset of substance abuse, the clustering of several signs should raise concern. Screening instruments/scales have been developed to assist in the early detection of substance abuse. For instance, the CRAFFT (car, relax, alone, forget, friends, trouble) asks about situations related to any drug use and recommends further inquiry when responders answer “Yes” on 2 out of the 6 items. Assessing substance abuse risk factors is instrumental in prevention and can be done using scales such as the Drug Usage Screening Instrument and the Problem-oriented Screening Instrument for Teenagers. Results of such screens can be shared with the patient and family. When no problematic drug use is detected, the clinician may reinforce this positive behavior by complimenting the patient’s ability to abstain from substances. In cases in which screening reveals drug use, the clinician can initially discuss the findings with the adolescent alone but in some circumstances may consider engaging the parents/caretakers, even if the adolescent objects. When symptoms warrant treatment, the family must be involved and a more detailed assessment is necessary to determine the most appropriate substance abuse–specific level of care (ie, outpatient vs inpatient).
Biologic treatments
The American Academy of Child and Adolescent Psychiatry has provided extensive guidelines for psychosocial comprehensive and multimodal treatments, the standard of care for adolescent SUD. Although comorbidity with psychiatric disorders is highly prevalent, this review does not address medication coadministration strategies for dually diagnosed patients. The present article focuses solely on the small, but emergent, available literature on the pharmacotherapy for specific SUD. Biologic agents are recommended in diverse settings to achieve goals that vary according to the patient’s level of acuity and the severity of the condition. For instance, treatments for substance-induced disorders are more likely to be conducted in a hospital or rehabilitation setting and, in severe cases, may require intensive medical interventions (eg, intubation, IV formulations, and continuous monitoring of vital signs) to quickly reverse the symptoms of intoxication and prevent or ameliorate withdrawal. In contrast, maintenance treatments for SUD attempt to improve maladaptive patterns in which the use of biologic agents is a helpful adjunct within the context of a comprehensive array of modalities (eg, group or supportive psychotherapy). Specific medications are recommended for treating various addictive disorders.
Alcohol
Treatment of acute intoxication and withdrawal
Alcohol intoxication rarely requires aggressive pharmacologic interventions unless ethanol plasma concentrations reach levels high enough to be potentially lethal. There are no specific antidotes for alcohol intoxication. The biochemical disturbances of intoxicated children 11 years of age and older resemble those of adults. Mild acidosis of a respiratory or metabolic origin and mild hypokalemia are common findings in young teenagers. Fluid replacement with glucose-containing fluids and follow-up are generally the only treatments needed for complete recovery. In cases of coma and respiratory depression, patients are generally intubated to protect the airway. Alcohol withdrawal, particularly in its most severe form of delirium tremens, has a 6% mortality and requires timely and adequate pharmacologic interventions. However, withdrawal develops late in the course of adolescent alcohol use and is an infrequent symptom among adolescents. If present, the most prominent early manifestations of withdrawal include fine motor tremor, dysphoria, and autonomic instability manifested by increased heart rate and blood pressure. Benzodiazepines, which have affinity for the same γ-aminobutyric acid (GABA)-A2 receptor as alcohol, are the treatment of choice and the long-acting agents are preferred. These agents include chlordiazepoxide (Librium) and diazepam (Valium), which can be further supplemented with short-acting agents such as lorazepam (Ativan) especially if as-needed interventions are required. Treatment can be started on a schedule of divided doses (ie, Librium 50 mg 4 times a day, total daily dose of 200–300 mg based on the patient’s weight, and a history of substance abuse and prior episodes of withdrawal) and is usually tapered off by decreasing the dose by 25% daily. The use of multivitamin preparations, particularly containing vitamin B complex, vitamin C, and ascorbic acid, is also advised. As noted earlier, acute alcohol withdrawal may present as a medical emergency and is best treated in a general medicine inpatient service. However, mild cases of withdrawal can be managed on an outpatient basis at specialized clinics.
Maintenance treatments
Three agents are approved by the FDA for the treatment of alcohol abuse in adults: disulfiram, naltrexone, and acamprosate. The use of these agents in adolescents has not been formally approved and information about efficacy and side effects is extrapolated mostly from adult data. A few adolescent studies have provided results generally concurring with those from adult trials.
Disulfiram (Antabuse) was serendipitously discovered in 1948 and its ability to produce unpleasant symptoms after alcohol intake led to the development of a preparation for the treatment of alcoholism. Disulfiram causes the irreversible inhibition of aldehyde dehydrogenase, an enzyme involved in the catabolism of ethanol. As a result, consuming alcohol while on disulfiram leads to the accumulation of acetaldehyde in the blood stream which produces a disulfiram-alcohol reaction. This reaction can occur as quickly as 5–10 minutes following the ingestion of alcohol and may last for 7 to 14 days after discontinuation. It is characterized by nausea, vomiting, flushing, and headache but may also progress to potentially more dangerous consequences related to dehydration and electrolyte imbalance secondary to vomiting. In severe cases, respiratory depression, cardiovascular collapse, acute heart failure, convulsions, loss of consciousness, and death can occur. The risk for such serious complications as well as the recent development of alternative alcohol treatment agents have resulted in decreased use of disulfiram. A report of two adolescent males described mixed results. One patient experienced prolonged abstinence from alcohol but the other had poor compliance resulting in early relapse. A randomized study that recruited 26 adolescents aged 16–19 years with chronic or episodic alcohol dependence, assigned patients to disulfiram or placebo. The mean cumulative abstinence duration was significantly greater in the disulfiram group and there was no difference in side effects between groups. Disulfiram is not a preferred agent for adolescents. Authors from both of the above studies advocate its judicious use only after a thorough medical and psychiatric evaluation, documentation of a serious alcohol use disorder, careful assessment for comorbid diagnoses, family involvement when possible, and securing of an informed consent that encompasses education about the nature and effects of disulfiram along with its potential interactions with other medications. The agent’s dosing is 250 mg daily and requires baseline liver function testing and regular follow-up monitoring of enzymes to rule out hepatotoxicity.
Acamprosate (Campral) is a putative glutamate modulator believed to block glutamatergic excitatory receptors and to activate the inhibitory GABA-A receptors. Chronic alcohol intake is hypothesized to produce overexpression of N -methyl- d -aspartate (NMDA) receptors and to stimulate the release of glutamate, causing the amount of glutamate released in the synaptic cleft to increase with time. Acamprosate seems to counteract this type of glutamate excitatory effect and to restore in time the balance between the excitatory glutamatergic and the inhibitory GABA-ergic neurotransmission. However, these effects do not take place fast enough for acamprosate to improve acute withdrawal symptoms and it is not indicated for the treatment of delirium tremens. Furthermore, it does not cause alcohol aversion or produce a disulfiram-alcohol type of reaction. Acamprosate is mostly beneficial in reducing the frequency of relapse during early remission by decreasing the pleasant sensation associated with alcohol consumption. Otherwise, it has negligible effects on the central nervous system and its use has not been associated with the development of tolerance or dependence. The efficacy of acamprosate for abstinence in adults has been extensively studied. A recent meta-analysis of unreported outcomes suggests that acamprosate has little effect on controlling consumption but could be helpful in supporting abstinence. It has well-documented safety and is most commonly used in combination with nonpharmacologic therapeutic modalities. Similarly to other agents, there is a dearth of clinical data for its use in youth. One double-blind, placebo-controlled study recruited 26 adolescents, aged 16 to 19 years, with chronic or episodic alcohol dependence, who were randomly assigned to acamprosate or placebo for 90 days. At the end of treatment, patients taking acamprosate were significantly more abstinent than placebo-treated patients. Although the evidence is sparse, acamprosate may be an effective and well-tolerated pharmacologic adjunct to psychosocial treatment programs. Usual dose is 666 mg 3 times per day. No baseline or follow-up laboratory measures are needed for initiation and maintenance of treatment. Empirical evidence from adult studies suggests that the agent can be safely used for 6 to 12 months and possibly longer.
Naltrexone (ReVia) is a partial opioid receptor antagonist FDA approved for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. It is hypothesized that its antagonistic effect on the opioid receptors can also reduce the rewarding effects of alcohol. Several studies have documented the efficacy of naltrexone in alcohol relapse prevention, both alone and in conjunction with psychosocial interventions. Combination of naltrexone with other alcohol treatment agents (eg, acamprosate) has produced mixed results, with some investigators showing benefit and others failing to find significant improvement. The recommended dosage is 50 mg per day in a single dose. Naltrexone can produce hepatotoxicity so periodic liver profile follow-up is advised. Long-term opioid therapy for chronic pain or heroin dependence is a contraindication because the drug could precipitate a severe withdrawal syndrome. It is also available in a depot preparation (Vivitrol) that showed efficacy in reducing heavy drinking and relapse among alcohol-dependent adults, with an adverse-event profile that seemed milder than that of oral naltrexone. The only published report of naltrexone in adolescents involves 5 youth studied in an open-label format. It was found to be safe, well tolerated, and to reduce alcohol consumption and craving.
The FDA-approved anticonvulsant agent topiramate (Topamax) has glutamatergic antagonist effects resulting in facilitation of GABA-A–mediated inhibition of mesocorticolimbic dopamine release, believed to be associated with craving for alcohol. Although not FDA approved for the treatment of alcoholism in any age group, it has shown efficacy superior to placebo for alcohol relapse and is compatible with, or possibly superior to, approved agents like naltrexone. Topiramate doses range between 100 mg to 300 mg daily in adults; no baseline laboratory work is required. Although no adolescent data have been published yet, an ongoing study scheduled for completion in December 2010 assessing the efficacy and tolerability of topiramate for the treatment of alcohol use disorders (alcohol abuse and dependence) in adolescents with bipolar disorder may provide guidance in the near future.
Stimulants and Cocaine
Natural and synthetic agents abused for their stimulant properties include cocaine, prescription agents for attention-deficit hyperactivity disorder (ie, amphetamines and methylphenidate), different forms of street/illegal amphetamines, and nicotine. From a neurobiological viewpoint, cocaine, amphetamines, and methylphenidate share similar neurophysiologic effects and are reviewed together in this article, whereas nicotine is reviewed separately.
Treatment of acute intoxication and withdrawal
DSM-IV outlines the same criteria for cocaine and amphetamine intoxication and withdrawal. Acute intoxication can present with pronounced cardiovascular symptoms that, in severe cases, may include acute myocardial infarction or brain insult. Unexpected cardiac events in young individuals, including chest pains and arrhythmias, should raise concerns about undiscovered stimulant drug abuse. Psychologically, stimulant intoxication can manifest as acute agitated or even psychotic state, and some individuals present with fully developed manic symptoms, including grandiosity, hyper-religiousness, reduced need for sleep, and hyperactivity. Other symptoms include papillary dilation, nausea and vomiting, weight loss, respiratory depression, confusion, seizures, dyskinesias, dystonias, and coma. Addressing the physiologic complications of the cocaine/stimulant intoxication should take priority and may necessitate treatments in the intensive care setting. The presentation of acute psychotic symptoms, such as hallucinations, delusions, and paranoia, is usually transient, and addressed by using sedatives and antipsychotics. Depression is a complication of cocaine/stimulant withdrawal and, in some cases, may be severe enough to produce suicidal behavior. Patients in acute abstinence from cocaine and other stimulants should be routinely assessed for suicidality, and psychiatric hospitalization should be initiated when warranted to assure safety.
Maintenance treatments
There are no FDA-approved agents for maintenance. Nevertheless, an expanding adult literature supports using agonistlike medications to treat stimulant abuse/dependence, although no studies have been done in youth. For instance, data suggest the use of a range of medications, from L-dopa/carbidopa to amphetamine preparations, depending on the severity of use. A recent review on cocaine abuse concluded that, despite 20 years of extensive research, the development of medication to successfully combat cocaine addiction remains elusive. Based on the known neurochemistry of cocaine, target compounds that have been studied include a D3 partial agonist compound, known as BP-897, and vanoxerine, a highly selective inhibitor of dopamine uptake. Other agents found effective (although non–FDA approved) in favoring abstinence in cocaine-abusing people include the antipsychotic aripiprazole and modafinil, approved for the treatment of narcolepsy. Some placebo-controlled studies also reported effectiveness of topiramate and tiagabine, both approved as anticonvulsants, in increasing cocaine abstinence with no serious adverse events. Among agents that affect the activation of the GABA circuits, baclofen and valproic acid have shown promising preliminary results of efficacy compared with placebo in reducing cocaine use in volunteers and chronic cocaine users. An interesting experimental concept is binding cocaine to immunoglobulins to prevent its crossing of the blood-brain barrier.
Cannabis
The endogenous cannabinoid system was discovered in the early 1990s and exerts action through specific receptors, CB(1) and CB(2), which are located predominantly in the brain and peripherally in adipose tissue, liver, skeletal muscle, and the gastrointestinal tract. These receptors mediate the multiple effects of marijuana that include reduced anxiety but also possibly impaired reality testing, hallucination, and paranoid delusion, and physiologic effects like increased appetitive drive, suppressed emetic reflex, and decreased pain sensitivity.
Treatment of acute intoxication and withdrawal
Although DSM identifies 4 signs/symptoms of cannabis intoxication (ie, conjunctival injection, increased appetite, dry mouth, and tachycardia), it sets no criteria for withdrawal. However, others describe a marijuana withdrawal syndrome that includes sleep disturbances, changes in appetite and weight, increased verbal and physical aggression, mood and sexual problems, and various physical signs such as headaches, sweating, chills, gastrointestinal disturbances, tremors, and muscle twitching. Although intoxication and withdrawal are not life threatening per se, cannabis is not free of potentially dangerous complications, related to concomitant abuse with other drugs. For instance, cannabis suppression of the emetic reflex could lead to high alcohol levels because alcohol-induced vomiting is a mechanism that prevents further plasma-level escalation. Moreover, cannabis is sometimes mixed with phencyclidine, which may result in the development of a psychotic state. Adolescents may not be aware that such mixing took place and may unwittingly take substances that they would usually refuse. It is therefore important to order a full toxicology screen even if patients insist that they have used nothing else but marijuana. When intoxication and withdrawal are complicated by severe psychotic symptoms, a psychiatric hospitalization needs to be considered. Some preliminary data suggest that symptomatic treatments for sleep and mood symptoms during cannabis withdrawal also decrease the resumption of cannabis self-administration in adult volunteers. Of the several agents tested in treating cannabis withdrawal, only oral tetrahydrocannabinol and the antidepressant mirtazapine (Remeron) have shown some efficacy. No data are available for the use of these agents in adolescents.
Maintenance treatments
There are no FDA-approved agents for the treatment of cannabis dependence. A recent review reported that, among the treatment agents evaluated to date, rimonabant (not available in the United States) and buspirone (Buspar) have shown promising results, whereas the use of oral tetrahydrocannabinol has failed to produce any clinically meaningful outcomes. Psychotherapy has been shown to be most helpful in increasing the percentage of adolescents who remain abstinent from cannabis.
Sedatives and Hypnotics
As noted earlier, there has been a significant increase in the abuse of prescription medications such as benzodiazepines.
Treatment of acute intoxication and withdrawal
Overdose with sedative/hypnotic agents may lead to life-threatening respiratory depression and require supportive treatment in intensive care settings. Priorities in management include assessment and establishment of effective ventilation and oxygenation, followed by hemodynamic support, and the administration of an antagonist. A specific antidote agent is available for benzodiazepines. Flumazenil, which competitively inhibits the activity of the GABA/benzodiazepine receptor complex and antagonizes the action of the benzodiazepines on the central nervous system, is indicated for the treatment of overdose in adults. Both short-acting (lorazepam) and long-acting benzodiazepine agents (chlordiazepoxide) are the treatment of choice for benzodiazepine withdrawal. No specific antidote agents exist for the treatment of barbiturate intoxication and withdrawal. These symptoms are rarely seen in adolescents at present, and treatment follows general intensive care principles that can be consulted elsewhere.
Maintenance treatments
No agents have been approved for the maintenance treatment of abuse and dependence of sedatives and hypnotics. Dependence is not frequently encountered in teenagers. The usual management approach involves tapering the dose of the abused agents over time and offering traditional services such as psychosocial support, group and individual psychotherapy, monitoring for possible withdrawal symptoms, and urine toxicology screening. These principles have been applied to both adult and adolescent patients.
Opioids
The 2009 Monitoring the Future drug use survey included more than 46,000 8th-, 10th-, and 12th-grade students and showed that heroin use declined, with annual prevalence in all 3 grades fluctuating between 0.7% and 0.9% from 2005 to 2009. Heroin is perceived as dangerous and has high disapproval levels. However, the use of narcotics other than heroin has been increasing, holding steady at historically high levels since 2002 among 12th graders. Oxycodone (OxyContin) use increased for all grades from 2002 (when it was first measured) to 2009, although the trend lines have been irregular. Annual prevalence in 2009 was 2.0%, 5.1%, and 4.9% in grades 8, 10, and 12, respectively. However, use of hydrocodone (Vicodin) has remained fairly constant since 2002, although at considerably higher levels. In 2009, annual prevalence rates were 2.5%, 8.1%, and 9.7% in grades 8, 10, and 12. Despite these statistics, there are few studies addressing the use of pharmacotherapy, the gold standard of adult treatment, for youth opioid abuse disorders.
Acute intoxication and withdrawal
In the 5-year period from 2004 to 2008, there were marked increases in the number of medical emergencies that involved the nonmedical use of narcotic pain relievers and resulted in emergency department visits. For patients younger than 21 years, the increase was of 113%, reaching a total of 29,196 visits. Regarding heroin, emergency room visits for 18 and 19 year olds increased more than 200% between 1995 and 2002. The classic findings of an opioid overdose are miosis, respiratory depression, and central nervous system depression. Hypoxia from respiratory depression is the principal cause of most deaths. Other manifestations of opioid overdose can include bronchospasm, noncardiogenic pulmonary edema, peripheral vasodilation, orthostatic hypotension, dysrhythmias, dysphoria, mydriasis, seizures, nausea, vomiting, constipation, flushing, and pruritus. Most of the morbidity and mortality attributable to opiate use occurs after acute ingestion. In particular, hypoxia, anaphylaxis, pulmonary edema, acute respiratory acidosis, and aspiration pneumonitis are life-threatening complications demanding urgent attention. The specific agent of choice is naloxone (Narcan), a short-acting, nonselective, specific opioid receptor antagonist with high affinity for the μ-opioid receptor. The reversal effect of this agent manifests in a few minutes. If no response is apparent after slow administration (to avoid withdrawal) of IV naloxone 10 mg in divided doses, isolated opioid toxicity is considered unlikely. Because the duration of activity of naloxone is shorter than that of most opioids, the drug may need to be administered repeatedly.
Opioid withdrawal produces craving, restlessness, muscle and bone pain, vomiting, insomnia, anxiety, yawning, lacrimation, rhinorrhea, diaphoresis, and mydriasis. Other signs that could start up to 3 days later include diarrhea, fever, chills, tremor, tachycardia, hypertension, and seizures. Withdrawal symptoms are uncomfortable but not life threatening. Symptoms peak between 48 and 72 hours after the last use, and then subside in a week. Detoxification is geared toward reducing or avoiding withdrawal. Treatment can take place with opioid agents, such as the full agonist methadone (not FDA approved in youth) and the partial agonist buprenorphine (available alone and combined with naloxone, FDA approved for ages 16 years and older). Alternatively, α2 adrenergic agents can be used, such as clonidine (not FDA approved for use in youth). The effectiveness of detoxification is assessed by evaluating symptom severity, duration of the withdrawal syndrome, and adherence to follow-up care. There are only 2 randomized controlled studies of detoxification in youth. There is a reported a trial of 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone maintenance compared with a 14-day buprenorphine taper. It concluded that continuing treatment with buprenorphine-naloxone improved the outcome compared with short-term detoxification. The direct medical costs that this cohort incurred were examined for 12 months, finding that extended buprenorphine treatment relative to brief detoxification was cost effective. Another study compared the relative efficacy of buprenorphine with clonidine in the detoxification of 36 opioid-dependent adolescents. Combining buprenorphine with behavioral interventions was significantly more efficacious in the treatment of opioid-dependent adolescents than combining clonidine and behavioral interventions. Methadone has been the most widely used agent in adults. Although few youth studies exist, data extrapolated from the adult literature offer additional guidance, although concerns about the potential cardiac side effects of methadone have increased. The recent availability of buprenorphine (Subutex) in the primary care setting has made it an appealing alternative and it is currently suggested as a safer alternative because of lower cardiac toxicity and reduced risk of overdose. Another advantage is that the combined buprenorphine/naloxone formulation (Suboxone) has reduced potential for abuse. Clonidine seems to have worse detoxification outcomes relative to agonist replacement agents.
Maintenance treatment
There are 2 approaches for maintenance: opioid agonist and opioid antagonist treatments.
Opioid agonist treatment
In the United States, there are currently 3 FDA-approved medications for opioid dependence in adults: oral methadone, sublingual buprenorphine, and sublingual combination buprenorphine-naloxone. However, only the buprenorphine preparations are FDA approved for use in youngsters 16 years of age and older. Naloxone is added to buprenorphine to reduce the abuse potential of the preparation. Methadone is only available at tightly regulated treatment centers but recent regulations allow specially licensed physicians to prescribe buprenorphine in the office setting. According to the literature, adolescents are appropriate for opioid replacement treatment when they have failed 2 detoxification or rehabilitation attempts. Although replacement is the gold standard for adults, there is reluctance to start youth on it, perhaps explaining the paucity of research on its use in this population. In addition to the adolescent buprenorphine studies mentioned earlier, only 1 other randomized controlled agonist replacement study exists to date. This study compared the outcomes of 37 adolescents who were assigned either to methadone or levo-α-acetyl-methadol (no longer available in the United States because of cardiac concerns) for 16 weeks of treatment and concluded that both treatments had similar favorable outcomes. However, other less rigorous studies also found favorable outcomes for replacement therapy in adolescents.
Opioid antagonist treatment
Naltrexone at an oral dose of 50 mg blocks the pharmacologic effects of 25 mg IV heroin for as long as 24 hours. Naltrexone, also mentioned in the alcohol section above, is considered an effective opioid dependence agent in many adult cases but it has not been widely utilized due to poor compliance. It is suggested that antagonist treatment may have better patient reception than agonist treatment in opioid-dependent youth who complete detoxification. A recent case review of 16 adolescents treated with extended-release naltrexone showed promise.
Tobacco
Cigarette smoking is a disorder that largely starts in adolescence. Ninety percent of adult smokers begin before the age of 18 years and each day in the United States approximately 3900 young people between 12 and 17 years of age smoke their first cigarette. An estimated 1000 of these youth go on to become daily cigarette smokers. Factors associated with youth tobacco use include low socioeconomic status, use by peers or siblings, lack of skills to resist influences to tobacco use, parental smoking, accessibility, availability and price of tobacco products, low levels of academic achievement, low self-esteem, and aggressive behavior. The significant long-term complications of smoking are well known. In the United States, chronic tobacco use results in an estimated 443,000 premature deaths and $193 billion in direct health care expenditures and productivity losses each year. However, for adolescents, severe consequences can be noted earlier. Youth smoking is associated with the initiation of other addicting patterns, psychiatric illness, negative health effects, and decreased quality of life. Cigarette use had begun to decline among US high school students in the late 1990s but the rate of decline slowed during 2003 to 2009. In 2009, 19.5% of 9th to 12th graders admitted to current cigarette use. The Healthy People 2010 national health objective of reducing use to less than 16% has not been met. Thus, as efforts to prevent the initiation of tobacco use seem to have stalled, treating current users has become even more imperative.
Treatment of withdrawal and maintenance
Acute nicotine intoxication is a rare occurrence, unrelated to the use of tobacco, and not even listed in the DSM-IV. A brief outline of the posited mechanisms involved in tobacco addiction helps in understanding the therapeutic action of the agents used for treatment. Nicotine is the principal substance implicated in tobacco addiction and smoking is an efficient form of nicotine delivery. Following inhalation, nicotine enters the circulation through the lungs and crosses the blood-brain barrier within seconds. Although smokeless tobacco products do not deliver nicotine so quickly, systemic levels of nicotine are similar in users of smokeless tobacco and smokers of cigarettes. Once it reaches the brain, nicotine binds to nicotinic cholinergic receptors, the same ones occupied during normal acetylcholine function. These receptors consist of several types of subunits of which the α4β2 receptor subtype seems to be the principal mediator of nicotine dependence, although other subunits also mediate some effects. When these receptors are activated, calcium is allowed to enter into the neuron, resulting in the release of neurotransmitters such as dopamine. Nicotine mediates the release of dopamine in the ventral tegmental area of the midbrain and in the shell of the nucleus accumbens. These regions are well known for their role in pleasure and reward mechanisms. Nicotine also augments both glutamate and GABA release, transmitters that participate in a complex mechanism of receptor excitation and desensitization that contributes to reinforcement and withdrawal mechanisms. In addition to nicotine, there are other substances that contribute to tobacco addiction. There is mounting evidence indicating that non-nicotinic components of tobacco smoke play a role by inhibiting monoamine oxidase, which leads to greater availability of dopamine.
Among several reinforcing reasons, smokers report that smoking is pleasurable, improves concentration, and reduces stress, anger, and anxiety. Reaction time and problem solving also improve. Smoke cessation results in nicotine withdrawal symptoms such as headache, nausea, constipation or diarrhea, decreasing heart rate and blood pressure, fatigue, drowsiness and insomnia, irritability, difficulty concentrating, anxiety, depression, increased hunger and caloric intake, increased pleasantness of the taste of sweets, and tobacco cravings. These symptoms peak at 48 hours and disappear within 6 months. Nicotine addiction results from a combination of conditioned behavior with positive reinforcements, including enhancement of mood, and avoidance of withdrawal symptoms. Research suggests that although a large number of adolescents express the desire to quit smoking, many also state that abstinence will be hard to achieve. Psychosocial treatments have been the main therapeutic modality for treating tobacco addiction in youth. Myriad psychotherapeutic approaches with documented efficacy exist. However, in contrast with the adult population for which a significant body of research has shown the efficacy of pharmacotherapy, results at the group level for the few studies conducted in the adolescent population have been less encouraging. Reasons for this low documented efficacy may include small sample sizes, low dosages, adherence problems, and short-term trial duration. In addition, none of the available agents are FDA approved for use in youth younger than 18 years. However, according to US Department of Health guidelines regarding pharmacologic agents in adolescence, “clinicians may consider their use when tobacco dependence is obvious.” Furthermore, addiction experts recommend that, “Behavior therapy in combination with the Transdermal Nicotine Patch should be the first line of treatment among adolescent daily smokers wanting to quit.”
There are 7 agents currently approved by the FDA for smoking cessation in adults: 5 nicotine replacement therapies (NRTs), bupropion (Wellbutrin), and varenicline (Chantix). Clonidine and nortriptyline effectiveness has been documented but they are not FDA approved for this indication and are not addressed here. A comprehensive review of adolescent pharmacotherapy trials and assessment procedures is available elsewhere. Varenicline seems to be the most effective agent in adults, but concerns regarding its potential psychiatric side effects may deter adolescent studies and, to date, there are no published effectiveness data regarding varenicline in youth. NRT and bupropion are used in conjunction with psychosocial treatments in adolescence.
NRT
NRT products in the United States are available in 5 different formulations. A nicotine patch, the only long-acting formulation, can be obtained over the counter (OTC). The 4 other formulations are short acting. A nicotine chewing gum and a nicotine lozenge are available OTC, whereas a nicotine nasal spray and a nicotine vapor inhaler require a prescription. NRT stimulates nicotinic receptors in the ventral tegmental area of the brain and the consequent release of dopamine in the nucleus accumbens. This process results in a reduction in nicotine withdrawal symptoms in regular smokers who abstain from smoking. NRT may also provide a coping mechanism, making cigarettes less rewarding to smoke. Adolescent data are available only for the patch and gum formulations. The patch is manufactured as 16- or 24-hour delivery systems. The 24-hour delivery system is available in 7-, 14-, or 21-mg doses. For youth smoking a pack per day, the starting recommended dose is the 21-mg patch for at least 3 weeks, tapering gradually for 6 to 12 weeks. Because the patch is not as effective for acute withdrawal symptoms, to minimize these it is recommended that the adolescent begins tapering the number of cigarettes smoked before using the patch. Smoking should stop once the patch is applied. Potential side effects are mild and include skin irritation, nausea, vomiting, sweating, and mood and sleep disturbances. Caution should be exercised in pregnancy and patients with cardiovascular illness.
Bupropion
This agent is FDA approved for treating depression and exerts its main mechanism of action through dopamine reuptake inhibition, thereby possibly compensating for the decreased dopaminergic stimulation resulting from smoking cessation. Bupropion also attenuates the stimulant effects of nicotine on the nicotinic acetylcholine receptors. Starting dose should be titrated according to weight and increased over time but it seems that better efficacy can be achieved by reaching doses of 300 mg per day. Because the actions of bupropion are not immediate and do not increase smoking toxicity, the adolescent can continue to smoke during the titration period while being encouraged to decrease daily consumption of cigarettes. A quit day can be set 2 weeks after bupropion is started. Commonly reported adverse events are insomnia, nausea, vomiting, and dizziness. There is a risk of seizures that, although low, seems to increase with higher doses. Bupropion carries the same black box suicide warning that is common to other antidepressants, so it is prudent to monitor the appearance of such ideation. The agent is contraindicated in seizure disorder, bulimia, or anorexia nervosa; and in situations in which there is already an increased risk of seizures, such as during abrupt discontinuation from alcohol or sedatives. Also, similarly to other antidepressants, it should not be used within 14 days of a monoamine oxidase inhibitor. Increased toxicity can occur if used concomitantly with other bupropion preparations approved for depression.
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