Substance Abuse in Patients With Attention-Deficit/Hyperactivity Disorder

Abstract

Substance use disorder (SUD) is a common comorbidity of attention-deficit/hyperactivity disorder (ADHD) that is frequently seen during adolescence. Physicians who treat patients with ADHD need to be aware of both the behavioral and medical signs of substance abuse and closely screen their patients for SUD. Optimal treatment of the symptoms of ADHD is the most effective way to reduce the incidence of SUD, but the use of stimulants, the first-line therapy for ADHD, is associated with an appreciable degree of abuse and misuse of therapeutic drugs. Cardiovascular and psychiatric risks with ADHD drugs have resulted in recent labeling changes for these drugs. A correct diagnosis of ADHD is important in validating the use of stimulant medication. New strategies for effectively treating ADHD that may minimize the risk for drug abuse are being developed and include extended-release formulations of currently used drugs, new nonstimulant drugs for the treatment of ADHD, and novel prodrugs that optimize therapeutic plasma concentrations of drugs. Nonmedication or psychosocial treatments, especially for adult ADHD, are also available. Further assessment of these strategies should permit the development of new approaches to the treatment of ADHD that reduce the risk for abuse and misuse of stimulant medications.

Introduction

Substance use disorder (SUD) is a common comorbidity of attention-deficit/hyperactivity disorder (ADHD). In children diagnosed with ADHD who were monitored during the transition into adolescence, alcohol, tobacco, and psychoactive drug use were all higher than in control groups of children without ADHD.[1,2] The lifetime risk for SUD is approximately 50% in subjects whose childhood ADHD persists into adulthood.[1] Similarly, studies of adult subjects treated for SUD have indicated that 15% to 25% have ADHD.[3] In all reported longitudinal studies, the onset of ADHD precedes that of SUD, suggesting that the psychopathology of ADHD is not secondary to SUD in the majority of patients.[3]

Because ADHD precedes SUD, it is not unreasonable to suppose that timely diagnosis and treatment of ADHD may reduce the occurrence and/or severity of SUD. Indeed, in a recent meta-analysis of 6 studies in which children with ADHD were treated with stimulants, the most common pharmacotherapy concluded that SUD was less common in adolescence in treated children than in children with ADHD who did not receive pharmacotherapy.[4] However, this protective effect of stimulant treatment does not appear to persist into adulthood.[4] Providing drugs with abuse potential to ADHD patients can also pose other problems. Patients with ADHD divert (not always sold for profit, often given to friends and family) and misuse their stimulant medications significantly more than non-ADHD patients receiving psychotropic medication for non-ADHD conditions.[5] A recent report of the Drug Abuse Warning Network indicated that 48% of the emergency department visits in 2004 that involved methylphenidate or amphetamines resulted from nonmedical use of prescribed drugs.[6]

Several theories have been proposed to explain the increased risk for SUD in patients with ADHD. Genetically mediated personality traits, such as novelty seeking and impulsivity (common to both ADHD and SUD), may provide a link and may result from common neurologic substrates.[3,7] It has also been proposed that patients with ADHD use addictive substances in an attempt to self-medicate the symptoms of the disorder,[8] and the poor judgment and impulsivity associated with ADHD contribute to the development of dependence.[3]

Diagnosing ADHD in Individuals Who Have SUD or Who Are at Risk for SUD

Optimal assessment practices will help to minimize inappropriate or unneeded treatment, iatrogenic problems, such as abuse or diversion of stimulant medications. Because there are no simple tests for ADHD, physicians must rely on a diagnostic interview that is based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and, when possible, informant observations. Components for optimal ADHD assessment that are common to diagnosis in children, adolescents, and adults include the use of collateral informants (parents, siblings, friends, or significant others who know the patient well), a structured and focused interview, and rating scales normalized for the specific age group. The focused interview should include a careful review of childhood development, past and current functioning at work (and/or school), social relationships, and activities of daily living[9,10] For adolescents, there are a number of well-validated rating scales for ADHD. There are 3 commonly used rating scales for adult ADHD. The DSM-IV symptoms for ADHD can be administered in a rating scale format, with the presence of each symptom rated on a 4-point Likert scale ranging from “Not at all” (0) to “Very much” (3) in both a 6-item “screener” and a full-criteria instrument.[9,11] In addition there are the Conners' Adult ADHD Rating Scales (CAARS)[12] and Brown Attention-Deficit Disorders Scales (BADDS).[13] The absence of an informant or early (childhood) symptoms of ADHD should prompt suspicion.

To avoid a misdiagnosis of ADHD, the clinician should rule out other diagnoses that could account for, or better explain, the symptoms attributed to ADHD. These include hearing and vision problems, learning disabilities, depression, chronic diseases and disorders, other medications, and even lead poisoning and anemia.

Recognizing and Addressing SUD in ADHD Patients

Despite recommendations that every primary care practice should screen adolescent patients for drug and alcohol use, the American Academy of Pediatrics estimates that less than 50% of pediatricians actually perform such screening.[14] Insufficient knowledge of treatment steps in the event of a positive screening and the age of the patient (adolescents require consent) are the most frequently cited reasons for failure to screen.

Screening has been made easier with the development of short, validated questionnaires that identify subjects who warrant closer examination for possible substance abuse problems. Such screening can be done during routine visits or during treatment for psychiatric emergencies. For adolescents, one of the most commonly used validated screening tools is the CRAFFT test, an easily administered series of 6 oral questions[15]:

C: Have you ever ridden in a Car driven by someone (including you) who was “high” or had been using alcohol or drugs?

R: Do you ever use alcohol or drugs to Relax, feel better about yourself, or fit in?

A: Do you ever use alcohol/drugs while you are by yourself, Alone?

F: Do you ever Forget things you did while using alcohol or drugs?

F: Do your Family or friends ever tell you that you should cut down on your drinking or drug use?

T: Have you ever gotten into Trouble while you were using alcohol or drugs?

Two or more yes answers are considered a positive result that should be further investigated. In patients with a CRAFFT score of 2 or higher, the CRAFFT test has an overall sensitivity of 76% and a specificity of 94% for problem drug use, abuse, or dependence. A similar 5-question instrument, the RAFFT test has been used in adults:

R: Do you drink/use drugs to Relax, feel better about yourself or fit in?

A: Do you ever drink/use drugs while you are by yourself, Alone?

F: Do any of your closest Friends drink/use drugs?

F: Does a close Family member have a problem with alcohol/drugs?

T: Have you ever gotten into Trouble from drinking/drugging?

In patients with 2 positive answers, the RAFFT test has a sensitivity of 96.5% and specificity of 51.2% for SUD alone or comorbid SUD.[16]

Subjects with positive screening tests should receive a follow-up diagnostic interview. During office visits, patients should be examined for both behavioral and medical manifestations of substance abuse.[17] For adolescents, an age-appropriate psychosocial history should be taken and reviewed for factors that predict substance abuse. Questions that assess aberrant drug-taking behaviors (eg, determining whether a patient has used another person's drugs, given or sold medication to others, or increased the dosage of a drug without conferring with a physician) may also be useful for detecting substance abuse.[18]

Similarly, it is important to take a family history to determine whether there is substance abuse in the home or in the biological relatives. Screening questions should go back at least 2 generations because SUD sometimes skips a generation. If evidence of substance abuse or a family history is detected, a discussion of the possible consequences of this behavior should also be held with the child and parents or guardians and, if necessary, referrals for appropriate treatment of family members arranged.

Information on how substance abuse affects the entire family and how substance abuse treatment providers can use principles from family therapy to change the interactions among family members has been published by the Substance Abuse and Mental Health Services Administration (SAMHSA).

A private interview with only the patient is the most direct means of obtaining a comprehensive substance abuse history.[17] The interview should be confidential and performed in an empathetic, nonjudgmental style to ensure development of physician-patient trust. In the course of the interview, information should be obtained with regard to specific drug use, including alcohol and tobacco; frequency of use; and the social context in which drug use takes place. The degree of social, educational, and job disruption attributable to drug use should also be ascertained. Because of the association of SUD with risk-taking behavior, inquiries should be made with regard to other risk behaviors, such as firearm use and driving under the influence of drugs.

Given the high occurrence of ADHD and SUD comorbidity, it is even more imperative that patients with ADHD be closely monitored for substance abuse. This close monitoring includes more frequent visits (weekly or biweekly), initial prescribing of smaller amounts of medication, and the use of urine drug screens or other forms of toxicologic monitoring of illicit substance use. Especially in adolescents, and even in many adults, having parents or others monitor the administration of medication may be advised. ADHD stimulant medication is a Drug Enforcement Administration Class II controlled substance, and prescriptions are limited to a 30-day supply, so use and effect should be correlated to supply. Adolescents with ADHD who smoke should be counseled that smoking increases their risk for subsequent alcohol and drug abuse compared with ADHD patients who do not smoke.[19]

Patients with ADHD should be counseled with regard to the risk for SUD, and their medication use should be closely tracked to ensure that optimal treatment efficacy is being achieved and that stimulants are not being abused or misdirected. A variety of Internet resources are available that can assist physicians in keeping abreast of general information about substance abuse. These include the National Institute on Drug Abuse, SAMHSA, and Youth Risk Behavior Surveillance. The Drug Abuse Warning Network monitors drug-related hospital visits and deaths on both a national and regional level, and is useful for monitoring trends of drug use in a given area.

Treatment of children with ADHD becomes more complicated as they move into adolescence and the potential for development of SUD increases. At this stage, diligent observation of patients is absolutely necessary. Physicians must be able to recognize risk factors for SUD in their ADHD patients and act preemptively to minimize the risk. Early and effective treatment of ADHD may be the best way to minimize development of SUD.[4] However, physicians must also be prepared to treat SUD if it develops while maintaining effective treatment of ADHD.

Choosing therapy for patients with both SUD and ADHD is difficult, given the limited number of controlled and blinded studies of SUD treatment in ADHD. In general, literature supports the use of multimodal therapy, but the role of stimulant pharmacotherapy is not well defined.[20] In a recent double-blind, randomized study of adult cocaine-dependent ADHD patients treated with cognitive-behavioral therapy and either methylphenidate or placebo, there was no significant difference in the 2 treatment groups in terms of mean improvement in symptoms of ADHD. However, patients whose ADHD symptoms improved with methylphenidate were more likely to have a reduction in cocaine abuse as assessed by urine testing.[21]

Pharmacologic Options to Reduce Risk for SUD in ADHD Patients

A number of strategies have been employed to reduce the abuse potential of ADHD treatment while maintaining efficacy. For stimulant drugs, such as methylphenidate, such strategies have typically focused on altering the pharmacokinetics of drug delivery in an effort to maximize the efficacy of stimulant therapy for ADHD while minimizing its reinforcing potential. In particular, the development of sustained-release formulations of methylphenidate was at least partially driven by the observation that the abuse potential of oral methylphenidate, measured as subjective likeability, is more strongly influenced by the drug delivery rate than by plasma concentration or brain dopamine transporter occupancy.[22,23] Extended-release formulations of methylphenidate typically have a longer time to both maximum plasma concentration and maximum dopamine transporter occupancy in the central nervous system.[23] In short-term clinical trials, extended-release versions of methylphenidate have proven to be more efficacious for treating the symptoms of ADHD in adolescents than placebo and have the advantage of providing a longer treatment period per dose.[24,25] Whether treatment with extended-release stimulants is actually associated with a lower rate of abuse and/or reduced prevalence of SUD is a question that will require longer term study.

The use of nonstimulant drugs to treat ADHD could potentially reduce the incidence of drug dependence, but this should not be at the expense of treatment efficacy. The American Academy of Pediatrics currently recommends only stimulants for first-line treatment of ADHD in children and adolescents.[26,27] Tricyclic antidepressants are noted to be possibly effective but are recommended only for patients whose symptoms are refractory to 2 or more stimulants.[26,27] Atomoxetine, a nonstimulant, which is US Food and Drug Administration (FDA)-approved for the treatment of ADHD, has been shown to be somewhat effective, but in a meta-analysis had a lower effect size than stimulants.[28]

Recent developments in novel drug delivery systems designed to minimize the more rapid peak plasma concentration of stimulants may also reduce the potential for SUD while maintaining treatment efficacy for ADHD. A methylphenidate transdermal patch recently approved by the FDA releases 10–30 mg of methylphenidate over a 9-hour period with peak plasma concentration being achieved after 8 hours.[29] In short-term clinical trials, improvement of ADHD symptoms in children treated with the patch was significantly better than in placebo-treated controls, and the safety profile was acceptable.

Another recent innovation in stimulant treatment is the development of lisdexamfetamine dimesylate (LDX), a prodrug stimulant. After oral administration, LDX is enzymatically hydrolyzed in the gut and converted to l-lysine and the active compound d-amphetamine. Under these conditions, the bioavailability of LDX may actually not lead to further increases in drug concentration at supratherapeutic drug doses if the enzyme becomes saturated.[30] This process could potentially reduce the risk for toxicity and, presumably, for drug abuse. In 2 double-blind crossover studies, LDX had a delayed mean peak effect compared with d-amphetamine, consistent with delayed and less intense pharmacodynamic effects.[30,31] The relative abuse potential of LDX, which is based on Liking scores and behavioral measures, was less than that for d-amphetamine.[30,31] LDX has been shown to be effective for the treatment of ADHD in 2 randomized, controlled, short-term trials[32,33] and 1 long-term study[34] with a safety profile similar to that of standard oral amphetamine.

Other Medical Risks for ADHD Medications

There have been rare reports of serious cardiovascular problems (eg, sudden death, heart attack, and stroke) in patients taking ADHD medications.[35] The FDA investigated these reports and found many involved patients who had undiagnosed cardiac abnormalities or defects. The FDA concluded that it was not possible to determine whether the heart defect, the medication, or a combination of these caused the reported cardiovascular events.[36] However, the FDA added a warning label to ADHD medications cautioning doctors about prescribing ADHD drugs to people who have heart defects and directed manufacturers of medications approved for the treatment of ADHD to develop Patient Medication Guides.[35] Although it appears that there is no increased risk for sudden death, heart attack, or stroke in otherwise healthy children, adolescents, or adults taking ADHD medications, adults, especially those with a history of current illicit drug use, may present further risk – albeit small – for cardiovascular problems from ADHD medications.

FDA review of ADHD medicines also revealed a slight increased risk (about 1 per 1000) for drug-related psychiatric adverse events, such as hearing voices, becoming suspicious for no reason, or becoming manic, even in patients who did not have previous psychiatric problems.[35] The psychiatric risks are also to be included in revised labeling and in the Patient Medication Guides.

Nonmedication Treatments

Clinicians have used a number of nonpharmacologic treatments for adult ADHD, including biofeedback or neuron feedback, cognitive-behavioral therapy, and ADHD coaching, which usually includes organization and time management.[10] Additional controlled studies are required to establish the efficacy of these alternative therapies for adults. Until further studies are conducted, these therapies can be viewed as adjuncts to medication or used when medication presents an unacceptable risk.

Conclusions

Although effective treatment of ADHD, typically with first-line stimulants, is the most effective way of reducing the incidence of SUD in ADHD patients, patients should be closely monitored, particularly during adolescence, to ensure that therapeutic drugs are not being misused or abused. Patients should also be carefully observed for incipient SUD, a frequent comorbidity of ADHD. SUD in patients with ADHD is typically managed with multimodal therapy. The role of pharmacotherapy in the treatment of comorbid ADHD and SUD is poorly defined. Development of both new drugs and novel delivery systems has the potential to minimize drug abuse and development of full-blown SUD in the ADHD population.

Funding Information

This study was funded by Shire Development Inc., Wayne, Pennsylvania.