From the University of South Carolina, Columbia, SC.

Abstract

• Objective: To provide a summary of the existing research on the characteristics of college students who report misusing prescription stimulant medications, to offer a set of clinical recommendations for practitioners, and to offer several possible prevention strategies.
• Methods: Literature review and research-based recommendations for clinical practice and prevention.
• Results: Misuse of prescription stimulant medication among college students is a prevalent and growing problem. Significant risk factors for misuse of stimulant medication include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Suggestions for preventing misuse and diversion of prescription stimulant medications, including strategies for the individual and potential policy changes on college campuses, are offered.
• Conclusions: Misuse and diversion of prescription stimulant medications is a growing concern among adolescents and young adults and should be addressed by health care practitioners. Additional research on effective intervention and prevention strategies is needed.

Prescription stimulant medications (eg, methylphenidate, amphetamines) are typically used for the treatment of attention-deficit/hyperactivity disorder (ADHD) to increase attentiveness, decrease distractibility, and improve daily functioning. Prescriptions for stimulant medications are on the rise; between 2002 and 2010, the number of prescriptions for ADHD medications for youth under 18 increased 46% [1].

A recent review of ADHD diagnosis among college students estimated a prevalence rate of 2% to 8% [2]. More individuals with ADHD are matriculating to college than in the past [3,4], as more supports have been put in place for college students diagnosed with ADHD, including improved educational/organizational treatments and accommodations [2]. Many college students with ADHD also use prescription stimulant medications as part of their treatment plan; McCabe, Teter, and Boyd reported that 2.2% of college students had prescriptions for stimulant medications annually [5].

As the number of individuals of all ages with stimulant medication prescriptions increase, more individuals without prescriptions are gaining access to stimulant medications. In a survey of college students with medication prescriptions, stimulants were the most commonly diverted medication, with 61.7% of students with these prescriptions reporting having shared or sold their medication at least once [6]. Studies report that as many as 43% of college students have misused stimulant medication in their lifetime [7], though prevalence rates vary by study. Throughout this review, “misuse of stimulant medication” refers to using prescription stimulant medications without a prescription or using more stimulant medication than prescribed (ie, a higher or more frequent dosage).

Given the ease with which college students are able to obtain stimulant medications, the alarming prevalence of stimulant medication misuse among this population, and the potentially serious health risks associated with misuse of stimulant medication (especially when combined with other substances, such as alcohol, that are commonly used by college students), there is a need to both better understand and ultimately reduce the misuse of stimulant medication among college students. Thus, the purpose of this paper is threefold. First, we provide a summary of the existing research literature on the characteristics of college students who report misusing stimulant medication. Second, we offer a set of clinical recommendations for practitioners, which includes stimulant medication indications, risks, benefits, and side effects, along with problems associated with stimulant medication diversion and misuse. Finally, we offer several prevention strategies, including strategies for the individual as well as several suggestions for changing policies on college campuses to prevent stimulant diversion and misuse. Importantly, although our literature review addresses prescription stimulant misuse among college students, our clinical recommendations are also appropriate for adolescents and young adults not enrolled in college.

Summary of the Literature

The following summary is based on a comprehensive search of the existing research literature on misuse of stimulant medication among college students, which ultimately identified 30 relevant studies using 21 unique samples. A study was included if: (1) the main focus of the study was misuse of stimulant medication, (2) it was a peer-reviewed, empirical study using quantitative data analytic techniques, (3) it was written in English, (4) only undergraduate students were included in the sample, (5) it did not focus on only one type of stimulant medication (eg, methylphenidate only), and (6) if the article discussed multiple prescription drug categories (eg, stimulants, opiates), the data must have been analyzed separately for each category. An extensive meta-analytic review of this literature will be published elsewhere (contact the corresponding author to request a reprint). The following is a brief summary of our findings.

Prevalence, Availability, and Demographic Characteristics

Among prevalence rates reported, lifetime rates of stimulant medication misuse were the most frequently reported, ranging from 8.1% [8] to 43% [7]. Rates of misuse of stimulant medications within the last year ranged from 5.3% [9] to 35.3% [10]. A number of the studies asked students how they obtained stimulant medications for misuse; peers were overwhelmingly the most common source for obtaining the medications. For example, DeSantis, Webb, and Noar [11] found that 91% of the undergraduates who were interviewed obtained stimulant medications from friends or significant others.

Perceived availability of stimulant medications was also measured in several studies. DeSantis, Webb, and Noar [11] found that 82% of students thought it was somewhat or very easy to obtain stimulant medication; however, Sharp and Rosén [12] found that only 55% of students thought it was somewhat or very easy to obtain stimulant medication. In another study that examined perceived availability, 37% of men and 29.2% of women agreed that they knew students who would provide them with stimulant medications [13].

Many of the studies reviewed examined the relation between particular demographic characteristics (eg, gender, race, socioeconomic status, religious affiliation, year in college, sorority or fraternity membership) and misuse of stimulant medication among college students. The vast majority of studies that examined gender as related to misuse of stimulant medication found that significantly more males misused stimulant medication than females. For example, one study found that 26% of males and 17.3% of females reported misusing stimulant medication [14]; another study found that 39% of males versus 30% of females reported misuse [11].

It is also clear from the existing literature that members of fraternities and sororities appear to be more at-risk for misuse of stimulant medication than non-Greek students. In multiple studies, Greek students had rates of misuse twice that of non-Greeks. For instance, 48% of Greeks misused in their lifetime compared to 22% of non-Greeks [11]; 12% of Greeks misused in the past year compared to 5% of non-Greeks [15]; and Greeks were 2.32 times more likely to initiate use than non-Greeks [9].

Unfortunately, results from studies examining other demographic characteristics (eg, race, socioeconomic status, religious affiliation, year in college) as related to misuse of stimulant medication are much less conclusive and these correlates therefore require further investigation.

Motives For Misuse and Perceived Risk

Researchers have also evaluated college students’ motives for misusing stimulant medication and the risks they associate with misuse. All of the studies that asked misusing students about their motives for misuse reported that the most commonly endorsed motives were related to academics. “To concentrate better while studying” [16], “to improve study skills” [17], “to stay awake to study longer” [11], and “to improve concentration” [18] were some of the most commonly endorsed motives in these studies. Nonacademic reasons, such as to get high, to prolong effects of alcohol and other drugs, and to lose weight, were less commonly endorsed [7,12,19]. In studies where participants were able to indicate multiple motives for misuse [16], very few students misused for only nonacademic reasons.

Several studies measured the relation between misuse of stimulant medication and perceived risk associated with misuse. Perceived risk was conceptualized as perceived harmfulness [20], perception of safety [14], concern with health risk [18], and the inverse of positive outcome expectancies [21]. These articles found that when college students perceive more risk or have less positive expectancies about stimulant medication misuse, they are less likely to misuse stimulant medication. For instance, those who associated stimulant medication misuse with low perceived harmfulness were over 10 times more likely to have used in the last year than those who associated misuse with high perceived harmfulness [20].

Academic Outcomes Associated with Misuse

Interestingly, despite academic motives being most common for college students who report misusing stimulant medication, a number of studies have found a negative association between academic outcomes and misuse of stimulant medication. For instance, nonusers reported an average grade-point average (GPA) of 3.28 compared to 3.16 for misusers [16]. Other research demonstrates that the lower the student’s GPA is, the greater the odds are of the student misusing stimulant medication [8]. Misuse is also significantly related to other detrimental academic behaviors such as skipping class and less studying [20,22].

Psychological Correlates of Misuse

Researchers have evaluated the relation between several different psychological variables and misuse of stimulant medication. The strongest association is between symptoms of ADHD and stimulant medication misuse. Studies are consistent in reporting a significant correlation between greater symptoms of ADHD and higher rates of misuse or a significant difference in rates of misuse between those who have an ADHD diagnosis and those who do not. One study found that 71.1% of stimulant medication misusers screened positive for adult ADHD symptoms [17]. Another study found that for every standard deviation increase in attention problems, the odds of becoming a stimulant misuser increased by 1.78 [9]. Two studies asked participants if they believed they had ADHD. Advokat, Guildry, and Martino found that 12% of misusers believed they had ADHD [7]. Twenty-nine percent of “self-diagnosers” reported misusing, compared to 11.4% of “non-diagnosers” in another study [18].

Although the literature base is smaller than for ADHD, several studies have suggested a significant difference in symptoms of depression between stimulant medication misusers and nonusers. Zullig and Divin [23] found that misusers were significantly more likely to feel very sad, feel depressed, and consider suicide than nonusers. More frequent misuse has also been shown to be significantly associated with depressed mood [24].

A number of studies demonstrate a clear association between high sensation-seeking and misuse of stimulant medication. These results are not surprising given the well-documented relation between sensation seeking and substance use [25–27]. One study found a significant interaction between sensation seeking and perceived harmfulness of misusing stimulant medication: those with high sensation seeking and low perceived harmfulness were most likely to misuse [20].

Other Substance Use Associated with Stimulant Misuse

Many of the reviewed studies found a positive correlation between misuse of stimulant medication and other substance use or a significant difference between stimulant misusers and nonusers in rates of other substance use. These findings held across all substances examined, including alcohol, cigarettes, marijuana, illicit stimulants (eg, ecstasy, cocaine, or amphetamines), and non-stimulant prescription medications. For instance, significant associations were found between misuse of stimulant medication and several alcohol-related constructs, such as binge drinking [28,29], problematic drinking behavior [30], or meeting the Diagnostic and Statistical Manual of Mental Disorders [21] criteria for alcohol abuse [22]. With respect to cigarettes, 50.3% of misusers were found to have smoked cigarettes in the last 6 months compared to 13.3% of nonusers [16]. Similar findings emerged for illicit drug use. One study found that 73.5% of stimulant medication misusers reported use of marijuana in the last 6 months, compared to 18.2% of nonusers [19], while another study found that 93% of misusers used marijuana in the last year compared to 34% of nonusers [5]. This same study found that 33% of stimulant medication misusers also reported cocaine use in the last year compared to 2% of stimulant nonusers [5]. Finally, many of the studies reviewed examined the association between other substance use in general and stimulant medication misuse. Results were striking; the odds of becoming a stimulant medication misuser increased by 3.81 for each standard deviation increase in the amount of other substance use [9].

Summary

The research literature reviewed in this section provides a descriptive characterization of which college students (and, by extension, adolescents and young adults not in college) may be at the greatest risk of misuse of stimulant medication. Significant risk factors include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. It is important to recognize that one, several, or many of these risk factors may be present in a given individual who is misusing stimulant medication. Moreover, there may be other risk factors not yet identified in the research literature. The following sections of this paper draw from the literature reviewed here to provide a number of clinical recommendations for reducing and preventing misuse of stimulant medications among college students, other young adults, and adolescents.

Clinical Recommendations

It is important for health care providers to be aware of the benefits and risks associated with stimulant medications, the prevalence of and risk factors for stimulant misuse, and the psychiatric, psychological, and medical comorbidities associated with the misuse of stimulant medication. Knowledge about stimulant medications, misuse of stimulant medications, and a thorough evaluation of the patient will enable health care providers to address the misuse, as well as any comorbidities or other factors that may contribute to stimulant medication misuse, either pharmacologically or through referral for more specified psychotherapeutic interventions.

Stimulant Medication Indications and Adverse Effects

Stimulant medications are efficacious for the treatment of ADHD and, when prescribed and used correctly, can improve attentiveness, decrease distractibility, and improve daily functioning in the short term [19]. When used by individuals without ADHD, patients may experience euphoria, stimulation, alertness, and are not likely to experience the cognitive benefits that those with ADHD receive [31]. Side effects can occur regardless of whether the individual is using the stimulant for ADHD, misusing, or is dependent, and include nervousness, headaches, tachycardia, poor appetite, depressed mood, and poor sleep [19,32]. Additionally, stimulant medications can cause psychosis, agitation, and hallucinations [31,33], which typically resolve after discontinuation of the stimulant within 2 to 6 days, though a longer time period to resolution has been reported [33]. Stimulant medications carry warnings about increased risk of sudden death, high blood pressure, cardiac arrest, and stroke, as well as a statement warning providers about abuse potential. Additionally, serious but rare medical complications, including seizures, tachycardia or dysrhythmias, and hyperthermia, can occur [31,34].

Physical Examination and Laboratory Data

Obtaining vital signs and performing a physical exam may reveal weight loss and an increase in heart rate or blood pressure. Methylphenidate and amphetamines are known to increase heart rate and blood pressure [35] and a recent study found an average increase in heart rate of 5.7 bpm and a 1.2–mm Hg increase in systolic and diastolic blood pressure in adults on stimulant medications compared to placebo [36]. No EKG abnormalities or changes are found with either methylphenidate or amphetamine [35]. Urine toxicology can be utilized to obtain further information if misuse is suspected. However, the clinician must be aware of the limitations of urine drug testing with stimulants [37]. The usual detection time for amphetamines is 48 hours from last use, though this may vary depending on the presence of metabolites, pharmacokinetics of the drug (eg, immediate release vs. sustained release formulations), and patient variables [37]. Additionally, a urine toxicology screen for amphetamines typically tests for amphetamines, racemic compounds such as dextroamphetamine and methamphetamine, and illicit compounds (ie, methylenedioxymethamphetamine), though there are many compounds that are structurally similar, such as weight loss agents, over-the-counter cold products, and other psychotropic medications, including methylphenidate, that can cause a false-positive result [37]. Urine toxicology should be obtained in conjunction with a thorough evaluation of patients’ alcohol and drug use patterns. These 2 components are essential to the accurate diagnosis and formulation of a comprehensive treatment plan. As noted above, stimulant medication misuse and alcohol and illicit drug use are highly comorbid and should be carefully and thoroughly assessed.

Psychiatric Comorbidity

ADHD

The prevalence of ADHD is higher among individuals with substance use disorders [38]. As noted above, patients commonly report misuse of stimulant medication to enhance academic performance. One explanation may be that individuals misusing stimulants may be self-medicating undiagnosed ADHD [39]. The prevalence of ADHD among adults is 4.1% and it is more common in men than women with a ratio of up to 6:1 [40]. Several studies have found that individuals with misuse of stimulant medications endorse symptoms of ADHD, including higher levels of inattention and hyperactivity [41]. Twelve percent of participants in one study that endorsed stimulant medication misuse also endorsed the belief they had ADHD [7]. Another study found that individuals with higher baseline self-reported ADHD symptoms were also more likely to misuse stimulants [42]. The majority of individuals with ADHD have been found to take medications appropriately, though there is a minority, often with comorbid conduct disorder or other substance use disorders, that divert or misuse stimulant medications, most often the immediate release formulations [43,44].

Accurate diagnosis of ADHD in patients with substance use disorders can be challenging given the symptom overlap between intoxication and withdrawal syndromes of substances and symptoms of ADHD. Evaluating for ADHD is an important part of a thorough assessment and can be completed in several ways. The gold standard is with a standardized diagnostic tool such as the Connors Adult ADHD Diagnostic Interview for DSM-IV (CAADID) [45], which can be time consuming for a clinician and would likely involve referral to a psychologist for completion. Other scales have been examined, and the Connors Adult ADHD Rating Scale (CAARS) has been found to closely agree with the CAADID when both are administered [45]. Other scales are available, including the Wender Utah Rating Scales (WURS) and the Adult ADHD Self-Report Scale (ASRS), and have been found to have adequate sensitivity and specificity [45]. In an international study, the ASRS, a relatively brief instrument, showed encouraging results with 84% sensitivity and 66% specificity in detecting ADHD upon entry into substance disorder treatment for treatment-seeking patients [46]. When diagnosing ADHD among adults, it is crucial not to rely only on self-reported symptoms. A thorough childhood history of ADHD symptom presentation should be collected from a parent or caregiver, and collateral concurrent report should be collected from someone who knows the patient well, such as an employer, close friend, significant other, or parent. Valid diagnosis, whether ADHD is present or not, is of utmost importance in this population as individuals with comorbid substance use disorders and ADHD tend to have worse outcomes overall [47]. It is also important to appreciate that inaccurately diagnosing ADHD in individuals misusing stimulants could potentially diminish the importance of the diagnosis [48].

If ADHD is found, there are medications available that have a lower abuse potential compared to stimulant medications. Atomoxetine is the only FDA-approved nonstimulant for ADHD; off-label or second-line treatments include antidepressants, such as bupropion, venlafaxine, or tricyclic antidepressants, for which the data is limited, and clonidine [34,49,50]. If these therapies are not effective and, after careful consideration of risks and benefits, it is determined that a trial with a stimulant is needed, longer-acting formulations appear to be less abused [34,44]. Education for both the patient and his or her family should be provided on abuse and diversion potential and appropriate use and misuse [34,43,51]. Pill counts [43], regular office visits [52], and random urine toxicology screens [34] with informed interpretation of the screens may be helpful in deterring misuse or diversion. While medications are the mainstay of treatment for ADHD, there are several psychosocial interventions available, including cognitive behavioral therapy, coaching, and behavioral modification therapies [34].

Other Comorbidities

Other psychiatric comorbidities also should be explored. Studies have found a relation between depression and misuse of stimulant medication in that there is an increased likelihood of depression and thoughts of suicide among those that misuse stimulant medication and vice versa [23,24,53]. The National Survey on Drug Use and Health in 2012 found that, of those that misused stimulants, nearly 20% had serious thoughts of suicide over the past year [54]. As noted earlier, stimulant medication can affect sleep and appetite. Among those that report misuse of stimulant medication for weight loss, these individuals are more likely to report other eating-disordered behaviors [55]. Sleep quality is worse and sleep disturbance greater in those that misuse stimulant medication [32]. Other traits and behaviors that have been described in individuals that misuse stimulant medications include impulsivity [56,57], sensation seeking [20], perfectionism [58], and poor time management skills or procrastination [59].

Appropriate treatment (which may include pharmacologic, psychological, or academic accommodation components) for individuals with these psychiatric disorders or psychological symptoms may reduce the misuse of stimulant medications among college students, especially if these students are misusing in order to reduce their symptoms (ie, a self-medication hypothesis).

Treatment

There are currently no FDA-approved medications to treat stimulant medication misuse. In fact, studies exploring pharmacotherapy for stimulant medication misuse are limited. Most trials focus on stimulants such as cocaine or methamphetamine and not stimulant medications alone. Additionally, these trials primarily include only individuals that meet criteria for stimulant dependence. Various medications and medication classes have been examined for the treatment of stimulant dependence, including naltrexone, various antipsychotics, and various antidepressants including bupropion, modafanil, baclofen, ondansetron, and dexamphetamine, with little to no effect [60]. In a review of the literature, one study examined the use of naltrexone versus placebo for stimulant dependence in 80 treatment-seeking Swedish individuals [61]. The different types of stimulants on which these individuals were dependent were not clearly delineated, though the study authors noted that the major amphetamine abused in Sweden was the racemic mixture d/l amphetamine and not methamphetamine. Naltrexone was superior to placebo in this trial, as evidenced by higher percentage of amphetamine-free urine samples. A large majority of this sample used intravenously (65%–76%) and had been using between 6 to 8 years, limiting the applicability to individuals with stimulant medication misuse. At this time, investigation into evidence-based pharmacotherapies for stimulant medication misuse remains in the early stages.

Generally speaking, efficacious behavioral treatments, such as contingency management (CM), cognitive behavioral therapy (CBT), skills training, motivational interviewing (MI), relapse prevention, couples and family treatments, and drug counseling, exist for drug abuse [62]. CBT, cognitive therapy, CM, MI, and community reinforcement approach (CRA) [63,64] have been explored for stimulant dependence and are currently the primary interventions for amphetamine-type stimulant dependence [60]. Similar to pharmacotherapy studies, most psychotherapy studies to date have examined primarily cocaine and methamphetamine dependence and not misuse of stimulant medications. In fact, no studies examining psychotherapy for stimulant medication misuse were found by our group in a search using the PubMed database. Therefore, discussion of psychotherapeutic interventions that may be efficacious for stimulant medication misuse extrapolates outcomes from studies of stimulant dependence, appreciating this is an approximation and imprecise as there are significant differences between stimulant medication misusers and those dependent upon stimulants such as methamphetamine or cocaine. As such, in a review from 2009 [63], Vocci and colleagues compared psychotherapy studies for cocaine and methamphetamine dependence and concluded that CBT and CM were moderately effective and that adding CM to standard treatment may help improve outcomes. A study of 214 amphetamine users (including methamphetamine users), with the majority (70%) enrolled in a methadone maintenance program and a large proportion (58.9%) using amphetamines intravenously, found that either 2 or 4 sessions of CBT, along with self-help material, increased rate of abstinence at 6 months post-intervention compared to the use of self-help material alone [65]. Baker and colleagues [64] recommend a practical stepped approach to treatment for stimulant dependence, including conducting a thorough assessment, offering education and self-help materials, monitoring use and consequences of use, and then transitioning to more intensive psychosocial interventions if needed, which may be applicable to those with stimulant medication misuse and is clinically reasonable. Offering a psychosocial intervention may require referral to more specialized treatment services than can be offered in a general primary care clinic. Additionally, harm reduction techniques for stimulant medication misusers to reduce the medical and social consequences can be considered as well as prevention strategies and methods, which can be utilized in any treatment setting or in high-risk populations, such as college students.

Prevention Strategies for the Individual

The research findings summarized in this review suggest several specific strategies for preventing and reducing the misuse of stimulant medication among college students, a high-risk population. First, college students with a prescription for stimulant medication play a critical role. Not only do these students have a high rate of misuse themselves [28,66], but they are also the most common source from which other students obtain stimulant medication to misuse [11,67]. It is therefore important for physicians who provide college students with prescriptions for stimulant medications to discuss the possible consequences of misusing or diverting medication, including potential negative health outcomes, legal consequences, and on-campus repercussions, for students caught diverting stimulant medications. These practitioners should also monitor their patients for signs of diversion, such as finishing a prescription early, doctor shopping, or urine drug screen which is negative for the prescribed substance. Utilizing a prescription monitoring program to access information on the prescribing and filling of controlled substances can be a valuable tool in detecting multiple concomitant prescriptions for stimulant medications, number of providers writing stimulant medication, and information on the use of other prescribed controlled medications. Providers should also discuss safe storage of stimulant medications with patients, particularly if the student is currently living in a dorm setting or another community-type setting with the potential for lots of individuals in and around their personal belongings. Additionally, providers may wish to consider dispensing a small amount at each office visit until the patient has established responsible use of the medication, particularly if there are other findings or comorbidities that perhaps increase their risk of misuse. Pill counts and frequent office visits, as noted earlier, may also help prevent diversion.

Perceived risk/harm associated with the use of stimulant medications has been negatively related to misuse [18,20]. If college students were more aware of the risks associated with stimulant medication misuse, with regards to both health and legal consequences, fewer students may choose to misuse stimulants. Educating patients and their families about the abuse potential of stimulants, as well as consequences of misuse such as psychosis and agitation, when prescriptions are given for stimulant medication, may help address the misperception that stimulant medications are benign, safe and without adverse consequences.

College Policy Changes for Prevention of Misuse

Policy changes on college campuses could also help to reduce diversion of stimulant medications. For instance, education about the risks associated with stimulant medication misuse could be incorporated into other alcohol and drug prevention programs that are already in place at colleges and universities. Many colleges/universities require all first-year students to complete an online substance use education/prevention/assessment tool. Some of these, such as AlcoholEdu and The Alcohol eCHECKUP TO GO have demonstrated some success in reducing college student alcohol use in follow-up evaluations [68]. Information about misuse of stimulant medication could be included in these existing programs. Moreover, members of certain organizations (eg, fraternities or sororities) that are known for an increased risk of substance use/abuse among members are also sometimes required by their national chapters or host colleges/universities to complete a “risk management” class, which addresses behaviors such as binge drinking and drunk driving. Since one of the demographic factors most strongly related to stimulant medication misuse is Greek organization membership [14], presenting information about stimulant medication misuse to these groups during these classes could help reduce misuse on college campuses.

Finally, the most commonly reported motives for misuse of stimulant medications among college students are academic in nature (eg, to study more, to concentrate better) [16], and many students who misuse for these reasons feel the desired effect is achieved. Colleges and universities may need to improve the identification of students who are in need of academic assistance/supports and offer these interventions earlier in students’ college careers to prevent stimulant medication misuse as a “quick fix.” Such interventions may include teaching students skills such as note-taking and academic goal setting and educating students about the link between sleep deprivation and poor concentration [69].

Summary

Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Diagnosing ADHD can be invaluable for individuals with the disorder, thus the ability to perform a thorough and accurate assessment is important; equally important is the ability to assess when ADHD is not present. Education and prevention strategies to prevent misuse and diversion should be provided if stimulant medications are indicated. College programs and policies can also utilize prevention strategies, provide education to students, and assist those with academic difficulties. Comorbidities are common and should be explored thoroughly as they may play a role in continued stimulant medication misuse and outcomes. Various treatment techniques and modalities can be explored further with each patient, based on the individual and their particular needs.

Corresponding author: Kate Flory, Univ. of South Carolina, Dept. of Psychology, Barnwell College, Columbia, SC 29208, [email protected].

Funding/support: Work on this paper was supported by a University of South Carolina Honors College Exploration Scholar Award and a University of South Carolina Magellan Fellowship, both awarded to Kari Benson.

Financial disclosures: None.

Author contributions: conception and design, KF, RAP, KB; drafting of article, KF, RAP, KB; critical revision of the article, KF, RAP, KB; literature search, KB.

From the University of South Carolina, Columbia, SC.

Abstract

• Objective: To provide a summary of the existing research on the characteristics of college students who report misusing prescription stimulant medications, to offer a set of clinical recommendations for practitioners, and to offer several possible prevention strategies.
• Methods: Literature review and research-based recommendations for clinical practice and prevention.
• Results: Misuse of prescription stimulant medication among college students is a prevalent and growing problem. Significant risk factors for misuse of stimulant medication include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Suggestions for preventing misuse and diversion of prescription stimulant medications, including strategies for the individual and potential policy changes on college campuses, are offered.
• Conclusions: Misuse and diversion of prescription stimulant medications is a growing concern among adolescents and young adults and should be addressed by health care practitioners. Additional research on effective intervention and prevention strategies is needed.

Prescription stimulant medications (eg, methylphenidate, amphetamines) are typically used for the treatment of attention-deficit/hyperactivity disorder (ADHD) to increase attentiveness, decrease distractibility, and improve daily functioning. Prescriptions for stimulant medications are on the rise; between 2002 and 2010, the number of prescriptions for ADHD medications for youth under 18 increased 46% [1].

A recent review of ADHD diagnosis among college students estimated a prevalence rate of 2% to 8% [2]. More individuals with ADHD are matriculating to college than in the past [3,4], as more supports have been put in place for college students diagnosed with ADHD, including improved educational/organizational treatments and accommodations [2]. Many college students with ADHD also use prescription stimulant medications as part of their treatment plan; McCabe, Teter, and Boyd reported that 2.2% of college students had prescriptions for stimulant medications annually [5].

As the number of individuals of all ages with stimulant medication prescriptions increase, more individuals without prescriptions are gaining access to stimulant medications. In a survey of college students with medication prescriptions, stimulants were the most commonly diverted medication, with 61.7% of students with these prescriptions reporting having shared or sold their medication at least once [6]. Studies report that as many as 43% of college students have misused stimulant medication in their lifetime [7], though prevalence rates vary by study. Throughout this review, “misuse of stimulant medication” refers to using prescription stimulant medications without a prescription or using more stimulant medication than prescribed (ie, a higher or more frequent dosage).

Given the ease with which college students are able to obtain stimulant medications, the alarming prevalence of stimulant medication misuse among this population, and the potentially serious health risks associated with misuse of stimulant medication (especially when combined with other substances, such as alcohol, that are commonly used by college students), there is a need to both better understand and ultimately reduce the misuse of stimulant medication among college students. Thus, the purpose of this paper is threefold. First, we provide a summary of the existing research literature on the characteristics of college students who report misusing stimulant medication. Second, we offer a set of clinical recommendations for practitioners, which includes stimulant medication indications, risks, benefits, and side effects, along with problems associated with stimulant medication diversion and misuse. Finally, we offer several prevention strategies, including strategies for the individual as well as several suggestions for changing policies on college campuses to prevent stimulant diversion and misuse. Importantly, although our literature review addresses prescription stimulant misuse among college students, our clinical recommendations are also appropriate for adolescents and young adults not enrolled in college.

Summary of the Literature

The following summary is based on a comprehensive search of the existing research literature on misuse of stimulant medication among college students, which ultimately identified 30 relevant studies using 21 unique samples. A study was included if: (1) the main focus of the study was misuse of stimulant medication, (2) it was a peer-reviewed, empirical study using quantitative data analytic techniques, (3) it was written in English, (4) only undergraduate students were included in the sample, (5) it did not focus on only one type of stimulant medication (eg, methylphenidate only), and (6) if the article discussed multiple prescription drug categories (eg, stimulants, opiates), the data must have been analyzed separately for each category. An extensive meta-analytic review of this literature will be published elsewhere (contact the corresponding author to request a reprint). The following is a brief summary of our findings.

Prevalence, Availability, and Demographic Characteristics

Among prevalence rates reported, lifetime rates of stimulant medication misuse were the most frequently reported, ranging from 8.1% [8] to 43% [7]. Rates of misuse of stimulant medications within the last year ranged from 5.3% [9] to 35.3% [10]. A number of the studies asked students how they obtained stimulant medications for misuse; peers were overwhelmingly the most common source for obtaining the medications. For example, DeSantis, Webb, and Noar [11] found that 91% of the undergraduates who were interviewed obtained stimulant medications from friends or significant others.

Perceived availability of stimulant medications was also measured in several studies. DeSantis, Webb, and Noar [11] found that 82% of students thought it was somewhat or very easy to obtain stimulant medication; however, Sharp and Rosén [12] found that only 55% of students thought it was somewhat or very easy to obtain stimulant medication. In another study that examined perceived availability, 37% of men and 29.2% of women agreed that they knew students who would provide them with stimulant medications [13].

Many of the studies reviewed examined the relation between particular demographic characteristics (eg, gender, race, socioeconomic status, religious affiliation, year in college, sorority or fraternity membership) and misuse of stimulant medication among college students. The vast majority of studies that examined gender as related to misuse of stimulant medication found that significantly more males misused stimulant medication than females. For example, one study found that 26% of males and 17.3% of females reported misusing stimulant medication [14]; another study found that 39% of males versus 30% of females reported misuse [11].

It is also clear from the existing literature that members of fraternities and sororities appear to be more at-risk for misuse of stimulant medication than non-Greek students. In multiple studies, Greek students had rates of misuse twice that of non-Greeks. For instance, 48% of Greeks misused in their lifetime compared to 22% of non-Greeks [11]; 12% of Greeks misused in the past year compared to 5% of non-Greeks [15]; and Greeks were 2.32 times more likely to initiate use than non-Greeks [9].

Unfortunately, results from studies examining other demographic characteristics (eg, race, socioeconomic status, religious affiliation, year in college) as related to misuse of stimulant medication are much less conclusive and these correlates therefore require further investigation.

Motives For Misuse and Perceived Risk

Researchers have also evaluated college students’ motives for misusing stimulant medication and the risks they associate with misuse. All of the studies that asked misusing students about their motives for misuse reported that the most commonly endorsed motives were related to academics. “To concentrate better while studying” [16], “to improve study skills” [17], “to stay awake to study longer” [11], and “to improve concentration” [18] were some of the most commonly endorsed motives in these studies. Nonacademic reasons, such as to get high, to prolong effects of alcohol and other drugs, and to lose weight, were less commonly endorsed [7,12,19]. In studies where participants were able to indicate multiple motives for misuse [16], very few students misused for only nonacademic reasons.

Several studies measured the relation between misuse of stimulant medication and perceived risk associated with misuse. Perceived risk was conceptualized as perceived harmfulness [20], perception of safety [14], concern with health risk [18], and the inverse of positive outcome expectancies [21]. These articles found that when college students perceive more risk or have less positive expectancies about stimulant medication misuse, they are less likely to misuse stimulant medication. For instance, those who associated stimulant medication misuse with low perceived harmfulness were over 10 times more likely to have used in the last year than those who associated misuse with high perceived harmfulness [20].

Academic Outcomes Associated with Misuse

Interestingly, despite academic motives being most common for college students who report misusing stimulant medication, a number of studies have found a negative association between academic outcomes and misuse of stimulant medication. For instance, nonusers reported an average grade-point average (GPA) of 3.28 compared to 3.16 for misusers [16]. Other research demonstrates that the lower the student’s GPA is, the greater the odds are of the student misusing stimulant medication [8]. Misuse is also significantly related to other detrimental academic behaviors such as skipping class and less studying [20,22].

Psychological Correlates of Misuse

Researchers have evaluated the relation between several different psychological variables and misuse of stimulant medication. The strongest association is between symptoms of ADHD and stimulant medication misuse. Studies are consistent in reporting a significant correlation between greater symptoms of ADHD and higher rates of misuse or a significant difference in rates of misuse between those who have an ADHD diagnosis and those who do not. One study found that 71.1% of stimulant medication misusers screened positive for adult ADHD symptoms [17]. Another study found that for every standard deviation increase in attention problems, the odds of becoming a stimulant misuser increased by 1.78 [9]. Two studies asked participants if they believed they had ADHD. Advokat, Guildry, and Martino found that 12% of misusers believed they had ADHD [7]. Twenty-nine percent of “self-diagnosers” reported misusing, compared to 11.4% of “non-diagnosers” in another study [18].

Although the literature base is smaller than for ADHD, several studies have suggested a significant difference in symptoms of depression between stimulant medication misusers and nonusers. Zullig and Divin [23] found that misusers were significantly more likely to feel very sad, feel depressed, and consider suicide than nonusers. More frequent misuse has also been shown to be significantly associated with depressed mood [24].

A number of studies demonstrate a clear association between high sensation-seeking and misuse of stimulant medication. These results are not surprising given the well-documented relation between sensation seeking and substance use [25–27]. One study found a significant interaction between sensation seeking and perceived harmfulness of misusing stimulant medication: those with high sensation seeking and low perceived harmfulness were most likely to misuse [20].

Other Substance Use Associated with Stimulant Misuse

Many of the reviewed studies found a positive correlation between misuse of stimulant medication and other substance use or a significant difference between stimulant misusers and nonusers in rates of other substance use. These findings held across all substances examined, including alcohol, cigarettes, marijuana, illicit stimulants (eg, ecstasy, cocaine, or amphetamines), and non-stimulant prescription medications. For instance, significant associations were found between misuse of stimulant medication and several alcohol-related constructs, such as binge drinking [28,29], problematic drinking behavior [30], or meeting the Diagnostic and Statistical Manual of Mental Disorders [21] criteria for alcohol abuse [22]. With respect to cigarettes, 50.3% of misusers were found to have smoked cigarettes in the last 6 months compared to 13.3% of nonusers [16]. Similar findings emerged for illicit drug use. One study found that 73.5% of stimulant medication misusers reported use of marijuana in the last 6 months, compared to 18.2% of nonusers [19], while another study found that 93% of misusers used marijuana in the last year compared to 34% of nonusers [5]. This same study found that 33% of stimulant medication misusers also reported cocaine use in the last year compared to 2% of stimulant nonusers [5]. Finally, many of the studies reviewed examined the association between other substance use in general and stimulant medication misuse. Results were striking; the odds of becoming a stimulant medication misuser increased by 3.81 for each standard deviation increase in the amount of other substance use [9].

Summary

The research literature reviewed in this section provides a descriptive characterization of which college students (and, by extension, adolescents and young adults not in college) may be at the greatest risk of misuse of stimulant medication. Significant risk factors include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. It is important to recognize that one, several, or many of these risk factors may be present in a given individual who is misusing stimulant medication. Moreover, there may be other risk factors not yet identified in the research literature. The following sections of this paper draw from the literature reviewed here to provide a number of clinical recommendations for reducing and preventing misuse of stimulant medications among college students, other young adults, and adolescents.

Clinical Recommendations

It is important for health care providers to be aware of the benefits and risks associated with stimulant medications, the prevalence of and risk factors for stimulant misuse, and the psychiatric, psychological, and medical comorbidities associated with the misuse of stimulant medication. Knowledge about stimulant medications, misuse of stimulant medications, and a thorough evaluation of the patient will enable health care providers to address the misuse, as well as any comorbidities or other factors that may contribute to stimulant medication misuse, either pharmacologically or through referral for more specified psychotherapeutic interventions.

Stimulant Medication Indications and Adverse Effects

Stimulant medications are efficacious for the treatment of ADHD and, when prescribed and used correctly, can improve attentiveness, decrease distractibility, and improve daily functioning in the short term [19]. When used by individuals without ADHD, patients may experience euphoria, stimulation, alertness, and are not likely to experience the cognitive benefits that those with ADHD receive [31]. Side effects can occur regardless of whether the individual is using the stimulant for ADHD, misusing, or is dependent, and include nervousness, headaches, tachycardia, poor appetite, depressed mood, and poor sleep [19,32]. Additionally, stimulant medications can cause psychosis, agitation, and hallucinations [31,33], which typically resolve after discontinuation of the stimulant within 2 to 6 days, though a longer time period to resolution has been reported [33]. Stimulant medications carry warnings about increased risk of sudden death, high blood pressure, cardiac arrest, and stroke, as well as a statement warning providers about abuse potential. Additionally, serious but rare medical complications, including seizures, tachycardia or dysrhythmias, and hyperthermia, can occur [31,34].

Physical Examination and Laboratory Data

Obtaining vital signs and performing a physical exam may reveal weight loss and an increase in heart rate or blood pressure. Methylphenidate and amphetamines are known to increase heart rate and blood pressure [35] and a recent study found an average increase in heart rate of 5.7 bpm and a 1.2–mm Hg increase in systolic and diastolic blood pressure in adults on stimulant medications compared to placebo [36]. No EKG abnormalities or changes are found with either methylphenidate or amphetamine [35]. Urine toxicology can be utilized to obtain further information if misuse is suspected. However, the clinician must be aware of the limitations of urine drug testing with stimulants [37]. The usual detection time for amphetamines is 48 hours from last use, though this may vary depending on the presence of metabolites, pharmacokinetics of the drug (eg, immediate release vs. sustained release formulations), and patient variables [37]. Additionally, a urine toxicology screen for amphetamines typically tests for amphetamines, racemic compounds such as dextroamphetamine and methamphetamine, and illicit compounds (ie, methylenedioxymethamphetamine), though there are many compounds that are structurally similar, such as weight loss agents, over-the-counter cold products, and other psychotropic medications, including methylphenidate, that can cause a false-positive result [37]. Urine toxicology should be obtained in conjunction with a thorough evaluation of patients’ alcohol and drug use patterns. These 2 components are essential to the accurate diagnosis and formulation of a comprehensive treatment plan. As noted above, stimulant medication misuse and alcohol and illicit drug use are highly comorbid and should be carefully and thoroughly assessed.

Psychiatric Comorbidity

ADHD

The prevalence of ADHD is higher among individuals with substance use disorders [38]. As noted above, patients commonly report misuse of stimulant medication to enhance academic performance. One explanation may be that individuals misusing stimulants may be self-medicating undiagnosed ADHD [39]. The prevalence of ADHD among adults is 4.1% and it is more common in men than women with a ratio of up to 6:1 [40]. Several studies have found that individuals with misuse of stimulant medications endorse symptoms of ADHD, including higher levels of inattention and hyperactivity [41]. Twelve percent of participants in one study that endorsed stimulant medication misuse also endorsed the belief they had ADHD [7]. Another study found that individuals with higher baseline self-reported ADHD symptoms were also more likely to misuse stimulants [42]. The majority of individuals with ADHD have been found to take medications appropriately, though there is a minority, often with comorbid conduct disorder or other substance use disorders, that divert or misuse stimulant medications, most often the immediate release formulations [43,44].

Accurate diagnosis of ADHD in patients with substance use disorders can be challenging given the symptom overlap between intoxication and withdrawal syndromes of substances and symptoms of ADHD. Evaluating for ADHD is an important part of a thorough assessment and can be completed in several ways. The gold standard is with a standardized diagnostic tool such as the Connors Adult ADHD Diagnostic Interview for DSM-IV (CAADID) [45], which can be time consuming for a clinician and would likely involve referral to a psychologist for completion. Other scales have been examined, and the Connors Adult ADHD Rating Scale (CAARS) has been found to closely agree with the CAADID when both are administered [45]. Other scales are available, including the Wender Utah Rating Scales (WURS) and the Adult ADHD Self-Report Scale (ASRS), and have been found to have adequate sensitivity and specificity [45]. In an international study, the ASRS, a relatively brief instrument, showed encouraging results with 84% sensitivity and 66% specificity in detecting ADHD upon entry into substance disorder treatment for treatment-seeking patients [46]. When diagnosing ADHD among adults, it is crucial not to rely only on self-reported symptoms. A thorough childhood history of ADHD symptom presentation should be collected from a parent or caregiver, and collateral concurrent report should be collected from someone who knows the patient well, such as an employer, close friend, significant other, or parent. Valid diagnosis, whether ADHD is present or not, is of utmost importance in this population as individuals with comorbid substance use disorders and ADHD tend to have worse outcomes overall [47]. It is also important to appreciate that inaccurately diagnosing ADHD in individuals misusing stimulants could potentially diminish the importance of the diagnosis [48].

If ADHD is found, there are medications available that have a lower abuse potential compared to stimulant medications. Atomoxetine is the only FDA-approved nonstimulant for ADHD; off-label or second-line treatments include antidepressants, such as bupropion, venlafaxine, or tricyclic antidepressants, for which the data is limited, and clonidine [34,49,50]. If these therapies are not effective and, after careful consideration of risks and benefits, it is determined that a trial with a stimulant is needed, longer-acting formulations appear to be less abused [34,44]. Education for both the patient and his or her family should be provided on abuse and diversion potential and appropriate use and misuse [34,43,51]. Pill counts [43], regular office visits [52], and random urine toxicology screens [34] with informed interpretation of the screens may be helpful in deterring misuse or diversion. While medications are the mainstay of treatment for ADHD, there are several psychosocial interventions available, including cognitive behavioral therapy, coaching, and behavioral modification therapies [34].

Other Comorbidities

Other psychiatric comorbidities also should be explored. Studies have found a relation between depression and misuse of stimulant medication in that there is an increased likelihood of depression and thoughts of suicide among those that misuse stimulant medication and vice versa [23,24,53]. The National Survey on Drug Use and Health in 2012 found that, of those that misused stimulants, nearly 20% had serious thoughts of suicide over the past year [54]. As noted earlier, stimulant medication can affect sleep and appetite. Among those that report misuse of stimulant medication for weight loss, these individuals are more likely to report other eating-disordered behaviors [55]. Sleep quality is worse and sleep disturbance greater in those that misuse stimulant medication [32]. Other traits and behaviors that have been described in individuals that misuse stimulant medications include impulsivity [56,57], sensation seeking [20], perfectionism [58], and poor time management skills or procrastination [59].

Appropriate treatment (which may include pharmacologic, psychological, or academic accommodation components) for individuals with these psychiatric disorders or psychological symptoms may reduce the misuse of stimulant medications among college students, especially if these students are misusing in order to reduce their symptoms (ie, a self-medication hypothesis).

Treatment

There are currently no FDA-approved medications to treat stimulant medication misuse. In fact, studies exploring pharmacotherapy for stimulant medication misuse are limited. Most trials focus on stimulants such as cocaine or methamphetamine and not stimulant medications alone. Additionally, these trials primarily include only individuals that meet criteria for stimulant dependence. Various medications and medication classes have been examined for the treatment of stimulant dependence, including naltrexone, various antipsychotics, and various antidepressants including bupropion, modafanil, baclofen, ondansetron, and dexamphetamine, with little to no effect [60]. In a review of the literature, one study examined the use of naltrexone versus placebo for stimulant dependence in 80 treatment-seeking Swedish individuals [61]. The different types of stimulants on which these individuals were dependent were not clearly delineated, though the study authors noted that the major amphetamine abused in Sweden was the racemic mixture d/l amphetamine and not methamphetamine. Naltrexone was superior to placebo in this trial, as evidenced by higher percentage of amphetamine-free urine samples. A large majority of this sample used intravenously (65%–76%) and had been using between 6 to 8 years, limiting the applicability to individuals with stimulant medication misuse. At this time, investigation into evidence-based pharmacotherapies for stimulant medication misuse remains in the early stages.

Generally speaking, efficacious behavioral treatments, such as contingency management (CM), cognitive behavioral therapy (CBT), skills training, motivational interviewing (MI), relapse prevention, couples and family treatments, and drug counseling, exist for drug abuse [62]. CBT, cognitive therapy, CM, MI, and community reinforcement approach (CRA) [63,64] have been explored for stimulant dependence and are currently the primary interventions for amphetamine-type stimulant dependence [60]. Similar to pharmacotherapy studies, most psychotherapy studies to date have examined primarily cocaine and methamphetamine dependence and not misuse of stimulant medications. In fact, no studies examining psychotherapy for stimulant medication misuse were found by our group in a search using the PubMed database. Therefore, discussion of psychotherapeutic interventions that may be efficacious for stimulant medication misuse extrapolates outcomes from studies of stimulant dependence, appreciating this is an approximation and imprecise as there are significant differences between stimulant medication misusers and those dependent upon stimulants such as methamphetamine or cocaine. As such, in a review from 2009 [63], Vocci and colleagues compared psychotherapy studies for cocaine and methamphetamine dependence and concluded that CBT and CM were moderately effective and that adding CM to standard treatment may help improve outcomes. A study of 214 amphetamine users (including methamphetamine users), with the majority (70%) enrolled in a methadone maintenance program and a large proportion (58.9%) using amphetamines intravenously, found that either 2 or 4 sessions of CBT, along with self-help material, increased rate of abstinence at 6 months post-intervention compared to the use of self-help material alone [65]. Baker and colleagues [64] recommend a practical stepped approach to treatment for stimulant dependence, including conducting a thorough assessment, offering education and self-help materials, monitoring use and consequences of use, and then transitioning to more intensive psychosocial interventions if needed, which may be applicable to those with stimulant medication misuse and is clinically reasonable. Offering a psychosocial intervention may require referral to more specialized treatment services than can be offered in a general primary care clinic. Additionally, harm reduction techniques for stimulant medication misusers to reduce the medical and social consequences can be considered as well as prevention strategies and methods, which can be utilized in any treatment setting or in high-risk populations, such as college students.

Prevention Strategies for the Individual

The research findings summarized in this review suggest several specific strategies for preventing and reducing the misuse of stimulant medication among college students, a high-risk population. First, college students with a prescription for stimulant medication play a critical role. Not only do these students have a high rate of misuse themselves [28,66], but they are also the most common source from which other students obtain stimulant medication to misuse [11,67]. It is therefore important for physicians who provide college students with prescriptions for stimulant medications to discuss the possible consequences of misusing or diverting medication, including potential negative health outcomes, legal consequences, and on-campus repercussions, for students caught diverting stimulant medications. These practitioners should also monitor their patients for signs of diversion, such as finishing a prescription early, doctor shopping, or urine drug screen which is negative for the prescribed substance. Utilizing a prescription monitoring program to access information on the prescribing and filling of controlled substances can be a valuable tool in detecting multiple concomitant prescriptions for stimulant medications, number of providers writing stimulant medication, and information on the use of other prescribed controlled medications. Providers should also discuss safe storage of stimulant medications with patients, particularly if the student is currently living in a dorm setting or another community-type setting with the potential for lots of individuals in and around their personal belongings. Additionally, providers may wish to consider dispensing a small amount at each office visit until the patient has established responsible use of the medication, particularly if there are other findings or comorbidities that perhaps increase their risk of misuse. Pill counts and frequent office visits, as noted earlier, may also help prevent diversion.

Perceived risk/harm associated with the use of stimulant medications has been negatively related to misuse [18,20]. If college students were more aware of the risks associated with stimulant medication misuse, with regards to both health and legal consequences, fewer students may choose to misuse stimulants. Educating patients and their families about the abuse potential of stimulants, as well as consequences of misuse such as psychosis and agitation, when prescriptions are given for stimulant medication, may help address the misperception that stimulant medications are benign, safe and without adverse consequences.

College Policy Changes for Prevention of Misuse

Policy changes on college campuses could also help to reduce diversion of stimulant medications. For instance, education about the risks associated with stimulant medication misuse could be incorporated into other alcohol and drug prevention programs that are already in place at colleges and universities. Many colleges/universities require all first-year students to complete an online substance use education/prevention/assessment tool. Some of these, such as AlcoholEdu and The Alcohol eCHECKUP TO GO have demonstrated some success in reducing college student alcohol use in follow-up evaluations [68]. Information about misuse of stimulant medication could be included in these existing programs. Moreover, members of certain organizations (eg, fraternities or sororities) that are known for an increased risk of substance use/abuse among members are also sometimes required by their national chapters or host colleges/universities to complete a “risk management” class, which addresses behaviors such as binge drinking and drunk driving. Since one of the demographic factors most strongly related to stimulant medication misuse is Greek organization membership [14], presenting information about stimulant medication misuse to these groups during these classes could help reduce misuse on college campuses.

Finally, the most commonly reported motives for misuse of stimulant medications among college students are academic in nature (eg, to study more, to concentrate better) [16], and many students who misuse for these reasons feel the desired effect is achieved. Colleges and universities may need to improve the identification of students who are in need of academic assistance/supports and offer these interventions earlier in students’ college careers to prevent stimulant medication misuse as a “quick fix.” Such interventions may include teaching students skills such as note-taking and academic goal setting and educating students about the link between sleep deprivation and poor concentration [69].

Summary

Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Diagnosing ADHD can be invaluable for individuals with the disorder, thus the ability to perform a thorough and accurate assessment is important; equally important is the ability to assess when ADHD is not present. Education and prevention strategies to prevent misuse and diversion should be provided if stimulant medications are indicated. College programs and policies can also utilize prevention strategies, provide education to students, and assist those with academic difficulties. Comorbidities are common and should be explored thoroughly as they may play a role in continued stimulant medication misuse and outcomes. Various treatment techniques and modalities can be explored further with each patient, based on the individual and their particular needs.

Corresponding author: Kate Flory, Univ. of South Carolina, Dept. of Psychology, Barnwell College, Columbia, SC 29208, [email protected].

Funding/support: Work on this paper was supported by a University of South Carolina Honors College Exploration Scholar Award and a University of South Carolina Magellan Fellowship, both awarded to Kari Benson.

Financial disclosures: None.

Author contributions: conception and design, KF, RAP, KB; drafting of article, KF, RAP, KB; critical revision of the article, KF, RAP, KB; literature search, KB.

From the University of South Carolina, Columbia, SC.

Abstract

• Objective: To provide a summary of the existing research on the characteristics of college students who report misusing prescription stimulant medications, to offer a set of clinical recommendations for practitioners, and to offer several possible prevention strategies.
• Methods: Literature review and research-based recommendations for clinical practice and prevention.
• Results: Misuse of prescription stimulant medication among college students is a prevalent and growing problem. Significant risk factors for misuse of stimulant medication include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Suggestions for preventing misuse and diversion of prescription stimulant medications, including strategies for the individual and potential policy changes on college campuses, are offered.
• Conclusions: Misuse and diversion of prescription stimulant medications is a growing concern among adolescents and young adults and should be addressed by health care practitioners. Additional research on effective intervention and prevention strategies is needed.

Prescription stimulant medications (eg, methylphenidate, amphetamines) are typically used for the treatment of attention-deficit/hyperactivity disorder (ADHD) to increase attentiveness, decrease distractibility, and improve daily functioning. Prescriptions for stimulant medications are on the rise; between 2002 and 2010, the number of prescriptions for ADHD medications for youth under 18 increased 46% [1].

A recent review of ADHD diagnosis among college students estimated a prevalence rate of 2% to 8% [2]. More individuals with ADHD are matriculating to college than in the past [3,4], as more supports have been put in place for college students diagnosed with ADHD, including improved educational/organizational treatments and accommodations [2]. Many college students with ADHD also use prescription stimulant medications as part of their treatment plan; McCabe, Teter, and Boyd reported that 2.2% of college students had prescriptions for stimulant medications annually [5].

As the number of individuals of all ages with stimulant medication prescriptions increase, more individuals without prescriptions are gaining access to stimulant medications. In a survey of college students with medication prescriptions, stimulants were the most commonly diverted medication, with 61.7% of students with these prescriptions reporting having shared or sold their medication at least once [6]. Studies report that as many as 43% of college students have misused stimulant medication in their lifetime [7], though prevalence rates vary by study. Throughout this review, “misuse of stimulant medication” refers to using prescription stimulant medications without a prescription or using more stimulant medication than prescribed (ie, a higher or more frequent dosage).

Given the ease with which college students are able to obtain stimulant medications, the alarming prevalence of stimulant medication misuse among this population, and the potentially serious health risks associated with misuse of stimulant medication (especially when combined with other substances, such as alcohol, that are commonly used by college students), there is a need to both better understand and ultimately reduce the misuse of stimulant medication among college students. Thus, the purpose of this paper is threefold. First, we provide a summary of the existing research literature on the characteristics of college students who report misusing stimulant medication. Second, we offer a set of clinical recommendations for practitioners, which includes stimulant medication indications, risks, benefits, and side effects, along with problems associated with stimulant medication diversion and misuse. Finally, we offer several prevention strategies, including strategies for the individual as well as several suggestions for changing policies on college campuses to prevent stimulant diversion and misuse. Importantly, although our literature review addresses prescription stimulant misuse among college students, our clinical recommendations are also appropriate for adolescents and young adults not enrolled in college.

Summary of the Literature

The following summary is based on a comprehensive search of the existing research literature on misuse of stimulant medication among college students, which ultimately identified 30 relevant studies using 21 unique samples. A study was included if: (1) the main focus of the study was misuse of stimulant medication, (2) it was a peer-reviewed, empirical study using quantitative data analytic techniques, (3) it was written in English, (4) only undergraduate students were included in the sample, (5) it did not focus on only one type of stimulant medication (eg, methylphenidate only), and (6) if the article discussed multiple prescription drug categories (eg, stimulants, opiates), the data must have been analyzed separately for each category. An extensive meta-analytic review of this literature will be published elsewhere (contact the corresponding author to request a reprint). The following is a brief summary of our findings.

Prevalence, Availability, and Demographic Characteristics

Among prevalence rates reported, lifetime rates of stimulant medication misuse were the most frequently reported, ranging from 8.1% [8] to 43% [7]. Rates of misuse of stimulant medications within the last year ranged from 5.3% [9] to 35.3% [10]. A number of the studies asked students how they obtained stimulant medications for misuse; peers were overwhelmingly the most common source for obtaining the medications. For example, DeSantis, Webb, and Noar [11] found that 91% of the undergraduates who were interviewed obtained stimulant medications from friends or significant others.

Perceived availability of stimulant medications was also measured in several studies. DeSantis, Webb, and Noar [11] found that 82% of students thought it was somewhat or very easy to obtain stimulant medication; however, Sharp and Rosén [12] found that only 55% of students thought it was somewhat or very easy to obtain stimulant medication. In another study that examined perceived availability, 37% of men and 29.2% of women agreed that they knew students who would provide them with stimulant medications [13].

Many of the studies reviewed examined the relation between particular demographic characteristics (eg, gender, race, socioeconomic status, religious affiliation, year in college, sorority or fraternity membership) and misuse of stimulant medication among college students. The vast majority of studies that examined gender as related to misuse of stimulant medication found that significantly more males misused stimulant medication than females. For example, one study found that 26% of males and 17.3% of females reported misusing stimulant medication [14]; another study found that 39% of males versus 30% of females reported misuse [11].

It is also clear from the existing literature that members of fraternities and sororities appear to be more at-risk for misuse of stimulant medication than non-Greek students. In multiple studies, Greek students had rates of misuse twice that of non-Greeks. For instance, 48% of Greeks misused in their lifetime compared to 22% of non-Greeks [11]; 12% of Greeks misused in the past year compared to 5% of non-Greeks [15]; and Greeks were 2.32 times more likely to initiate use than non-Greeks [9].

Unfortunately, results from studies examining other demographic characteristics (eg, race, socioeconomic status, religious affiliation, year in college) as related to misuse of stimulant medication are much less conclusive and these correlates therefore require further investigation.

Motives For Misuse and Perceived Risk

Researchers have also evaluated college students’ motives for misusing stimulant medication and the risks they associate with misuse. All of the studies that asked misusing students about their motives for misuse reported that the most commonly endorsed motives were related to academics. “To concentrate better while studying” [16], “to improve study skills” [17], “to stay awake to study longer” [11], and “to improve concentration” [18] were some of the most commonly endorsed motives in these studies. Nonacademic reasons, such as to get high, to prolong effects of alcohol and other drugs, and to lose weight, were less commonly endorsed [7,12,19]. In studies where participants were able to indicate multiple motives for misuse [16], very few students misused for only nonacademic reasons.

Several studies measured the relation between misuse of stimulant medication and perceived risk associated with misuse. Perceived risk was conceptualized as perceived harmfulness [20], perception of safety [14], concern with health risk [18], and the inverse of positive outcome expectancies [21]. These articles found that when college students perceive more risk or have less positive expectancies about stimulant medication misuse, they are less likely to misuse stimulant medication. For instance, those who associated stimulant medication misuse with low perceived harmfulness were over 10 times more likely to have used in the last year than those who associated misuse with high perceived harmfulness [20].

Academic Outcomes Associated with Misuse

Interestingly, despite academic motives being most common for college students who report misusing stimulant medication, a number of studies have found a negative association between academic outcomes and misuse of stimulant medication. For instance, nonusers reported an average grade-point average (GPA) of 3.28 compared to 3.16 for misusers [16]. Other research demonstrates that the lower the student’s GPA is, the greater the odds are of the student misusing stimulant medication [8]. Misuse is also significantly related to other detrimental academic behaviors such as skipping class and less studying [20,22].

Psychological Correlates of Misuse

Researchers have evaluated the relation between several different psychological variables and misuse of stimulant medication. The strongest association is between symptoms of ADHD and stimulant medication misuse. Studies are consistent in reporting a significant correlation between greater symptoms of ADHD and higher rates of misuse or a significant difference in rates of misuse between those who have an ADHD diagnosis and those who do not. One study found that 71.1% of stimulant medication misusers screened positive for adult ADHD symptoms [17]. Another study found that for every standard deviation increase in attention problems, the odds of becoming a stimulant misuser increased by 1.78 [9]. Two studies asked participants if they believed they had ADHD. Advokat, Guildry, and Martino found that 12% of misusers believed they had ADHD [7]. Twenty-nine percent of “self-diagnosers” reported misusing, compared to 11.4% of “non-diagnosers” in another study [18].

Although the literature base is smaller than for ADHD, several studies have suggested a significant difference in symptoms of depression between stimulant medication misusers and nonusers. Zullig and Divin [23] found that misusers were significantly more likely to feel very sad, feel depressed, and consider suicide than nonusers. More frequent misuse has also been shown to be significantly associated with depressed mood [24].

A number of studies demonstrate a clear association between high sensation-seeking and misuse of stimulant medication. These results are not surprising given the well-documented relation between sensation seeking and substance use [25–27]. One study found a significant interaction between sensation seeking and perceived harmfulness of misusing stimulant medication: those with high sensation seeking and low perceived harmfulness were most likely to misuse [20].

Other Substance Use Associated with Stimulant Misuse

Many of the reviewed studies found a positive correlation between misuse of stimulant medication and other substance use or a significant difference between stimulant misusers and nonusers in rates of other substance use. These findings held across all substances examined, including alcohol, cigarettes, marijuana, illicit stimulants (eg, ecstasy, cocaine, or amphetamines), and non-stimulant prescription medications. For instance, significant associations were found between misuse of stimulant medication and several alcohol-related constructs, such as binge drinking [28,29], problematic drinking behavior [30], or meeting the Diagnostic and Statistical Manual of Mental Disorders [21] criteria for alcohol abuse [22]. With respect to cigarettes, 50.3% of misusers were found to have smoked cigarettes in the last 6 months compared to 13.3% of nonusers [16]. Similar findings emerged for illicit drug use. One study found that 73.5% of stimulant medication misusers reported use of marijuana in the last 6 months, compared to 18.2% of nonusers [19], while another study found that 93% of misusers used marijuana in the last year compared to 34% of nonusers [5]. This same study found that 33% of stimulant medication misusers also reported cocaine use in the last year compared to 2% of stimulant nonusers [5]. Finally, many of the studies reviewed examined the association between other substance use in general and stimulant medication misuse. Results were striking; the odds of becoming a stimulant medication misuser increased by 3.81 for each standard deviation increase in the amount of other substance use [9].

Summary

The research literature reviewed in this section provides a descriptive characterization of which college students (and, by extension, adolescents and young adults not in college) may be at the greatest risk of misuse of stimulant medication. Significant risk factors include being male, being a member of a college sorority or fraternity, struggling academically, having elevated symptoms of ADHD and/or depression, being a high sensation-seeker, and using/misusing alcohol, cigarettes, and/or other illicit drugs. It is important to recognize that one, several, or many of these risk factors may be present in a given individual who is misusing stimulant medication. Moreover, there may be other risk factors not yet identified in the research literature. The following sections of this paper draw from the literature reviewed here to provide a number of clinical recommendations for reducing and preventing misuse of stimulant medications among college students, other young adults, and adolescents.

Clinical Recommendations

It is important for health care providers to be aware of the benefits and risks associated with stimulant medications, the prevalence of and risk factors for stimulant misuse, and the psychiatric, psychological, and medical comorbidities associated with the misuse of stimulant medication. Knowledge about stimulant medications, misuse of stimulant medications, and a thorough evaluation of the patient will enable health care providers to address the misuse, as well as any comorbidities or other factors that may contribute to stimulant medication misuse, either pharmacologically or through referral for more specified psychotherapeutic interventions.

Stimulant Medication Indications and Adverse Effects

Stimulant medications are efficacious for the treatment of ADHD and, when prescribed and used correctly, can improve attentiveness, decrease distractibility, and improve daily functioning in the short term [19]. When used by individuals without ADHD, patients may experience euphoria, stimulation, alertness, and are not likely to experience the cognitive benefits that those with ADHD receive [31]. Side effects can occur regardless of whether the individual is using the stimulant for ADHD, misusing, or is dependent, and include nervousness, headaches, tachycardia, poor appetite, depressed mood, and poor sleep [19,32]. Additionally, stimulant medications can cause psychosis, agitation, and hallucinations [31,33], which typically resolve after discontinuation of the stimulant within 2 to 6 days, though a longer time period to resolution has been reported [33]. Stimulant medications carry warnings about increased risk of sudden death, high blood pressure, cardiac arrest, and stroke, as well as a statement warning providers about abuse potential. Additionally, serious but rare medical complications, including seizures, tachycardia or dysrhythmias, and hyperthermia, can occur [31,34].

Physical Examination and Laboratory Data

Obtaining vital signs and performing a physical exam may reveal weight loss and an increase in heart rate or blood pressure. Methylphenidate and amphetamines are known to increase heart rate and blood pressure [35] and a recent study found an average increase in heart rate of 5.7 bpm and a 1.2–mm Hg increase in systolic and diastolic blood pressure in adults on stimulant medications compared to placebo [36]. No EKG abnormalities or changes are found with either methylphenidate or amphetamine [35]. Urine toxicology can be utilized to obtain further information if misuse is suspected. However, the clinician must be aware of the limitations of urine drug testing with stimulants [37]. The usual detection time for amphetamines is 48 hours from last use, though this may vary depending on the presence of metabolites, pharmacokinetics of the drug (eg, immediate release vs. sustained release formulations), and patient variables [37]. Additionally, a urine toxicology screen for amphetamines typically tests for amphetamines, racemic compounds such as dextroamphetamine and methamphetamine, and illicit compounds (ie, methylenedioxymethamphetamine), though there are many compounds that are structurally similar, such as weight loss agents, over-the-counter cold products, and other psychotropic medications, including methylphenidate, that can cause a false-positive result [37]. Urine toxicology should be obtained in conjunction with a thorough evaluation of patients’ alcohol and drug use patterns. These 2 components are essential to the accurate diagnosis and formulation of a comprehensive treatment plan. As noted above, stimulant medication misuse and alcohol and illicit drug use are highly comorbid and should be carefully and thoroughly assessed.

Psychiatric Comorbidity

ADHD

The prevalence of ADHD is higher among individuals with substance use disorders [38]. As noted above, patients commonly report misuse of stimulant medication to enhance academic performance. One explanation may be that individuals misusing stimulants may be self-medicating undiagnosed ADHD [39]. The prevalence of ADHD among adults is 4.1% and it is more common in men than women with a ratio of up to 6:1 [40]. Several studies have found that individuals with misuse of stimulant medications endorse symptoms of ADHD, including higher levels of inattention and hyperactivity [41]. Twelve percent of participants in one study that endorsed stimulant medication misuse also endorsed the belief they had ADHD [7]. Another study found that individuals with higher baseline self-reported ADHD symptoms were also more likely to misuse stimulants [42]. The majority of individuals with ADHD have been found to take medications appropriately, though there is a minority, often with comorbid conduct disorder or other substance use disorders, that divert or misuse stimulant medications, most often the immediate release formulations [43,44].

Accurate diagnosis of ADHD in patients with substance use disorders can be challenging given the symptom overlap between intoxication and withdrawal syndromes of substances and symptoms of ADHD. Evaluating for ADHD is an important part of a thorough assessment and can be completed in several ways. The gold standard is with a standardized diagnostic tool such as the Connors Adult ADHD Diagnostic Interview for DSM-IV (CAADID) [45], which can be time consuming for a clinician and would likely involve referral to a psychologist for completion. Other scales have been examined, and the Connors Adult ADHD Rating Scale (CAARS) has been found to closely agree with the CAADID when both are administered [45]. Other scales are available, including the Wender Utah Rating Scales (WURS) and the Adult ADHD Self-Report Scale (ASRS), and have been found to have adequate sensitivity and specificity [45]. In an international study, the ASRS, a relatively brief instrument, showed encouraging results with 84% sensitivity and 66% specificity in detecting ADHD upon entry into substance disorder treatment for treatment-seeking patients [46]. When diagnosing ADHD among adults, it is crucial not to rely only on self-reported symptoms. A thorough childhood history of ADHD symptom presentation should be collected from a parent or caregiver, and collateral concurrent report should be collected from someone who knows the patient well, such as an employer, close friend, significant other, or parent. Valid diagnosis, whether ADHD is present or not, is of utmost importance in this population as individuals with comorbid substance use disorders and ADHD tend to have worse outcomes overall [47]. It is also important to appreciate that inaccurately diagnosing ADHD in individuals misusing stimulants could potentially diminish the importance of the diagnosis [48].

If ADHD is found, there are medications available that have a lower abuse potential compared to stimulant medications. Atomoxetine is the only FDA-approved nonstimulant for ADHD; off-label or second-line treatments include antidepressants, such as bupropion, venlafaxine, or tricyclic antidepressants, for which the data is limited, and clonidine [34,49,50]. If these therapies are not effective and, after careful consideration of risks and benefits, it is determined that a trial with a stimulant is needed, longer-acting formulations appear to be less abused [34,44]. Education for both the patient and his or her family should be provided on abuse and diversion potential and appropriate use and misuse [34,43,51]. Pill counts [43], regular office visits [52], and random urine toxicology screens [34] with informed interpretation of the screens may be helpful in deterring misuse or diversion. While medications are the mainstay of treatment for ADHD, there are several psychosocial interventions available, including cognitive behavioral therapy, coaching, and behavioral modification therapies [34].

Other Comorbidities

Other psychiatric comorbidities also should be explored. Studies have found a relation between depression and misuse of stimulant medication in that there is an increased likelihood of depression and thoughts of suicide among those that misuse stimulant medication and vice versa [23,24,53]. The National Survey on Drug Use and Health in 2012 found that, of those that misused stimulants, nearly 20% had serious thoughts of suicide over the past year [54]. As noted earlier, stimulant medication can affect sleep and appetite. Among those that report misuse of stimulant medication for weight loss, these individuals are more likely to report other eating-disordered behaviors [55]. Sleep quality is worse and sleep disturbance greater in those that misuse stimulant medication [32]. Other traits and behaviors that have been described in individuals that misuse stimulant medications include impulsivity [56,57], sensation seeking [20], perfectionism [58], and poor time management skills or procrastination [59].

Appropriate treatment (which may include pharmacologic, psychological, or academic accommodation components) for individuals with these psychiatric disorders or psychological symptoms may reduce the misuse of stimulant medications among college students, especially if these students are misusing in order to reduce their symptoms (ie, a self-medication hypothesis).

Treatment

There are currently no FDA-approved medications to treat stimulant medication misuse. In fact, studies exploring pharmacotherapy for stimulant medication misuse are limited. Most trials focus on stimulants such as cocaine or methamphetamine and not stimulant medications alone. Additionally, these trials primarily include only individuals that meet criteria for stimulant dependence. Various medications and medication classes have been examined for the treatment of stimulant dependence, including naltrexone, various antipsychotics, and various antidepressants including bupropion, modafanil, baclofen, ondansetron, and dexamphetamine, with little to no effect [60]. In a review of the literature, one study examined the use of naltrexone versus placebo for stimulant dependence in 80 treatment-seeking Swedish individuals [61]. The different types of stimulants on which these individuals were dependent were not clearly delineated, though the study authors noted that the major amphetamine abused in Sweden was the racemic mixture d/l amphetamine and not methamphetamine. Naltrexone was superior to placebo in this trial, as evidenced by higher percentage of amphetamine-free urine samples. A large majority of this sample used intravenously (65%–76%) and had been using between 6 to 8 years, limiting the applicability to individuals with stimulant medication misuse. At this time, investigation into evidence-based pharmacotherapies for stimulant medication misuse remains in the early stages.

Generally speaking, efficacious behavioral treatments, such as contingency management (CM), cognitive behavioral therapy (CBT), skills training, motivational interviewing (MI), relapse prevention, couples and family treatments, and drug counseling, exist for drug abuse [62]. CBT, cognitive therapy, CM, MI, and community reinforcement approach (CRA) [63,64] have been explored for stimulant dependence and are currently the primary interventions for amphetamine-type stimulant dependence [60]. Similar to pharmacotherapy studies, most psychotherapy studies to date have examined primarily cocaine and methamphetamine dependence and not misuse of stimulant medications. In fact, no studies examining psychotherapy for stimulant medication misuse were found by our group in a search using the PubMed database. Therefore, discussion of psychotherapeutic interventions that may be efficacious for stimulant medication misuse extrapolates outcomes from studies of stimulant dependence, appreciating this is an approximation and imprecise as there are significant differences between stimulant medication misusers and those dependent upon stimulants such as methamphetamine or cocaine. As such, in a review from 2009 [63], Vocci and colleagues compared psychotherapy studies for cocaine and methamphetamine dependence and concluded that CBT and CM were moderately effective and that adding CM to standard treatment may help improve outcomes. A study of 214 amphetamine users (including methamphetamine users), with the majority (70%) enrolled in a methadone maintenance program and a large proportion (58.9%) using amphetamines intravenously, found that either 2 or 4 sessions of CBT, along with self-help material, increased rate of abstinence at 6 months post-intervention compared to the use of self-help material alone [65]. Baker and colleagues [64] recommend a practical stepped approach to treatment for stimulant dependence, including conducting a thorough assessment, offering education and self-help materials, monitoring use and consequences of use, and then transitioning to more intensive psychosocial interventions if needed, which may be applicable to those with stimulant medication misuse and is clinically reasonable. Offering a psychosocial intervention may require referral to more specialized treatment services than can be offered in a general primary care clinic. Additionally, harm reduction techniques for stimulant medication misusers to reduce the medical and social consequences can be considered as well as prevention strategies and methods, which can be utilized in any treatment setting or in high-risk populations, such as college students.

Prevention Strategies for the Individual

The research findings summarized in this review suggest several specific strategies for preventing and reducing the misuse of stimulant medication among college students, a high-risk population. First, college students with a prescription for stimulant medication play a critical role. Not only do these students have a high rate of misuse themselves [28,66], but they are also the most common source from which other students obtain stimulant medication to misuse [11,67]. It is therefore important for physicians who provide college students with prescriptions for stimulant medications to discuss the possible consequences of misusing or diverting medication, including potential negative health outcomes, legal consequences, and on-campus repercussions, for students caught diverting stimulant medications. These practitioners should also monitor their patients for signs of diversion, such as finishing a prescription early, doctor shopping, or urine drug screen which is negative for the prescribed substance. Utilizing a prescription monitoring program to access information on the prescribing and filling of controlled substances can be a valuable tool in detecting multiple concomitant prescriptions for stimulant medications, number of providers writing stimulant medication, and information on the use of other prescribed controlled medications. Providers should also discuss safe storage of stimulant medications with patients, particularly if the student is currently living in a dorm setting or another community-type setting with the potential for lots of individuals in and around their personal belongings. Additionally, providers may wish to consider dispensing a small amount at each office visit until the patient has established responsible use of the medication, particularly if there are other findings or comorbidities that perhaps increase their risk of misuse. Pill counts and frequent office visits, as noted earlier, may also help prevent diversion.

Perceived risk/harm associated with the use of stimulant medications has been negatively related to misuse [18,20]. If college students were more aware of the risks associated with stimulant medication misuse, with regards to both health and legal consequences, fewer students may choose to misuse stimulants. Educating patients and their families about the abuse potential of stimulants, as well as consequences of misuse such as psychosis and agitation, when prescriptions are given for stimulant medication, may help address the misperception that stimulant medications are benign, safe and without adverse consequences.

College Policy Changes for Prevention of Misuse

Policy changes on college campuses could also help to reduce diversion of stimulant medications. For instance, education about the risks associated with stimulant medication misuse could be incorporated into other alcohol and drug prevention programs that are already in place at colleges and universities. Many colleges/universities require all first-year students to complete an online substance use education/prevention/assessment tool. Some of these, such as AlcoholEdu and The Alcohol eCHECKUP TO GO have demonstrated some success in reducing college student alcohol use in follow-up evaluations [68]. Information about misuse of stimulant medication could be included in these existing programs. Moreover, members of certain organizations (eg, fraternities or sororities) that are known for an increased risk of substance use/abuse among members are also sometimes required by their national chapters or host colleges/universities to complete a “risk management” class, which addresses behaviors such as binge drinking and drunk driving. Since one of the demographic factors most strongly related to stimulant medication misuse is Greek organization membership [14], presenting information about stimulant medication misuse to these groups during these classes could help reduce misuse on college campuses.

Finally, the most commonly reported motives for misuse of stimulant medications among college students are academic in nature (eg, to study more, to concentrate better) [16], and many students who misuse for these reasons feel the desired effect is achieved. Colleges and universities may need to improve the identification of students who are in need of academic assistance/supports and offer these interventions earlier in students’ college careers to prevent stimulant medication misuse as a “quick fix.” Such interventions may include teaching students skills such as note-taking and academic goal setting and educating students about the link between sleep deprivation and poor concentration [69].

Summary

Health care providers, particularly those that see adolescent or college-aged individuals, need to be informed about stimulant medication indications, risks, benefits, and side effects and aware and attuned to problems associated with stimulant medication diversion and misuse. Diagnosing ADHD can be invaluable for individuals with the disorder, thus the ability to perform a thorough and accurate assessment is important; equally important is the ability to assess when ADHD is not present. Education and prevention strategies to prevent misuse and diversion should be provided if stimulant medications are indicated. College programs and policies can also utilize prevention strategies, provide education to students, and assist those with academic difficulties. Comorbidities are common and should be explored thoroughly as they may play a role in continued stimulant medication misuse and outcomes. Various treatment techniques and modalities can be explored further with each patient, based on the individual and their particular needs.

Corresponding author: Kate Flory, Univ. of South Carolina, Dept. of Psychology, Barnwell College, Columbia, SC 29208, [email protected].

Funding/support: Work on this paper was supported by a University of South Carolina Honors College Exploration Scholar Award and a University of South Carolina Magellan Fellowship, both awarded to Kari Benson.

Financial disclosures: None.

Author contributions: conception and design, KF, RAP, KB; drafting of article, KF, RAP, KB; critical revision of the article, KF, RAP, KB; literature search, KB.

Micrograph showing MCL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) who are unsuitable for hematopoietic stem cell transplant.

Bortezomib is already approved in the European Union to treat multiple myeloma, either as monotherapy or in combination with other treatment regimens.

The CHMP’s decision to expand the approved use of bortezomib is based on data from the phase 3 LYM-3002 study. Results from this trial were presented at the 2014 ASCO Annual Meeting (abstract 8500).

LYM-3002 included 487 patients newly diagnosed with MCL who were ineligible, or not considered, for transplant. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AE) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85%, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3%, respectively.

The CHMP’s positive opinion will be reviewed by the European Commission, which has the authority to grant a label extension for medicines in the European Economic Area. A final decision on the use of bortezomib in MCL is expected early next year.

Micrograph showing MCL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) who are unsuitable for hematopoietic stem cell transplant.

Bortezomib is already approved in the European Union to treat multiple myeloma, either as monotherapy or in combination with other treatment regimens.

The CHMP’s decision to expand the approved use of bortezomib is based on data from the phase 3 LYM-3002 study. Results from this trial were presented at the 2014 ASCO Annual Meeting (abstract 8500).

LYM-3002 included 487 patients newly diagnosed with MCL who were ineligible, or not considered, for transplant. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AE) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85%, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3%, respectively.

The CHMP’s positive opinion will be reviewed by the European Commission, which has the authority to grant a label extension for medicines in the European Economic Area. A final decision on the use of bortezomib in MCL is expected early next year.

Micrograph showing MCL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) who are unsuitable for hematopoietic stem cell transplant.

Bortezomib is already approved in the European Union to treat multiple myeloma, either as monotherapy or in combination with other treatment regimens.

The CHMP’s decision to expand the approved use of bortezomib is based on data from the phase 3 LYM-3002 study. Results from this trial were presented at the 2014 ASCO Annual Meeting (abstract 8500).

LYM-3002 included 487 patients newly diagnosed with MCL who were ineligible, or not considered, for transplant. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median PFS times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median PFS times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AE) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85%, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3%, respectively.

The CHMP’s positive opinion will be reviewed by the European Commission, which has the authority to grant a label extension for medicines in the European Economic Area. A final decision on the use of bortezomib in MCL is expected early next year.

Haruko Obokata, PhD

Credit: Associated Press

After months of trying, Haruko Obokata, PhD, and a team of researchers at her institution, RIKEN, have failed to produce stimulus-triggered acquisition of pluripotency (STAP) cells.

Officials from RIKEN said they have accepted Dr Obokata’s resignation, and the institution has decided to end its efforts to recreate the STAP cell phenomenon.

Dr Obokata and her colleagues initially reported the creation of STAP cells in an article and a letter published in Nature last January. The researchers said they had induced pluripotency in somatic cells by exposing the cells to a low-pH environment.

Not long after the papers were published, members of the scientific community began to question the validity of the research.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

In August, the group reported initial results, saying their attempts had failed, but they would continue trying to create STAP cells until March 2015. Meanwhile, Dr Obokata was trying to recreate the STAP cell phenomenon on her own, under supervision.

Shinichi Aizawa, PhD, the leader of RIKEN’s team, explained the final results of their experiments, as well as Dr Obokata’s, in a press conference in Tokyo on Friday.

Dr Obokata was able to show a fluorescent phenomenon that indicates the possibility of pluripotency in cells, albeit at a very low rate. However, she could not confirm the pluripotency of STAP cells in mice.

The RIKEN team had similar results. So they have decided not to continue with the experiments.

RIKEN accepted Dr Obokata’s resignation, and a disciplinary committee has been discussing how they will reprimand her for research misconduct. RIKEN officials said they will make an announcement once the decision has been made.

Haruko Obokata, PhD

Credit: Associated Press

After months of trying, Haruko Obokata, PhD, and a team of researchers at her institution, RIKEN, have failed to produce stimulus-triggered acquisition of pluripotency (STAP) cells.

Officials from RIKEN said they have accepted Dr Obokata’s resignation, and the institution has decided to end its efforts to recreate the STAP cell phenomenon.

Dr Obokata and her colleagues initially reported the creation of STAP cells in an article and a letter published in Nature last January. The researchers said they had induced pluripotency in somatic cells by exposing the cells to a low-pH environment.

Not long after the papers were published, members of the scientific community began to question the validity of the research.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

In August, the group reported initial results, saying their attempts had failed, but they would continue trying to create STAP cells until March 2015. Meanwhile, Dr Obokata was trying to recreate the STAP cell phenomenon on her own, under supervision.

Shinichi Aizawa, PhD, the leader of RIKEN’s team, explained the final results of their experiments, as well as Dr Obokata’s, in a press conference in Tokyo on Friday.

Dr Obokata was able to show a fluorescent phenomenon that indicates the possibility of pluripotency in cells, albeit at a very low rate. However, she could not confirm the pluripotency of STAP cells in mice.

The RIKEN team had similar results. So they have decided not to continue with the experiments.

RIKEN accepted Dr Obokata’s resignation, and a disciplinary committee has been discussing how they will reprimand her for research misconduct. RIKEN officials said they will make an announcement once the decision has been made.

Haruko Obokata, PhD

Credit: Associated Press

After months of trying, Haruko Obokata, PhD, and a team of researchers at her institution, RIKEN, have failed to produce stimulus-triggered acquisition of pluripotency (STAP) cells.

Officials from RIKEN said they have accepted Dr Obokata’s resignation, and the institution has decided to end its efforts to recreate the STAP cell phenomenon.

Dr Obokata and her colleagues initially reported the creation of STAP cells in an article and a letter published in Nature last January. The researchers said they had induced pluripotency in somatic cells by exposing the cells to a low-pH environment.

Not long after the papers were published, members of the scientific community began to question the validity of the research.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

In August, the group reported initial results, saying their attempts had failed, but they would continue trying to create STAP cells until March 2015. Meanwhile, Dr Obokata was trying to recreate the STAP cell phenomenon on her own, under supervision.

Shinichi Aizawa, PhD, the leader of RIKEN’s team, explained the final results of their experiments, as well as Dr Obokata’s, in a press conference in Tokyo on Friday.

Dr Obokata was able to show a fluorescent phenomenon that indicates the possibility of pluripotency in cells, albeit at a very low rate. However, she could not confirm the pluripotency of STAP cells in mice.

The RIKEN team had similar results. So they have decided not to continue with the experiments.

RIKEN accepted Dr Obokata’s resignation, and a disciplinary committee has been discussing how they will reprimand her for research misconduct. RIKEN officials said they will make an announcement once the decision has been made.

Several months ago, a 51-year-old woman first noticed brownish red lesions on her leg. She initially dismissed them as insect bites and regarded them as mostly a cosmetic concern. When the lesions failed to disappear after six months, her primary care provider referred the patient to dermatology. (In the interim, a friend did suggest ringworm as a diagnosis, but the OTC tolnaftate cream the patient tried had no effect.)

The patient claims to be quite healthy, which she attributes to walking several miles a day and working out at the gym every other day. She denies any shortness of breath, unexplained fever, or night sweats. There is no personal history of diabetes, but she has had glucose tolerance tests every six months for years because of a significant family history of the disease.

EXAMINATION
There are four intradermal shiny round nodules, averaging about 1.8 cm, on the upper anterior tibial area. The margins of the lesions are sharply drawn, and there is no surrounding erythema or increased warmth on palpation. The surfaces are quite uniform in texture.

Examination of her skin elsewhere reveals no noteworthy lesions. There is no palpable adenopathy in the groin on the affected side.

Results of a punch biopsy show interstitial and palisaded granulomas of the subcutaneous tissue, especially the dermis. Thickening of blood vessel walls and endothelial cell swelling are also noted.

What is the diagnosis?

DISCUSSION
Based on the appearance of the lesions, the patient’s family history, and the histopathologic findings, a diagnosis of necrobiosis lipoidica (NL) was made. When NL was first described in 1929, it was only seen in diabetic persons and thus was named necrobiosis lipoidica diabeticorum. By 1932, however, cases of NL were being reported in persons without diabetes—so the “diabeticorum” was dropped.

Only 0.3% of diabetic persons develop NL. In 15% of cases, NL precedes diabetes; in 60%, diabetes manifests first. Simultaneous diagnosis of both occurs about 25% of the time.

The cause of NL is still unknown. Most theories suggest it is related in some way to diabetes, since most persons with NL have a personal or family history of diabetes or register abnormal results to glucose tolerance testing. Furthermore, the microvascular changes seen in NL lesions are reminiscent of those seen in microangiopathic lesions in diabetic patients. Oddly enough, though, the presence or progression of NL does not correlate with how well controlled the patient’s diabetes is.

Other theories center on an autoimmune mechanism, based on demonstrable deposition of immunoglobulins, components of complement, and fibrinogen in vessel walls. High levels of TNF-a are found in many cases of NL, a fact that researchers are pursuing vigorously.

NL can manifest anywhere but is most common on the legs, where 75% of patients report no symptoms beyond a slight loss of sensation. The remaining 25% do report moderate to severe pain.

In terms of diagnosis, the appearance and history are sufficient in most cases. In this particular case, the lesions were fairly new and small, and the differential thus included such worrisome items as sarcoidosis or even Hansen’s disease. Less concerning differential items included granuloma annulare, other xanthomatous processes, and rheumatoid nodules.

In this case, a punch biopsy was necessary (the defect from which was closed carefully with interrupted sutures). Such procedures are discouraged in patients with larger and more advanced lesions, for fear of inducing a nonhealing wound. In fact, ulceration, usually from trauma, is the most feared complication of NL—and effective treatment is hard to come by.

This patient was treated with perilesional injection of triamcinolone suspension 10 mg per cc and given a prescription for 0.1% tacrolimus cream (to be applied twice daily). A follow-up visit was arranged for two months down the road. Her long-term prognosis is guarded, at best. Since she was already acutely aware of her risk for diabetes, there was no need for additional action in that arena.

Many other treatments have been tried for NL, with varying success, including dihydrochloroquine (Plaquenil and others) pentoxifylline, and TNF-a inhibitors.

TAKE-HOME LEARNING POINTS
• Early manifestations of necrobiosis lipoidica (NL) can be puzzling, and biopsy may be required for diagnosis.

• However, with advanced, obvious lesions, it is preferable to make the diagnosis of NL without biopsy, since punch biopsy can result in a nonhealing wound.

• Mature NL lesions become atrophic and yellowed, with marked telangiectasia formation on their surfaces.

• Just 0.3% of diabetic patients ever develop NL, but most affected persons have a family history of diabetes or an abnormal glucose tolerance test results, if not a personal history of diabetes.

Several months ago, a 51-year-old woman first noticed brownish red lesions on her leg. She initially dismissed them as insect bites and regarded them as mostly a cosmetic concern. When the lesions failed to disappear after six months, her primary care provider referred the patient to dermatology. (In the interim, a friend did suggest ringworm as a diagnosis, but the OTC tolnaftate cream the patient tried had no effect.)

The patient claims to be quite healthy, which she attributes to walking several miles a day and working out at the gym every other day. She denies any shortness of breath, unexplained fever, or night sweats. There is no personal history of diabetes, but she has had glucose tolerance tests every six months for years because of a significant family history of the disease.

EXAMINATION
There are four intradermal shiny round nodules, averaging about 1.8 cm, on the upper anterior tibial area. The margins of the lesions are sharply drawn, and there is no surrounding erythema or increased warmth on palpation. The surfaces are quite uniform in texture.

Examination of her skin elsewhere reveals no noteworthy lesions. There is no palpable adenopathy in the groin on the affected side.

Results of a punch biopsy show interstitial and palisaded granulomas of the subcutaneous tissue, especially the dermis. Thickening of blood vessel walls and endothelial cell swelling are also noted.

What is the diagnosis?

DISCUSSION
Based on the appearance of the lesions, the patient’s family history, and the histopathologic findings, a diagnosis of necrobiosis lipoidica (NL) was made. When NL was first described in 1929, it was only seen in diabetic persons and thus was named necrobiosis lipoidica diabeticorum. By 1932, however, cases of NL were being reported in persons without diabetes—so the “diabeticorum” was dropped.

Only 0.3% of diabetic persons develop NL. In 15% of cases, NL precedes diabetes; in 60%, diabetes manifests first. Simultaneous diagnosis of both occurs about 25% of the time.

The cause of NL is still unknown. Most theories suggest it is related in some way to diabetes, since most persons with NL have a personal or family history of diabetes or register abnormal results to glucose tolerance testing. Furthermore, the microvascular changes seen in NL lesions are reminiscent of those seen in microangiopathic lesions in diabetic patients. Oddly enough, though, the presence or progression of NL does not correlate with how well controlled the patient’s diabetes is.

Other theories center on an autoimmune mechanism, based on demonstrable deposition of immunoglobulins, components of complement, and fibrinogen in vessel walls. High levels of TNF-a are found in many cases of NL, a fact that researchers are pursuing vigorously.

NL can manifest anywhere but is most common on the legs, where 75% of patients report no symptoms beyond a slight loss of sensation. The remaining 25% do report moderate to severe pain.

In terms of diagnosis, the appearance and history are sufficient in most cases. In this particular case, the lesions were fairly new and small, and the differential thus included such worrisome items as sarcoidosis or even Hansen’s disease. Less concerning differential items included granuloma annulare, other xanthomatous processes, and rheumatoid nodules.

In this case, a punch biopsy was necessary (the defect from which was closed carefully with interrupted sutures). Such procedures are discouraged in patients with larger and more advanced lesions, for fear of inducing a nonhealing wound. In fact, ulceration, usually from trauma, is the most feared complication of NL—and effective treatment is hard to come by.

This patient was treated with perilesional injection of triamcinolone suspension 10 mg per cc and given a prescription for 0.1% tacrolimus cream (to be applied twice daily). A follow-up visit was arranged for two months down the road. Her long-term prognosis is guarded, at best. Since she was already acutely aware of her risk for diabetes, there was no need for additional action in that arena.

Many other treatments have been tried for NL, with varying success, including dihydrochloroquine (Plaquenil and others) pentoxifylline, and TNF-a inhibitors.

TAKE-HOME LEARNING POINTS
• Early manifestations of necrobiosis lipoidica (NL) can be puzzling, and biopsy may be required for diagnosis.

• However, with advanced, obvious lesions, it is preferable to make the diagnosis of NL without biopsy, since punch biopsy can result in a nonhealing wound.

• Mature NL lesions become atrophic and yellowed, with marked telangiectasia formation on their surfaces.

• Just 0.3% of diabetic patients ever develop NL, but most affected persons have a family history of diabetes or an abnormal glucose tolerance test results, if not a personal history of diabetes.

Several months ago, a 51-year-old woman first noticed brownish red lesions on her leg. She initially dismissed them as insect bites and regarded them as mostly a cosmetic concern. When the lesions failed to disappear after six months, her primary care provider referred the patient to dermatology. (In the interim, a friend did suggest ringworm as a diagnosis, but the OTC tolnaftate cream the patient tried had no effect.)

The patient claims to be quite healthy, which she attributes to walking several miles a day and working out at the gym every other day. She denies any shortness of breath, unexplained fever, or night sweats. There is no personal history of diabetes, but she has had glucose tolerance tests every six months for years because of a significant family history of the disease.

EXAMINATION
There are four intradermal shiny round nodules, averaging about 1.8 cm, on the upper anterior tibial area. The margins of the lesions are sharply drawn, and there is no surrounding erythema or increased warmth on palpation. The surfaces are quite uniform in texture.

Examination of her skin elsewhere reveals no noteworthy lesions. There is no palpable adenopathy in the groin on the affected side.

Results of a punch biopsy show interstitial and palisaded granulomas of the subcutaneous tissue, especially the dermis. Thickening of blood vessel walls and endothelial cell swelling are also noted.

What is the diagnosis?

DISCUSSION
Based on the appearance of the lesions, the patient’s family history, and the histopathologic findings, a diagnosis of necrobiosis lipoidica (NL) was made. When NL was first described in 1929, it was only seen in diabetic persons and thus was named necrobiosis lipoidica diabeticorum. By 1932, however, cases of NL were being reported in persons without diabetes—so the “diabeticorum” was dropped.

Only 0.3% of diabetic persons develop NL. In 15% of cases, NL precedes diabetes; in 60%, diabetes manifests first. Simultaneous diagnosis of both occurs about 25% of the time.

The cause of NL is still unknown. Most theories suggest it is related in some way to diabetes, since most persons with NL have a personal or family history of diabetes or register abnormal results to glucose tolerance testing. Furthermore, the microvascular changes seen in NL lesions are reminiscent of those seen in microangiopathic lesions in diabetic patients. Oddly enough, though, the presence or progression of NL does not correlate with how well controlled the patient’s diabetes is.

Other theories center on an autoimmune mechanism, based on demonstrable deposition of immunoglobulins, components of complement, and fibrinogen in vessel walls. High levels of TNF-a are found in many cases of NL, a fact that researchers are pursuing vigorously.

NL can manifest anywhere but is most common on the legs, where 75% of patients report no symptoms beyond a slight loss of sensation. The remaining 25% do report moderate to severe pain.

In terms of diagnosis, the appearance and history are sufficient in most cases. In this particular case, the lesions were fairly new and small, and the differential thus included such worrisome items as sarcoidosis or even Hansen’s disease. Less concerning differential items included granuloma annulare, other xanthomatous processes, and rheumatoid nodules.

In this case, a punch biopsy was necessary (the defect from which was closed carefully with interrupted sutures). Such procedures are discouraged in patients with larger and more advanced lesions, for fear of inducing a nonhealing wound. In fact, ulceration, usually from trauma, is the most feared complication of NL—and effective treatment is hard to come by.

This patient was treated with perilesional injection of triamcinolone suspension 10 mg per cc and given a prescription for 0.1% tacrolimus cream (to be applied twice daily). A follow-up visit was arranged for two months down the road. Her long-term prognosis is guarded, at best. Since she was already acutely aware of her risk for diabetes, there was no need for additional action in that arena.

Many other treatments have been tried for NL, with varying success, including dihydrochloroquine (Plaquenil and others) pentoxifylline, and TNF-a inhibitors.

TAKE-HOME LEARNING POINTS
• Early manifestations of necrobiosis lipoidica (NL) can be puzzling, and biopsy may be required for diagnosis.

• However, with advanced, obvious lesions, it is preferable to make the diagnosis of NL without biopsy, since punch biopsy can result in a nonhealing wound.

• Mature NL lesions become atrophic and yellowed, with marked telangiectasia formation on their surfaces.

• Just 0.3% of diabetic patients ever develop NL, but most affected persons have a family history of diabetes or an abnormal glucose tolerance test results, if not a personal history of diabetes.

Clinical question: What is the benefit associated with a depletive fluid management strategy on ventilator-associated complication (VAC) and ventilator-associated pneumonia (VAP) during weaning from mechanical ventilation?

Background: VAP is common in the ICU. Pulmonary edema predisposes patients to pneumonia by altering the alveolar microenvironment through enhancement of bacterial colonization and infectivity and a decrease in host bactericidal capacities. A fluid management strategy aimed at lowering lung fluid balance may prove useful in reducing both VAC and VAP.

Study design: Randomized controlled trial.

Setting: Nine ICUs in Europe and South America, between May 2007 and July 2009.

Synopsis: Data from the B-type Natriuretic Peptide for the Management of Weaning (BMW) trial was used to compare the cumulative incidence of VAC and VAP between the biomarker-driven, depletive fluid management group and the usual care group during the 14 days following randomization. The trial enrolled 304 randomized patients, 152 in each group.

Compared with usual care, the interventional strategy was associated with a higher proportion of patients receiving diuretics, in higher doses, resulting in a significantly more negative fluid balance during weaning and a shorter duration of mechanical ventilation. VAC (as defined by worsening oxygenation) occurred in 13.2% of patients during the 14 days following randomization: 17.8% in the usual care group and 8.6% in the interventional group. VAP occurred in 13.5% during the 14 days following randomization: 17.8% in the usual care group and 9.2% in the interventional group.

Bottom line: A biomarker-driven, depletive fluid strategy decreases the cumulative incidence of VAC and VAP.

Citation: Mekontso Dessap A, Katsahian S, Roche-Campo F, et al. Ventilator-associated pneumonia during weaning from mechanical ventilation: role of fluid management. Chest. 2014;146(1):58-65.

Visit our website for more physician reviews of HM-related research.

Clinical question: What is the benefit associated with a depletive fluid management strategy on ventilator-associated complication (VAC) and ventilator-associated pneumonia (VAP) during weaning from mechanical ventilation?

Background: VAP is common in the ICU. Pulmonary edema predisposes patients to pneumonia by altering the alveolar microenvironment through enhancement of bacterial colonization and infectivity and a decrease in host bactericidal capacities. A fluid management strategy aimed at lowering lung fluid balance may prove useful in reducing both VAC and VAP.

Study design: Randomized controlled trial.

Setting: Nine ICUs in Europe and South America, between May 2007 and July 2009.

Synopsis: Data from the B-type Natriuretic Peptide for the Management of Weaning (BMW) trial was used to compare the cumulative incidence of VAC and VAP between the biomarker-driven, depletive fluid management group and the usual care group during the 14 days following randomization. The trial enrolled 304 randomized patients, 152 in each group.

Compared with usual care, the interventional strategy was associated with a higher proportion of patients receiving diuretics, in higher doses, resulting in a significantly more negative fluid balance during weaning and a shorter duration of mechanical ventilation. VAC (as defined by worsening oxygenation) occurred in 13.2% of patients during the 14 days following randomization: 17.8% in the usual care group and 8.6% in the interventional group. VAP occurred in 13.5% during the 14 days following randomization: 17.8% in the usual care group and 9.2% in the interventional group.

Bottom line: A biomarker-driven, depletive fluid strategy decreases the cumulative incidence of VAC and VAP.

Citation: Mekontso Dessap A, Katsahian S, Roche-Campo F, et al. Ventilator-associated pneumonia during weaning from mechanical ventilation: role of fluid management. Chest. 2014;146(1):58-65.

Visit our website for more physician reviews of HM-related research.

Clinical question: What is the benefit associated with a depletive fluid management strategy on ventilator-associated complication (VAC) and ventilator-associated pneumonia (VAP) during weaning from mechanical ventilation?

Background: VAP is common in the ICU. Pulmonary edema predisposes patients to pneumonia by altering the alveolar microenvironment through enhancement of bacterial colonization and infectivity and a decrease in host bactericidal capacities. A fluid management strategy aimed at lowering lung fluid balance may prove useful in reducing both VAC and VAP.

Study design: Randomized controlled trial.

Setting: Nine ICUs in Europe and South America, between May 2007 and July 2009.

Synopsis: Data from the B-type Natriuretic Peptide for the Management of Weaning (BMW) trial was used to compare the cumulative incidence of VAC and VAP between the biomarker-driven, depletive fluid management group and the usual care group during the 14 days following randomization. The trial enrolled 304 randomized patients, 152 in each group.

Compared with usual care, the interventional strategy was associated with a higher proportion of patients receiving diuretics, in higher doses, resulting in a significantly more negative fluid balance during weaning and a shorter duration of mechanical ventilation. VAC (as defined by worsening oxygenation) occurred in 13.2% of patients during the 14 days following randomization: 17.8% in the usual care group and 8.6% in the interventional group. VAP occurred in 13.5% during the 14 days following randomization: 17.8% in the usual care group and 9.2% in the interventional group.

Bottom line: A biomarker-driven, depletive fluid strategy decreases the cumulative incidence of VAC and VAP.

Citation: Mekontso Dessap A, Katsahian S, Roche-Campo F, et al. Ventilator-associated pneumonia during weaning from mechanical ventilation: role of fluid management. Chest. 2014;146(1):58-65.

Visit our website for more physician reviews of HM-related research.

Hospitalists need not fear negative consequences when prescribing guideline-recommended antibiotic therapy for children hospitalized with community-acquired pneumonia (CAP), according to a recent study conducted at Cincinnati Children’s Hospital Medical Center (CCHMC).

"Guideline-recommended therapy for pediatric pneumonia did not result in different outcomes than nonrecommended [largely cephalosporin] therapy," lead author and CCHMC-based hospitalist Joanna Thomson MD, MPH, says in an email to The Hospitalist.

Published in the Journal of Hospital Medicine, the study followed the outcomes of 168 pediatric inpatients ages 3 months to 18 years who were prescribed empiric guideline-recommended therapy, which advises using an aminopenicillin first rather than a broad-spectrum antibiotic. The study focused on patients’ outcomes, specifically length of stay (LOS), total cost of hospitalization, and inpatient pharmacy costs, and found no difference in LOS or costs for patients treated according to guidelines compared with those whose treatment varied from the recommendations.

"Given growing concerns regarding antimicrobial resistance, it is pretty easy to extrapolate the benefits of using narrow-spectrum therapy, but we wanted to make sure that it wasn't resulting in negative unintended consequences," Dr. Thomson says. "Indeed, use of guideline-recommended therapy did not change our outcomes."

However, most patients hospitalized with CAP do not currently receive guideline-recommended therapy, according to Dr. Thomson. CCHMC had been one of those institutions overprescribing cephalosporin, with nearly 70% of children admitted with pneumonia receiving the antibiotic. That practice has since changed, she notes.

"The majority of hospitalized patients in the U.S. still receive broad-spectrum cephalosporins," Dr. Thomson says. "I suspect that this may partially be due to fears of unintended negative consequences. We should all be good stewards and prescribe guideline-recommended therapy whenever possible."

Visit our website for more information on antibiotic prescription practices.

Hospitalists need not fear negative consequences when prescribing guideline-recommended antibiotic therapy for children hospitalized with community-acquired pneumonia (CAP), according to a recent study conducted at Cincinnati Children’s Hospital Medical Center (CCHMC).

"Guideline-recommended therapy for pediatric pneumonia did not result in different outcomes than nonrecommended [largely cephalosporin] therapy," lead author and CCHMC-based hospitalist Joanna Thomson MD, MPH, says in an email to The Hospitalist.

Published in the Journal of Hospital Medicine, the study followed the outcomes of 168 pediatric inpatients ages 3 months to 18 years who were prescribed empiric guideline-recommended therapy, which advises using an aminopenicillin first rather than a broad-spectrum antibiotic. The study focused on patients’ outcomes, specifically length of stay (LOS), total cost of hospitalization, and inpatient pharmacy costs, and found no difference in LOS or costs for patients treated according to guidelines compared with those whose treatment varied from the recommendations.

"Given growing concerns regarding antimicrobial resistance, it is pretty easy to extrapolate the benefits of using narrow-spectrum therapy, but we wanted to make sure that it wasn't resulting in negative unintended consequences," Dr. Thomson says. "Indeed, use of guideline-recommended therapy did not change our outcomes."

However, most patients hospitalized with CAP do not currently receive guideline-recommended therapy, according to Dr. Thomson. CCHMC had been one of those institutions overprescribing cephalosporin, with nearly 70% of children admitted with pneumonia receiving the antibiotic. That practice has since changed, she notes.

"The majority of hospitalized patients in the U.S. still receive broad-spectrum cephalosporins," Dr. Thomson says. "I suspect that this may partially be due to fears of unintended negative consequences. We should all be good stewards and prescribe guideline-recommended therapy whenever possible."

Visit our website for more information on antibiotic prescription practices.

Hospitalists need not fear negative consequences when prescribing guideline-recommended antibiotic therapy for children hospitalized with community-acquired pneumonia (CAP), according to a recent study conducted at Cincinnati Children’s Hospital Medical Center (CCHMC).

"Guideline-recommended therapy for pediatric pneumonia did not result in different outcomes than nonrecommended [largely cephalosporin] therapy," lead author and CCHMC-based hospitalist Joanna Thomson MD, MPH, says in an email to The Hospitalist.

Published in the Journal of Hospital Medicine, the study followed the outcomes of 168 pediatric inpatients ages 3 months to 18 years who were prescribed empiric guideline-recommended therapy, which advises using an aminopenicillin first rather than a broad-spectrum antibiotic. The study focused on patients’ outcomes, specifically length of stay (LOS), total cost of hospitalization, and inpatient pharmacy costs, and found no difference in LOS or costs for patients treated according to guidelines compared with those whose treatment varied from the recommendations.

"Given growing concerns regarding antimicrobial resistance, it is pretty easy to extrapolate the benefits of using narrow-spectrum therapy, but we wanted to make sure that it wasn't resulting in negative unintended consequences," Dr. Thomson says. "Indeed, use of guideline-recommended therapy did not change our outcomes."

However, most patients hospitalized with CAP do not currently receive guideline-recommended therapy, according to Dr. Thomson. CCHMC had been one of those institutions overprescribing cephalosporin, with nearly 70% of children admitted with pneumonia receiving the antibiotic. That practice has since changed, she notes.

"The majority of hospitalized patients in the U.S. still receive broad-spectrum cephalosporins," Dr. Thomson says. "I suspect that this may partially be due to fears of unintended negative consequences. We should all be good stewards and prescribe guideline-recommended therapy whenever possible."

Visit our website for more information on antibiotic prescription practices.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

The US Food and Drug Administration (FDA) has approved the INTERCEPT Blood System for platelets, the first system of its kind to be approved in the US.

It is used to inactivate viruses, bacteria, spirochetes, parasites, and leukocytes in apheresis platelet components.

This can reduce the risk of transfusion-transmitted infection and, potentially, transfusion-associated graft-vs-host disease, although the system cannot inactivate all pathogens.

Certain non-enveloped viruses (such as HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to the INTERCEPT process.

Earlier this week, the FDA approved the INTERCEPT Blood System for plasma (also the first system of its kind to gain FDA approval).

The platelet and plasma systems use the same illumination device, the same active compound (amotosalen), and very similar production steps.

The INTERCEPT systems target a basic biological difference between the therapeutic components of blood. Platelets, plasma, and red blood cells do not require functional DNA or RNA for therapeutic efficacy. But pathogens and white blood cells do, in order to transmit infection.

The INTERCEPT systems use a proprietary molecule that, when activated by UVA light, binds to and blocks the replication of DNA and RNA, preventing nucleic acid replication and rendering the pathogen inactive.

The INTERCEPT Blood System for platelets has been approved in Europe since 2002 and is currently used in 20 countries.

The system was recently made available in the US and its territories under an investigational device exemption study to reduce the risk of transfusion-transmitted dengue and Chikungunya viruses, both of which are epidemic in the Caribbean region, including Puerto Rico, as well as sporadically in the southern US. No approved blood bank screening tests are available for either virus.

Researchers have evaluated INTERCEPT-processed platelets in 10 controlled clinical trials. Details on these trials can be found in the package insert.

The US Food and Drug Administration (FDA) has approved the INTERCEPT Blood System for platelets, the first system of its kind to be approved in the US.

It is used to inactivate viruses, bacteria, spirochetes, parasites, and leukocytes in apheresis platelet components.

This can reduce the risk of transfusion-transmitted infection and, potentially, transfusion-associated graft-vs-host disease, although the system cannot inactivate all pathogens.

Certain non-enveloped viruses (such as HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to the INTERCEPT process.

Earlier this week, the FDA approved the INTERCEPT Blood System for plasma (also the first system of its kind to gain FDA approval).

The platelet and plasma systems use the same illumination device, the same active compound (amotosalen), and very similar production steps.

The INTERCEPT systems target a basic biological difference between the therapeutic components of blood. Platelets, plasma, and red blood cells do not require functional DNA or RNA for therapeutic efficacy. But pathogens and white blood cells do, in order to transmit infection.

The INTERCEPT systems use a proprietary molecule that, when activated by UVA light, binds to and blocks the replication of DNA and RNA, preventing nucleic acid replication and rendering the pathogen inactive.

The INTERCEPT Blood System for platelets has been approved in Europe since 2002 and is currently used in 20 countries.

The system was recently made available in the US and its territories under an investigational device exemption study to reduce the risk of transfusion-transmitted dengue and Chikungunya viruses, both of which are epidemic in the Caribbean region, including Puerto Rico, as well as sporadically in the southern US. No approved blood bank screening tests are available for either virus.

Researchers have evaluated INTERCEPT-processed platelets in 10 controlled clinical trials. Details on these trials can be found in the package insert.

The US Food and Drug Administration (FDA) has approved the INTERCEPT Blood System for platelets, the first system of its kind to be approved in the US.

It is used to inactivate viruses, bacteria, spirochetes, parasites, and leukocytes in apheresis platelet components.

This can reduce the risk of transfusion-transmitted infection and, potentially, transfusion-associated graft-vs-host disease, although the system cannot inactivate all pathogens.

Certain non-enveloped viruses (such as HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to the INTERCEPT process.

Earlier this week, the FDA approved the INTERCEPT Blood System for plasma (also the first system of its kind to gain FDA approval).

The platelet and plasma systems use the same illumination device, the same active compound (amotosalen), and very similar production steps.

The INTERCEPT systems target a basic biological difference between the therapeutic components of blood. Platelets, plasma, and red blood cells do not require functional DNA or RNA for therapeutic efficacy. But pathogens and white blood cells do, in order to transmit infection.

The INTERCEPT systems use a proprietary molecule that, when activated by UVA light, binds to and blocks the replication of DNA and RNA, preventing nucleic acid replication and rendering the pathogen inactive.

The INTERCEPT Blood System for platelets has been approved in Europe since 2002 and is currently used in 20 countries.

The system was recently made available in the US and its territories under an investigational device exemption study to reduce the risk of transfusion-transmitted dengue and Chikungunya viruses, both of which are epidemic in the Caribbean region, including Puerto Rico, as well as sporadically in the southern US. No approved blood bank screening tests are available for either virus.

Researchers have evaluated INTERCEPT-processed platelets in 10 controlled clinical trials. Details on these trials can be found in the package insert.

Blood for transfusion

Credit: Elise Amendola

Two studies shed new light on the prevalence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in the US.

The research showed that postoperative TRALI is significantly underreported and more common than previously thought, with an overall rate of 1.4%.

And the rate of TACO is on the decline, but the risk to surgical patients remains high, at 4%, similar to previous TACO estimates in non-surgical patients.

“An accurate understanding of the risks associated with blood transfusions is essential when determining the safety and appropriateness of transfusion therapies for patients,” said Daryl Kor, MD, senior author of both studies and an associate professor at Mayo Clinic in Rochester, Minnesota.

“Our research provides a greater awareness of the incidence of TRALI and TACO in surgical patients, a population that has been perhaps underrepresented in studies in this area. We believe this to be an important first step in our efforts to prevent these life-threatening transfusion complications.”

Dr Kor and his colleagues described this research in Anesthesiology alongside a related editorial.

In the two retrospective studies, the researchers examined the incidence of TRALI in 3379 patients and TACO in 4070 patients who received blood transfusions during non-cardiac surgery under general anesthesia in 2004 and 2011.

Using a novel algorithm, followed by a rigorous manual review, the team performed a detailed epidemiologic analysis for both complications.

The first study showed that TRALI occurred in 1.4% of surgical patients, with higher rates in specific surgical populations such as those having surgery inside the chest cavity, on major blood vessels, or having an organ transplant. Patients who received larger volumes of blood were also at increased risk.

Previous studies investigating TRALI rates have primarily focused on the critically ill and reported variable incidence rates. Many studies have reported incidences between 0.02% and 0.05%.

The second study showed that TACO occurs in 4.3% of surgical patients, with higher rates associated with increased volume of blood transfused, advanced age, and total intraoperative fluid balance. Again, patients having surgery inside the chest cavity, on major blood vessels, or organ transplants were at the greatest risk.

The study also revealed that the rate of TACO decreased significantly from 2004 to 2011—from 5.5% to 3%. This decline was not fully explained by any of the patient or transfusion characteristics evaluated in the study.

The researchers said future studies are needed to further explore which mechanisms and risk factors are responsible for TACO and TRALI.

“With improved understanding of the mechanisms underlying TRALI and TACO, we may be able to refine the novel electronic algorithms used to screen patients in these studies,” Dr Kor said. “Ultimately, we hope to develop a real-time prediction model for these complications so that we can identify those at greatest risk and perhaps implement strategies to reduce this risk.”

Blood for transfusion

Credit: Elise Amendola

Two studies shed new light on the prevalence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in the US.

The research showed that postoperative TRALI is significantly underreported and more common than previously thought, with an overall rate of 1.4%.

And the rate of TACO is on the decline, but the risk to surgical patients remains high, at 4%, similar to previous TACO estimates in non-surgical patients.

“An accurate understanding of the risks associated with blood transfusions is essential when determining the safety and appropriateness of transfusion therapies for patients,” said Daryl Kor, MD, senior author of both studies and an associate professor at Mayo Clinic in Rochester, Minnesota.

“Our research provides a greater awareness of the incidence of TRALI and TACO in surgical patients, a population that has been perhaps underrepresented in studies in this area. We believe this to be an important first step in our efforts to prevent these life-threatening transfusion complications.”

Dr Kor and his colleagues described this research in Anesthesiology alongside a related editorial.

In the two retrospective studies, the researchers examined the incidence of TRALI in 3379 patients and TACO in 4070 patients who received blood transfusions during non-cardiac surgery under general anesthesia in 2004 and 2011.

Using a novel algorithm, followed by a rigorous manual review, the team performed a detailed epidemiologic analysis for both complications.

The first study showed that TRALI occurred in 1.4% of surgical patients, with higher rates in specific surgical populations such as those having surgery inside the chest cavity, on major blood vessels, or having an organ transplant. Patients who received larger volumes of blood were also at increased risk.

Previous studies investigating TRALI rates have primarily focused on the critically ill and reported variable incidence rates. Many studies have reported incidences between 0.02% and 0.05%.

The second study showed that TACO occurs in 4.3% of surgical patients, with higher rates associated with increased volume of blood transfused, advanced age, and total intraoperative fluid balance. Again, patients having surgery inside the chest cavity, on major blood vessels, or organ transplants were at the greatest risk.

The study also revealed that the rate of TACO decreased significantly from 2004 to 2011—from 5.5% to 3%. This decline was not fully explained by any of the patient or transfusion characteristics evaluated in the study.

The researchers said future studies are needed to further explore which mechanisms and risk factors are responsible for TACO and TRALI.

“With improved understanding of the mechanisms underlying TRALI and TACO, we may be able to refine the novel electronic algorithms used to screen patients in these studies,” Dr Kor said. “Ultimately, we hope to develop a real-time prediction model for these complications so that we can identify those at greatest risk and perhaps implement strategies to reduce this risk.”

Blood for transfusion

Credit: Elise Amendola

Two studies shed new light on the prevalence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in the US.

The research showed that postoperative TRALI is significantly underreported and more common than previously thought, with an overall rate of 1.4%.

And the rate of TACO is on the decline, but the risk to surgical patients remains high, at 4%, similar to previous TACO estimates in non-surgical patients.

“An accurate understanding of the risks associated with blood transfusions is essential when determining the safety and appropriateness of transfusion therapies for patients,” said Daryl Kor, MD, senior author of both studies and an associate professor at Mayo Clinic in Rochester, Minnesota.

“Our research provides a greater awareness of the incidence of TRALI and TACO in surgical patients, a population that has been perhaps underrepresented in studies in this area. We believe this to be an important first step in our efforts to prevent these life-threatening transfusion complications.”

Dr Kor and his colleagues described this research in Anesthesiology alongside a related editorial.

In the two retrospective studies, the researchers examined the incidence of TRALI in 3379 patients and TACO in 4070 patients who received blood transfusions during non-cardiac surgery under general anesthesia in 2004 and 2011.

Using a novel algorithm, followed by a rigorous manual review, the team performed a detailed epidemiologic analysis for both complications.

The first study showed that TRALI occurred in 1.4% of surgical patients, with higher rates in specific surgical populations such as those having surgery inside the chest cavity, on major blood vessels, or having an organ transplant. Patients who received larger volumes of blood were also at increased risk.

Previous studies investigating TRALI rates have primarily focused on the critically ill and reported variable incidence rates. Many studies have reported incidences between 0.02% and 0.05%.

The second study showed that TACO occurs in 4.3% of surgical patients, with higher rates associated with increased volume of blood transfused, advanced age, and total intraoperative fluid balance. Again, patients having surgery inside the chest cavity, on major blood vessels, or organ transplants were at the greatest risk.

The study also revealed that the rate of TACO decreased significantly from 2004 to 2011—from 5.5% to 3%. This decline was not fully explained by any of the patient or transfusion characteristics evaluated in the study.

The researchers said future studies are needed to further explore which mechanisms and risk factors are responsible for TACO and TRALI.

“With improved understanding of the mechanisms underlying TRALI and TACO, we may be able to refine the novel electronic algorithms used to screen patients in these studies,” Dr Kor said. “Ultimately, we hope to develop a real-time prediction model for these complications so that we can identify those at greatest risk and perhaps implement strategies to reduce this risk.”

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has published a final guidance recommending the anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) as an option for treating and preventing recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

The guidance says dabigatran can provide a benefit for these patients, with cost- and clinical-effectiveness similar to rivaroxaban and added convenience compared to warfarin.

“For many people, using warfarin can be difficult because of the need for frequent tests to see if the blood is clotting properly, and having to adjust the dose of the

drug if it is not,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The appraisal committee felt that dabigatran represents a potential benefit for many people who have had a DVT or PE, particularly those who have risk factors for recurrence of a blood clot and who therefore need longer-term treatment. We are pleased, therefore, to be able to recommend dabigatran as a cost-effective option for treating DVT and PE and preventing further episodes in adults.”

NICE expects dabigatran to be available on the National Health Service within 3 months.

Cost considerations

Dabigatran costs £65.90 for a 60-capsule pack of the 150 mg or 110 mg doses (excluding tax) and £2.20 per day of treatment, although costs may vary in different settings.

The most plausible incremental cost-effectiveness ratio (ICER) for dabigatran compared with warfarin for acute treatment was uncertain.

However, both Boehringer Ingelheim’s and the evidence review group’s exploratory ICER remained in the range that could be considered a cost-effective use of National Health Service resources. That is, both were under £20,000 per quality-adjusted life-year gained (QALY).

Neither Boehringer Ingelheim nor the evidence review group found any significant difference in efficacy between dabigatran and rivaroxaban for acute treatment of venous thromboembolism (VTE) in their indirect comparisons, and the costs were also very similar between these two treatments.

For combined treatment and secondary prevention of VTE, the appraisal committee said the company’s base case ICER for dabigatran compared with warfarin was likely too low (£9973 per QALY gained).

But the evidence review group’s exploratory base case for dabigatran compared with warfarin may have overestimated the ICER (£35,786 per QALY gained). So the ICER probably lies somewhere between these estimates.

Clinical evidence

To assess the clinical effectiveness of dabigatran, the appraisal committee evaluated data from the RECOVER, RE-MEDY, and RESONATE trials.

In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms.

However, patients were more likely to discontinue dabigatran due to adverse events. Results from this trial were presented at ASH 2009 and published in NEJM.

The RE-COVER II trial also suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths, and dabigatran was associated with a lower rate of major bleeding.

Rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms. Results from this trial were published in Circulation in 2013.

The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.

The RE-MEDY trial suggested that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.

Results of the RE-SONATE trial indicated that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has published a final guidance recommending the anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) as an option for treating and preventing recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

The guidance says dabigatran can provide a benefit for these patients, with cost- and clinical-effectiveness similar to rivaroxaban and added convenience compared to warfarin.

“For many people, using warfarin can be difficult because of the need for frequent tests to see if the blood is clotting properly, and having to adjust the dose of the

drug if it is not,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The appraisal committee felt that dabigatran represents a potential benefit for many people who have had a DVT or PE, particularly those who have risk factors for recurrence of a blood clot and who therefore need longer-term treatment. We are pleased, therefore, to be able to recommend dabigatran as a cost-effective option for treating DVT and PE and preventing further episodes in adults.”

NICE expects dabigatran to be available on the National Health Service within 3 months.

Cost considerations

Dabigatran costs £65.90 for a 60-capsule pack of the 150 mg or 110 mg doses (excluding tax) and £2.20 per day of treatment, although costs may vary in different settings.

The most plausible incremental cost-effectiveness ratio (ICER) for dabigatran compared with warfarin for acute treatment was uncertain.

However, both Boehringer Ingelheim’s and the evidence review group’s exploratory ICER remained in the range that could be considered a cost-effective use of National Health Service resources. That is, both were under £20,000 per quality-adjusted life-year gained (QALY).

Neither Boehringer Ingelheim nor the evidence review group found any significant difference in efficacy between dabigatran and rivaroxaban for acute treatment of venous thromboembolism (VTE) in their indirect comparisons, and the costs were also very similar between these two treatments.

For combined treatment and secondary prevention of VTE, the appraisal committee said the company’s base case ICER for dabigatran compared with warfarin was likely too low (£9973 per QALY gained).

But the evidence review group’s exploratory base case for dabigatran compared with warfarin may have overestimated the ICER (£35,786 per QALY gained). So the ICER probably lies somewhere between these estimates.

Clinical evidence

To assess the clinical effectiveness of dabigatran, the appraisal committee evaluated data from the RECOVER, RE-MEDY, and RESONATE trials.

In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms.

However, patients were more likely to discontinue dabigatran due to adverse events. Results from this trial were presented at ASH 2009 and published in NEJM.

The RE-COVER II trial also suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths, and dabigatran was associated with a lower rate of major bleeding.

Rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms. Results from this trial were published in Circulation in 2013.

The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.

The RE-MEDY trial suggested that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.

Results of the RE-SONATE trial indicated that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has published a final guidance recommending the anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) as an option for treating and preventing recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

The guidance says dabigatran can provide a benefit for these patients, with cost- and clinical-effectiveness similar to rivaroxaban and added convenience compared to warfarin.

“For many people, using warfarin can be difficult because of the need for frequent tests to see if the blood is clotting properly, and having to adjust the dose of the

drug if it is not,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The appraisal committee felt that dabigatran represents a potential benefit for many people who have had a DVT or PE, particularly those who have risk factors for recurrence of a blood clot and who therefore need longer-term treatment. We are pleased, therefore, to be able to recommend dabigatran as a cost-effective option for treating DVT and PE and preventing further episodes in adults.”

NICE expects dabigatran to be available on the National Health Service within 3 months.

Cost considerations

Dabigatran costs £65.90 for a 60-capsule pack of the 150 mg or 110 mg doses (excluding tax) and £2.20 per day of treatment, although costs may vary in different settings.

The most plausible incremental cost-effectiveness ratio (ICER) for dabigatran compared with warfarin for acute treatment was uncertain.

However, both Boehringer Ingelheim’s and the evidence review group’s exploratory ICER remained in the range that could be considered a cost-effective use of National Health Service resources. That is, both were under £20,000 per quality-adjusted life-year gained (QALY).

Neither Boehringer Ingelheim nor the evidence review group found any significant difference in efficacy between dabigatran and rivaroxaban for acute treatment of venous thromboembolism (VTE) in their indirect comparisons, and the costs were also very similar between these two treatments.

For combined treatment and secondary prevention of VTE, the appraisal committee said the company’s base case ICER for dabigatran compared with warfarin was likely too low (£9973 per QALY gained).

But the evidence review group’s exploratory base case for dabigatran compared with warfarin may have overestimated the ICER (£35,786 per QALY gained). So the ICER probably lies somewhere between these estimates.

Clinical evidence

To assess the clinical effectiveness of dabigatran, the appraisal committee evaluated data from the RECOVER, RE-MEDY, and RESONATE trials.

In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms.

However, patients were more likely to discontinue dabigatran due to adverse events. Results from this trial were presented at ASH 2009 and published in NEJM.

The RE-COVER II trial also suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths, and dabigatran was associated with a lower rate of major bleeding.

Rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms. Results from this trial were published in Circulation in 2013.

The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.

The RE-MEDY trial suggested that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.

Results of the RE-SONATE trial indicated that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.