What Every Parent Should Know About Off‐Label Use of ADHD Medications Literature Review Sue Tolleson‐Rinehart, Sara Massie, and Jessica Hughes prepared for ADHD Parent Education Brochure Consensus Committee UNC Center for Education and Research on Therapeutics Chapel Hill, North Carolina, July 17, 2007 Introduction Unlike a standard systematic review of the scientific literature, the organization and format of this literature review is designed to help inform the subsequent development of the parent education tool. For example, the headings in the tool could potentially mirror the headings offered here. The content of this review will serve as the foundation to a more concise, accessible, and easily comprehended tool for physician and parent use. We used PubMed to locate articles relevant to our topic, off‐label/nonmedical use of Adderall. The biomedical literature does not yet include many studies of off‐label use of ADHD medications for weight loss (although, surely, studies are likely to be published in the future, given the attention this off‐label use is getting). We did find, however, relevant literature on a wider range of topics, including stimulant medications, nonprescription use, abuse patterns, and other topics. For the most part, the literature in PubMed focused exclusively on the use of Adderall (and especially Ritalin [methylphenidate]) to treat ADHD in children and adolescents. We turned up limited data on nonmedical use of prescription medications and relatively little on stimulants/amphetamines specifically. What literature we did find on this topic was mostly on stimulants/amphetamines misuse among the college student population. We used the MeSH terms ‘amphetamines’ and ‘central nervous system stimulants’, and limited to articles in English, on humans, and in the “All Child (0‐18)” population. We focused our search on literature published in the past five years. We identified other relevant literature by using PubMed’s “Related Articles” and “Related Links” features and by reviewing the reference lists of the articles that we found in our original PubMed search. 1 This review first briefly describes ADHD and its treatment, and then provides the evidence on misuse and abuse. It ends with specific recommendations for parents. What is ADHD? Attention‐deficit/hyperactivity disorder (ADHD) is a chronic disorder characterized by inattention, hyperactivity, and impulsive behavior. Persons with ADHD often struggle with low self‐esteem, troubled personal relationships, and poor performance in school or at work. Factors that may play a role in the development of ADHD are altered brain function and anatomy; heredity; maternal smoking, drug use, and exposure to toxins; and childhood exposure to environmental toxins (Mayo Clinic, 2007). Epidemiology of ADHD According to the Diagnostic and Statistical Manual of Mental Disorders‐IV, Text Revision (APA, 2000), approximately 3 to 7% of school‐aged children have ADHD. Data from the 2003 National Survey of Children’s Health (Visser, Lesesne, and Perou, 2007) showed that 7.8% of youth ages 4 to 7 were diagnosed with ADHD by a healthcare professional. Over half of those youth (56%), or 4.3% of all youth ages 4 to 17, were taking medication for an ADHD diagnosis. These findings indicate that, in 2003, an estimated 4.4 million youth ages 4 to 17 had an ADHD diagnosis, and 2.5 million of those youth were receiving medication for its treatment. In the study, more boys (11%) than girls (4.4%) had an ADHD diagnosis, but boys were no more likely than girls were to be receiving medication. Medication use rates were the highest (64%) among 9‐12 year olds diagnosed with ADHD. The percentage of youth taking medication for ADHD was lowest in California (2.13%) and highest in Alabama (6.5%). In North Carolina, 6.1% of youth received treatment for ADHD (Visser and Lesesne, 2005). Diagnosis and levels of medication show interesting patterns of regional variation, as the map reprinted from the CDC study, and presented below, demonstrates. In general, the eastern United States, and particularly the southeast and mid‐Atlantic, see to have the highest rates of diagnosis and medication, with other high‐prevalence areas in the northeast and Midwest. Understanding this regional variation would be valuable, particularly because it is reasonable to assume an association between high levels of diagnosis and treatment, and high levels of abuse or at least nonmedical use (no doubt at least in part because youth in regions with high prescription prevalence have more opportunities to acquire medication from friends who have prescriptions. 2 In results published on the CDC Web site, the percentage of youth taking medication for ADHD was lowest in California (2.13%) and highest in Alabama (6.5%); in North Carolina, 6.1% of youth received treatment for ADHD (Visser and Lesesne, 2005). Figure 1. Regional Differences in Diagnosis and Medication of ADHD. SOURCE: http://www.cdc.gov/ncbddd/adhd/adhdmedicated.htm (last accessed 10 July 2007). Diagnosis and treatment also show sex, age, and ethnicity differences. Table 1 shows Table 1. Age, Ethnicity, Sex, and Health Access Differences in Prevalance of ADHD Age, y 4-8 9-12 13-17 Race White Black Multiracial Other Ethnicity Hispanic/Latino Non-Hispanic/Latino Any health care coverage Yes No Past 12 mo any health contact Yes No ADHD Diagnosis (%) Boys Medicated (%) Girls Medicated (%) 4.1 9.7 9.7 60.2 65.2 48.7 70.1 61.3 43.9 8.6 7.7 9.7 4.5 40.7 49.5 51.7 53.7 57.3 42.3 51.7 58.9 8.6 3.7 56.2 42.4 44.3 56.2 8.1 4.9 58.5 27.0 56.2 39.5 8.5 4.2 59.3 31.5 56.0 44.0 3 SOURCE: figures extracted from ʺTable Weighted Prevalence Estimates of ADHD Ever Diagnosed…ʺ in Visser and Lesense 2005, available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5434a2.htm (last accessed 10 July 2007). that White and Hispanic children (the latter of any race) are more likely to be diagnosed than are Black children (the finding of higher rates of diagnoses for multiracial children may be an artifact of the smaller N of cases in this category). Counter to both what the media (emphasizing treatment of boys) and the scientific literature (usually emphasizing no sex differences) say, the published CDC findings show that younger girls (age 4 to 8) are more likely to be medicated than are children and youth in any other group. It is beyond the scope of this review to speculate on that finding, but investigations into whether sex role stereotypes about appropriate behavior in young girls may be clashing with the reality of behavior of girls with ADHD explain these much higher rates of medication. Health care coverage and health contact seem to be associated with levels of both diagnosis and medication, probably for the logical reason that children without medical homes are simply less likely to see providers who could potentially diagnose and treat them. How is ADHD treated? Central nervous system stimulants (amphetamines) are effective in the pharmacological treatment of ADHD. These medications include Adderall and Adderall XR (mixed‐salts amphetamine; extended release), Ritalin (methylphenidate), Concerta (sustained‐release capsule of methylphenidate), Dexedrine (dextroamphetamine), and recently‐approved Vyvanse (lisdexamfetamine). The U.S. Federal Government has classified all of these medications as Schedule II drugs, meaning they have high abuse potential, accepted medical indications with severe restrictions, and the possibility of leading to severe psychological or physical dependence (Hertz and Knight, 2005). Of late, Adderall may be on the way to becoming the drug of choice in the treatment of ADHD, surpassing Ritalin, because it can be taken in a once‐daily dose (as opposed to the twice‐daily regiment for Ritalin), its effects last longer, and its performance may be more satisfactory to the patient, at least as measured by less likelihood of switching medications over a six month period (Grcevich, Rowane, Marcellino, and Sullivan‐ Hurst, 2001citation). As cited in Forrester (2007), Adderall abuse reports to poison control centers in the US increased during 1997‐2001, and Adderall represented a rising proportion of the ADHD medications adolescents abused. Our media analysis (see attached) has also revealed that Adderall has become more popular among prescription 4 stimulant abusers than Ritalin in recent years. Adderallʹs growing presence in the consumer and research marketplace and its increasing uses both on‐ and off‐label persuaded us to target our literature review to Adderall rather than to Ritalin or to both agents. Adderall Adderall (Shire Pharmaceuticals Group) is approved for treatment of ADHD in the pediatric population (see packet insert for labeling information). The label provides dosing information for children ages 6 and older and states that amphetamines are not recommended for children age 3 and under. In a retrospective study of Adderall and methylphenidate to treat ADHD (Grcevich, Rowane, Marcellino, and Sullivan‐Hurst, 2001), researchers found no statistically significant difference in the efficacy or safety of the drugs. They did find that patients receiving Adderall were less likely to require twice‐ or thrice‐daily dosing than those receiving methylphenidate (p<0.001). In addition, during the initial 6‐month treatment period, compared to patients on methylphenidate, patients on Adderall were less likely to switch medications (p = 0.0002). What are the potential side effects and adverse effects of Adderall use? Stimulant medications are far less addicting when taken orally for medical treatment. The pharmacodynamic and pharmacokinetic properties of oral therapeutic stimulants differ from those of methamphetamine and cocaine (Greenhill, 2006). According to its label (see Appendix A), the adverse effects of Adderall use are heart‐ related problems (sudden death in patients who have heart problems or heart defects, stroke and heart attack in adults, and increased blood pressure and heart rate) and psychiatric problems (for all patients: new or worse behavior and thought problems, new or worse bipolar illness, and new or worse aggressive behavior or hostility; for children and teenagers: new psychotic symptoms [such as hearing voices, believing things that are not true, are suspicious] or new manic symptoms). The side effects listed in the label include slowing of growth (height and weight) in children; seizures, mainly in patients with a history of seizures; eyesight changes or blurred vision. Other common side effects include headache, decreased appetite, 5 stomach ache, nervousness, trouble sleeping, mood swings, weight loss, dizziness, dry mouth, and fast heart beat. As cited in Forrester (2007), the peer‐reviewed literature reports these adverse clinical effects of Adderall use: tachycardia, agitation, hypertension, insomnia, drowsiness, dizziness, headache, tremors, hallucination, nystagmus, dry mouth, nausea, vomiting, diarrhea, constipation, abdominal pain, reduced appetite, and anorexia. The side effects listed on the label and those most often emphasized in the literature are not exactly congruent. For example, “slowing of growth” is listed on the label, but not emphasized in the research studies, and “hallucination” – an alarming side effect, to be sure – is present in the literature but not listed on the label. Forrester’s analysis of Adderall abuse in six poison control centers in Texas from 1998‐ 2004 showed that the three most common types of adverse clinical effects for all exposures (abuse and nonabuse) were neurological (24.5%) and cardiovascular (13.4%). The most common neurological effect was agitation (15.7%) and the most common cardiovascular effect was tachycardia (11.2%). There was a statistically significant difference between the ratio of intentional abuse and nonabuse exposures for these adverse effects: chest pain, hypertension, tachycardia, nausea, dizziness, numbness, tremor, nystagmus, and hyperventilation. Abuse occurs when the drugs are taken in high doses (orally) or when administered intranasally or by injection, neither of which is an approved route. Who is using prescription stimulants such as Adderall for nonmedical purposes? Use of prescription stimulants for nonmedical purposes is most common among college students; studies show that it is also present among middle and high school student. The literature uses several terms to describe the use of prescription stimulants for nonmedical purposes (see Appendix A). In this review, when we describe a study, we use the language of the study authors. In our general discussion, we use the term nonmedical use to describe prescription drug use for any reason other than that for which it was prescribed. The terminology that we use in the parent tool warrants discussion. McCabe and colleagues (2006) studied medical and illicit use of abusable prescription medications (opioid, stimulant, sedative/anxiety, and sleeping) in a sample of approximately 9,000 undergraduates at a large, public university. Two percent of the sample reported illicit use of stimulant medication. Among the four classes of drugs, the illicit use‐medical use ratio for stimulant medication was the highest. 6 A recent study of medical and nonmedical use of prescription drugs among high school students (McCabe, Boyd, Young, 2007), showed that 2.4% of youth in grades 9‐12 had used prescription stimulants for a nonmedical purpose. This figure is similar to the rate found in another study of 7th‐12th grade students, where 2% of the sample had taken a stimulant for a nonmedical purpose (Boyd, McCabe, Cranford, and Young, 2006). These figures are slightly lower than those of another study, in which 4.5% of the study sample (youth grades 6‐11) admitted to illicit use of prescription stimulants (McCabe, Teter, and Boyd, 2004). One college campus study reported that some students, in preparation for an exam or writing a paper, volunteered that they ʺstockpileʺ medication and take a higher does than prescribed to stay awake and concentrate (White, Becker‐Blease, and Grace‐ Bishop, 2006); this finding, though suggestive, is not accompanied by systematic evidence. Parents and providers, however, may want to be aware that at least some students – who may have legitimate prescriptions ‐‐ reported to at least one group of researchers that they stockpile the drug. The literature suggests overall either that nonmedical use does not vary by sex, or that such use is more prevalent among boys. Routes of administration Among college students, researchers have found that illicit users report administering prescription stimulants orally (95.3%), intranasally (38.1%), and by smoking (5.6%); less than 1% report of users inhaled or injected prescription stimulants (Teter, McCabe, LaGrange et al. 2006). What motivates youth to use Adderall? In a recent survey of college students at a private liberal arts college in New England (Carroll, McLaughlin, and Blake, 2006), researchers found that 10% of the respondents reported nonmedical use of stimulants; moreover, 71.7% reported nonmedical use of stimulants among their peers and 53.3% knew of someone selling ADHD medications to students. In this study, the top four reasons nonprescription users cited for taking stimulants were to study longer (96.8%), stay awake (96.8%), study better (83.9%), and lose weight (51.7%). 7 At the University of Michigan, researchers used a Web‐based survey to examine the motives to abuse prescription stimulants in a random sample of 9,161 undergraduates. Of these students, 8.1% reported lifetime illicit use of prescription stimulants, and 5.4% reported past year illicit use. Men were more likely than women to report lifetime use (9.3% vs 7.2%, p < 0.001). The top three motives for use were for concentration (58%), to increase alertness (43%), and to obtain ʺa highʺ (43%). There were no sex differences in motives for illicit use (Teter, McCabe, Cranford et al., 2005). Another study of 150 students at a small college found that three most popular reasons for abusing prescription amphetamines were to improve intellectual performance (23.3%), to be more efficient on academic assignments (22.0%), and to use in combination with alcohol (19.3%) (Low and Gendaszek, 2002). The authors report that a small number (no figure provided) of women reported using stimulants for appetite or weight control. In this study, no sex differences in motivation for use existed, but men reported significantly more illicit use than did women (p<0.001) How are they getting it? Researchers from the National Center on Birth Defects and Developmental Disabilities (Daniel, Honein, and Moore, 2003) analyzed data from a mail survey (Youthstyles) of boys and girls aged 9 to 18. Of the 1,568 valid respondents, 10% reported having ever shared their prescription medications with someone else, and 13.5% reported having ever borrowed someone else’s medication. More girls (20.1%) than boys (13.4%) reported ever sharing or borrowing prescription medications. These behaviors were most common among girls 15‐18 years old (29.2%) Although no empirical evidence exists, anecdotal evidence suggests that parents and youth seek ADHD drugs directly from a clinician. Students fake the symptoms of ADHD to get a diagnosis for it. Clinicians around the country report that parent seek out these drugs for their children because they want them to excel in school; a means of doing that is ʺacademic doping” (Clayton, 2006). What are the signs and symptoms of stimulant drug misuse? Hertz and Knight (2005), citing Schydlower (2002), report that the signs and symptoms of stimulant drug misuse include 8 Physical effects: Central Nervous System (mydriasis, exhilaration, euphoria, self‐ confidence, and excitement; long‐term use may result in depression or agitation); Cognitive (increased concentration and alertness; with tolerance, may lead to paranoia, confusion. Psychosis may occur early or late in treatment, which may be accompanied by visual, tactile, or olfactory hallucinations); Gastrointestinal (decreased appetite, weight loss); Vital signs (hypertension, tachycardia) Toxic effects: Central Nervous System (restlessness, insomnia, tremor, hyperreflexia; severe toxic effects include seizure and coma); Mood (irritability); Cutaneous (diaphoresis, flushing); Vascular (risk for intracerebral hemorrhage, shock); Vitals (hypertension, tachypnea, mild hyperthermia; severe toxic effects may lead to hypertensive crisis, dysrhythmias) Withdrawal: Peak symptoms occur 2‐3 days after last dose. They may include mood swings including depression with suicidality and homicidality, increased appetite, drug craving, and exhaustion. What is the treatment for stimulant drug misuse or abuse? Oral overdose: ipecac syrup followed by activated charcoal and a cathartic (magnesium citrate); treat hypertension and hyperthermia; chlorpromazine may be used to treat the stimulant effects Withdrawal: nonspecific, symptomatic relief, monitoring of mental status for mood labiality, depression, suicidality; monitor vital signs Long‐term treatment: specialized chemical dependency program; relapse prevention may be necessary; close follow‐up; urine testing What are the nonmedical consequences of diverting, misusing, and abusing stimulants? [section to be included by time of meeting] What can parents do? Parents need to be educated on the potential for children and adolescents to abuse stimulant medications (Teeter, McCabe, Cranford, et al., 2005). The literature suggests 9 several ways in which parents can become involved in the effort to reduce the non‐ prescription medicines. Parents can do these things (among others yet to be discussed): 1. Monitor the dosage and frequency of use of medications in their ADHD‐ diagnosed children in order to detect possible signs of diversion (McCabe, Teeter, and Boyd 2004). 2. Emphasize the use of good study skills without resorting to medication (c.f. Sussman, Pentz, Spruijt and Miller 2006 for a general recommendation of this sort that we believe can be imparted to parents). 2. Educate themselves on the potential for abuse with stimulant medications (Teeter, McCabe, Cranford et al., 2005). 3. Educate children and adolescents about the risks of prescription medication sharing. 4. Keep prescription medicines in a secure place, where children and adolescents cannot get to them. 5. Be present at teen parties. Prescription and illegal drugs are 15 times more likely to be available at teen parties where parents are not present (CASA, 2007). 10 References American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders (DSM‐IV‐TR). Washington, DC: American Psychiatric Association. Boyd CJ, McCabe SE, Cranford JA, Young A. Adolescentsʹ motivations to abuse prescription medications. Pediatrics. 2006 Dec;118(6):2472‐80. Carroll BC, McLaughlin TJ, Blake DR. Patterns and knowledge of nonmedical use of stimulants among college students. Arch Pediatr Adolesc Med. 2006 May;160(5):481‐5. CASA (National Center on Addiction and Substance Abuse at Columbia University). “Eleventh Annual Teen Survey Reveals Teen Parties Filled with Alcohol and Drugs,” 2006 Annual Report, National Center on Addiction and Substance Abuse at Columbia University, 2007. Clayton, Victoria. Seeking straight Aʹs, parents push for pills: Pediatricians report increasing requests for ʹacademic doping.ʹ Sept 7, 2006. Available at http://www.msnbc.msn.com/id/14590058/. Last accessed July 10, 2007. Forrester MB. Adderall abuse in Texas, 1998‐2004. J Toxicol Environ Health A. 2007 Apr 1;70(7):658‐64. Grcevich S, Rowane WA, Marcellino B, Sullivan‐Hurst S. Retrospective comparison of Adderall and methylphenidate in the treatment of attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2001 Spring;11(1):35‐41. Hall KM, Irwin M, Bowman KA, Frankenberger W, Jewett DC. Illicit use of prescribed stimulant medication among college students. J Am Coll Health 53(4):167‐174. Hertz JA, Knight JR. Prescription drug misuse: a growing national problem. Adolesc Med Clin. 2006 Oct;17(3):751‐69. Low KG, Gendaszek AE: Illicit use of psychostimulants among college students: A preliminary study. Psychol Health Med 2002, 7:283‐287. 11 MayoClinic Online (2007). Attention Deficit‐Hyperactivity Disorder. Available at http://www.mayoclinic.com/health/adhd/DS00275/DSECTION=1. Last accessed on July 9, 2007. McCabe SE, Boyd CJ, Young A. Medical and nonmedical use of prescription drugs among secondary school students. J Adolesc Health. 2007 Jan;40(1):76‐83. Epub 2006 Oct 5. McCabe SE, Knight JR, Teter CJ, Wechsler H. Non‐medical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction. 2005 Jan;100(1):96‐106. Erratum in: Addiction. 2005 Apr;100(4):573. McCabe SE, Teter CJ, Boyd CJ. Medical use, illicit use, and diversion of abusable prescription drugs. J Am Coll Health. 2006 Mar‐Apr;54(5):269‐78. McCabe SE, Teter CJ, Boyd CJ. The use, misuse and diversion of prescription stimulants among middle and high school students. Subst Use Misuse. 2004 Jun;39(7):1095‐ 116. Schydlower M, editor. Substance abuse: a guide for health professionals. 2nd edition. Elk Grove Village, IL: American Academy of Pediatrics, 2002. Sussman S, Pentz MA, Spruijt‐Metz D, Miller T. Misuse of ʺstudy drugs:ʺ prevalence, consequences, and implications for policy. Subst Abuse Treat Prev Policy. 2006 Jun 9;1:15. Teter CJ, McCabe SE, Cranford JA, Boyd CJ, Guthrie SK: Prevalence and motives for illicit use of prescription stimulants in an undergraduate student sample. J Am Coll Health 2005, 53:253‐262. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ. Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy. 2006 Oct;26(10):1501‐10. Visser SN, Lesesne CA, Perou R. National estimates and factors associated with medication treatment for childhood attention‐deficit/hyperactivity disorder. Pediatrics. 2007 Feb;119 Suppl 1:S99‐106. 12 Visser SN, Lesesne CA. Mental Health in the United States: Prevalence of Diagnosis and Medication Treatment for Attention‐Deficit/Hyperactivity Disorder ‐‐‐ United States, 2003. Division of Human Development and Disability, National Center on Birth Defects and Developmental Disabilities, CDC. MMR Weekly September 2, 2005, 54(34);842‐847. White BP, Becker‐Blease KA, Grace‐Bishop K. Stimulant medication use, misuse, and abuse in an undergraduate and graduate student sample. J Am Coll Health. 2006 Mar‐Apr;54(5):261‐8. 13 Appendix A. Prescription Drug Misuse and Abuse Definitions Boyd and colleagues (2006) acknowledge that one problem with the literature on nonmedical use of prescription drugs is that researchers from different disciplines use different terms to describe this phenomenon. In their view, nonmedical use, prescription drug abuse, and illicit use of prescription medications all refer to the use of a prescription medication to create an altered state, to get high, or for reasons other than those intended by the prescribing clinician. The terms medical misuse and noncompliant use of prescription medications refers to patients who use a medication in ways other than those explicitly provided in the prescription (e.g., changing the prescribed dose and/or time interval). In their study, Boyd and colleagues used the term nonmedical use; other researchers have favored this term as well (Carroll, McLaughlin, and Blake, 2006; McCabe, Knight, Teter, et al., 2005). Other researchers use these terms to refer to nonmedical use: Prescription drug misuse – inappropriate use of prescription medications (Hertz and Knight, 2005) Illicit use or abuse – use of a prescription drug without a prescription (Teter, McCabe, LaGrange, et al., 2006; Teter, McCabe, Cranford, et al., 2005; Hall, Irwin, Bowman, et al., 2005; McCabe, Teter, Boyd, 2004; Low and Gendaszek, 2002) [these articles are among those that use the various terms in slightly different ways, and consistent use of terminology is something on which the working group needs to agree as we develop the tool.] Other relevant terms for this topic include: Diversion is both (a) the selling, giving, or trading prescribed medications to individuals other than the patient for whom they are intended, and (b) theft or fraud involving prescribed medications (Hertz and Knight, 2005). Off‐label use is use of a drug for any purpose other the indications listed on the label. 14