New strategies may help reduce the nonmedical use of prescription stimulants.
Prescription stimulants used to treat attention-deficit/hyperactivity disorder (ADHD) have lower levels of abuse than are seen with the other two categories of controlled substances that are most widely used in out-patient settings, the opioid analgesics and the benzodiazepines. Nonetheless, there is a substantial level of nonmedical use of prescription stimulants (unpublished data, 2005). Within the class of prescription stimulants, there is evidence that the nonmedical use of methylphenidate occurs at a lower rate than the nonmedical use of dextroamphetamine, and that the patterns and consequences of the nonmedical use of both methylphenidate and dextroamphetamine are noticeably different from the abuse patterns commonly seen with cocaine and methamphetamine, the two stimulants that cause the most serious consequences as the result of nonmedical use.
The separation of methylphenidate and dextroamphetamine from cocaine and methamphetamine is seen most clearly in the dramatically lower levels of availability of methylphenidate and dextroamphetamine in the illegal drug markets (as captured in law enforcement data) and in patients seeking treatment for problems with those drugs (as captured in the treatment admissions data). Both types of data show that, while there are relatively substantial levels of non-medical use of both methylphenidate and dextroamphetamine, there is a significant contrast in the type and intensity of problems they cause, as compared with the problems related to the use of cocaine and methamphetamine.
The nonmedical use of prescription stimulants that is identified, especially on college campuses, appears not to involve “drug dealers” in the usual sense. Instead it depends on direct transactions between legitimate medical patients using these medicines and their classmates, family members, and friends who are the nonmedical users of these products. Many of these transactions involve no cost to the nonmedical user.
Equally important is that most of the nonmedical use of prescription stimulants seen on college campuses is to enhance academic performance, rather than to pursue a mood change. While many of the misusers of prescription stimulants also are regular misusers of other drugs, their use of these particular pharmaceutical products to enhance their performance poses a challenge to drug abuse prevention that is not seen with most other nonmedical use of prescription controlled substances. Indeed, it is more closely related to the abuse of anabolic steroids to enhance physical performance.1 When prescription stimulants are used nonmedically in association with the nonmedical use of other drugs — a pattern of use that is less common than the nonmedical use to enhance academic performance — prescription stimulants typically are used as adjuncts to more preferred drugs and not as primary drugs of abuse. Examples are the use of prescription stimulants to drink more alcohol, to overcome the sedation of marijuana use, and to function more alertly after a cocaine binge.
Another significant epidemiologic finding for understanding nonmedical use of prescription stimulants is that few of the nonmedical users of prescription stimulants have their own prescriptions for these medicines.
There has been a century-long effort to find medicines that retain (or even improve on) the therapeutic benefits of opiate analgesics, while at the same time finding ways to discourage nonmedical use.2 The clear distinction between methylphenidate and dextroampheta-mine on one hand and cocaine and methamphetamine on the other hand can be seen as a partial confirmation of the value of this approach. Some chemicals are inherently less subject to abuse than others. The pharmacology of these four substances supports the view that the two stimulants commonly used to treat ADHD are less subject to abuse than either cocaine or methamphetamine. More important, data also show that this difference is not merely a matter of availability or fashion, but that it has a biological basis.
Many of the stimulants referenced in this article in the treatment of ADHD contain the same chemical —methylphenidate — as their biologically active component. To explain the difference in patterns of abuse among methylphenidate products, it is necessary to turn to the biology of addiction, which shows that most experienced drug abusers prefer to use drugs by routes of administration that produce rapidly rising and relatively high blood levels of the drug. This rapidly rising level is produced most reliably by the three commonly used routes of administration chosen by experienced drug users — shooting, smoking, and snorting.
When the oral route of administration is used by experienced drug users, they prefer to use drugs in ways that produce rapid onset and high doses. These patterns of use are required to produce the sought-after euphoria or high. Therapeutic uses of these chemicals generally require relatively stable blood levels over many hours, while drug abusers prefer both rapidly rising and rapidly falling blood levels. It is this “rapid-on, rapid-off” pattern that is most attractive to the majority of nonmedical users. This pharmacokinetic picture is in clear contrast to that of most therapeutic drugs, for which a more gradual onset and prolonged, relatively steady blood levels usually produce the greatest medical benefit.3
Immediate-release (IR) products have a relatively greater abuse potential than extended-release (ER) products made with the same active ingredients. When taken orally, IR products are more rapidly absorbed and have a shorter duration of action. Because of the importance of high blood levels, experienced drug abusers have difficulty differentiating methylphenidate from placebo until the methylphenidate dose is 40 mg or higher, while therapeutic doses of IR methylphenidate rarely are above 20 mg. By taking oral doses of the IR products at dose levels higher than those usually given for therapeutic purposes, drug abusers are able to achieve euphoric effects. IR methylphenidate and dextroamphetamine products also are relatively easy to crush and snort, or to dissolve in small amounts of water and inject, making them attractive to experienced nonmedical users and abusers.
By contrast, ER methylphenidate and dextroamphetamine products produce a slower onset of action following oral administration, as well as an extended period of relatively steady blood levels of the drug. This pharmacokinetic pattern is not effective in producing euphoria. However, many currently available ER products, such as coated beads, are easily crushed so that the extended release property is circumvented. When crushed, most ER products become functionally equivalent to IR products, including the ease with which they are snorted or mixed with a solvent, often water, and injected intravenously.
For example, the Concerta brand tablet of methylphenidate appears to be different from the other ER methylphenidate products for two reasons. First, it is not easily crushed. Second, if it is crushed, the crushed material is not easily snorted. If the crushed tablet is mixed with common solvents including water, the polymer and other excipients that are used to create the ER feature make it undesirable for injection. If the contents of a Concerta tablet are dissolved in water after the tablet is crushed, substantial amounts of the polymer are retained in the solution, so that, when it is injected into animals, the polymer produces fatal pulmonary hypertension.
It is possible to extract the methylphenidate from a Concerta tablet by crushing the tablet and dissolving the residual material in water, which can then be taken orally. When a tablet is put into water but not crushed, however, the methylphenidate is released and can be consumed orally or injected. This mode of ingestion appears seldom used, presumably because the easier to use IR methylphenidate and dextroamphetamine products are readily available.
A small amount (approximately 22%) of the methylphenidate in a Concerta tablet is available for immediate release, so it is possible to swallow several tablets to achieve a reinforcing dose of IR methylphenidate. However, this is a relatively unattractive dosing pattern for drug abusers because methylphenidate continues to be released over the following 12 hours, which is aversive to those who seek the “rapid rise, rapid fall” pattern.
The implications of these findings for drug abuse prevention extend far beyond the treatment of ADHD and even beyond the use of prescription stimulants. In fact, they have relevance to all controlled substances. Simply put, a dosage form that effectively reduces the potential for use of a controlled substance by the routes of administration preferred by chronic drug abusers — ie, intravenous injection, inhalation (smoking), and insufflation (snorting) — may have a significant effect in preventing the abuse of that product. Moreover, a dosage form that ensures slow absorption and the extended release of the active ingredient further reduces the abuse potential of a drug by the oral route of administration because it prevents the rapid increase of blood levels that is a consistent feature of drugs preferred for abuse.
The widespread nonmedical use of prescription stimulants to enhance academic performance unrelated to ADHD or any other clinical diagnosis, on the other hand, creates a significant new challenge for drug abuse prevention efforts. Such nonmedical use is unlikely to be influenced by routine law enforcement activity aimed at interrupting drug supply, because the distribution of the commonly used prescription stimulants does not involve typical drug dealers or illegal drug distribution networks. It is more closely related to the problem faced in sports, where the use of performance-enhancing drugs has become a major problem at all levels of competition, from middle school to professional sports. In athletics, the challenge has been addressed in a variety of ways, the most notable of which is the use of mandatory random drug testing. It is not unreasonable to speculate that in the future, those students who take a test (especially an important test such as the SAT) also might be subject to random drug testing to “level the playing field” of academic competition and to discourage nonmedical use of prescription stimulants.4
The more immediately promising prevention strategy employs modification of dosage forms to reduce the attractiveness of these products for nonmedical use. A reliable sign that abuse of a particular product is inhibited effectively by its dosage form is the finding of relatively few mentions of the product in law enforcement data on illicit drug markets. Another is relatively few reports of non-medical use among patients admitted to addiction treatment programs, despite wide availability of the product within the medical treatment community.
In looking at the nonmedical use of prescription stimulants that does occur, a single pattern is clear: the preferred products are IR forms, or ER products in which the extended-release feature is overcome easily. A dosage form that reduces snorting or easy transformation to IR reduces the attractiveness of the product, even with the unusual drug abuse pattern commonly seen with prescription stimulants.
The data cited in this article make that case for the dosage form employed in manufacturing Concerta tablets. While there is relatively little evidence of the attractiveness of any prescription stimulants seen in either law enforcement or treatment data, there is some misuse of these drugs, which shows more common nonmedical use of dextroamphetamine than methylphenidate. Further, there is a demonstrably lower rate of nonmedical use of Concerta than is seen with other dosage forms of methylphenidate.
In attempting to reduce the nonmedical use of controlled substances, a reasonable step is to educate the physicians prescribing controlled substances, including the prescription stimulants used to treat ADHD, as well as patients and family members, about the risks of non-medical use and the dangers of giving or selling these medicines to persons for whom they were not prescribed. Patients who find benefits in the use of such medicines have a significant interest in protecting their continued access to them. Such access is potentially threatened by concerns about widespread nonmedical use. Physicians can help protect the appropriate medical use of prescription stimulants by considering the abuse potential of various medicines used to treat patients with ADHD, especially when these patients also have a history of nonmedical substance use.
In addition, we suggest that today there is an opportunity to add a new and perhaps more hopeful paradigm: the wider use of drug delivery systems that make products less attractive to drug abusers. This new drug abuse prevention paradigm holds great promise for efforts to reduce the nonmedical use of prescription controlled substances, including the prescription stimulants used to treat ADHD. To achieve the full potential of this new paradigm to reduce prescription drug abuse, it will be necessary to develop standards to assess the relative abuse resistance of various drug formulations and delivery systems, as well as meaningful incentives to foster the development of these abuse-resistant delivery systems for controlled substances.5
- Weiss N. Academic performance-enhancing drugs: The Stanford steroid. The Stanford Daily [Web site]. November5, 2004. Available at: http://daily.stanford.edu/tempo?page=content&id=15181&repository=0001_article. Accessed February 4, 2005.
- Acker CJ. Creating the American Junkie: Addiction Research in the Classic Era of Narcotic Control. Baltimore, MD: The Johns Hopkins University Press; 2002.
- Volkow ND, Swanson JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry. 2003;160(11):1909–1918. doi:10.1176/appi.ajp.160.11.1909 [CrossRef]14594733
- Zamiska N. Pressed to do well on admissions tests, students take drugs. The Wall Street Journal. November8, 2004:A1.
- Cone EJ, Fant RV, Rohay JM, et al. Oxycodone involvement in drug abuse deaths: a DAWN-based classification scheme applied to an oxycodone postmortem database containing over 1000 cases. J Anal Toxicol. 2003;27(2):57–67. doi:10.1093/jat/27.2.57 [CrossRef]12669998