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Abuse of prescription drugs and the risk of addiction
Drug and Alcohol Dependence 83S (2006) S4–S7
Abuse of prescription drugs and the risk of addiction夽 Wilson M. Compton ∗ , Nora D. Volkow National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 6001 Executive Blvd., Bethesda, MD 20892, USA Received 16 August 2005; received in revised form 6 October 2005; accepted 17 October 2005
Abstract Abuse of several categories of prescription drugs has increased markedly in the United States in the past decade and is now at alarming levels for certain agents, especially opioid analgesics and stimulants. Prescription drugs of abuse fit into the same pharmacological classes as their non-prescription counterparts. Thus, the potential factors associated with abuse or addiction versus safe therapeutic use of these agents relates to the expected variables: dose, route of administration, co-administration with other drugs, context of use, and expectations. Future scientific work on prescription drug abuse will include identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, and the development of clinically effective agents that minimize the risks for abuse. With the high rates of prescription drug abuse among teenagers in the United States, a particularly urgent priority is the investigation of best practices for effective prevention and treatment for adolescents, as well as the development of strategies to reduce diversion and abuse of medications intended for medical use. Published by Elsevier Ireland Ltd. Keywords: Prescription drug abuse; Drug dependence; Addiction; Opioid analgesic
1. Background/identification of the problem All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing a poison. Paracelsus 1493–1541. Pharmaceutical products have been abused throughout the ages, and the current epidemic of prescription drug abuse in the United States represents the newest wave of a long-standing problem. The extent of the problem is staggering, with national surveys showing that in 2003 approximately 15 million Americans, ages 12 and older used a psycho-therapeutic for a condition other than medical use (Substance Abuse and Mental Health Services Administration (SAMHSA), 2004). This includes non-medical use of opioid analgesics, sedatives/tranquilizers and stimulant medications. Prescription drug misuse was second, after marijuana, in terms of prevalence among the illicit substances among 12th graders, with prevalences between 2002 and 2004 ranging from 9 to 10% for Vicodin, 4 to 5% for 夽
This article is part of a supplemental issue of the journal devoted entirely to papers on how abuse liability of medications is affected by their formulation for medical use. ∗ Corresponding author. Tel.: +1 301 443 6504; fax: +1 301 443 2636. E-mail address: [email protected] (W.M. Compton). 0376-8716/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.drugalcdep.2005.10.020
OxyContin, 9 to 10% for amphetamine and 5 to 6% for Ritalin (Johnston et al., 2005). Particularly worrisome is that recent epidemiological data (Fig. 1) has shown that prescription drug abuse has increased significantly in the past decade. Notably, the incidence of analgesic abuse increased from 628,000 initiates in 1990 to 2.4 million initiates in 2001 (SAMHSA, 2004). A limitation to the interpretation of the existing research is that the terms “misuse”, “abuse”, “dependence” and “addiction” are applied in idiosyncratic ways. We propose that definitions be specified in each report, and for this paper, we define prescription drug abuse as any intentional use of a medication with intoxicating properties outside of a physician’s prescription for a bona fide medical condition, excluding accidental misuse. This definition of abuse includes use of medications prescribed for another user, even if for a physical condition, because this behavior can be risky. However, such misuse likely has a different pattern of social, familial and individual predictors than the typical abuse of prescription drugs for their intoxicating properties, and research to describe the different patterns of prescription drug abuse is needed. It should be noted that our use of the term “abuse” is distinct from the abuse diagnosis specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994). To avoid confusion with physical dependence, the term
W.M. Compton, N.D. Volkow / Drug and Alcohol Dependence 83S (2006) S4–S7
Fig. 1. Annual number of new abusers of psychotherapeutics in the United States: 1965–2002. (Source: National Survey on Drug Use and Health, Substance Abuse and Mental Health Services Administration, 2004).
addiction is used here instead of dependence, which is the clinical term favored by the DSM-IV. Physical dependence results in withdrawal symptoms when drugs such as benzodiazepines and opiates are discontinued, but the adaptations responsible for these effects are different from those that underlie addiction. Like other drug-related conditions, prescription drug abuse is mostly concentrated in adolescents and young adults (SAMHSA, 2004); yet, little is known about the effects of these drugs in adolescence. Rapid brain development during this developmental stage implies that early exposure to prescription drugs may result in neurobiological changes and behavioral consequences that differ from those we have seen in adults. Given these concerns, the purposes of this commentary are to: (1) review potential factors associated with abuse or addiction compared to safe therapeutic use of prescription drugs, and (2) review scientific questions related to research on prescription drug abuse and addiction. 2. Potential factors associated with prescription drug abuse and addiction From a pharmacological perspective, prescription drugs fit into the same drug classes as the usual illicit drugs. Methylphenidate and amphetamines fit into the stimulant category, like cocaine and methamphetamine, while hydrocodone and oxycodone fit into the category of opioids, like heroin. Thus, the same general pharmacological factors associated with abuse and addiction to non-prescription drugs apply to prescription drug abuse. Key variables that influence the abuse and addiction potential of these agents are: dose, route of administration, co-administration with other drugs, context and expectations (Volkow and Swanson, 2003). 2.1. Dose In general, doses utilized therapeutically are lower than doses that are abused. For example, the doses of methylphenidate used for attention deficit disorder are typically below the level
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expected to produce reinforcement (Volkow and Swanson, 2003). For opioid analgesics, this is not always the case. The doses required in some instances for adequate pain control can be identical to those taken by drug abusers (Fischman, 1989). In addition, non-drug abusing populations can experience unpleasant effects from doses of opioid analgesics reported to be highly reinforcing by persons addicted to these substances (Zacny et al., 2003; Zacny and Gutierrez, 2003), highlighting the relevance of individual differences in the sensitivity to the reinforcing effects of these drugs. Frequency of use is also likely to influence the risk for abuse and addiction. This is not just related to the total dose administered, but also to the intervals between doses that can either facilitate or minimize the chances for the neuroadaptations that result in addiction. In this way, even an oral route of administration can be reinforcing if high doses are administered frequently and at short intervals. 2.2. Rate of onset of action Reinforcement from drugs is inversely related to rate of onset of action (e.g. O’Brien, 2001). Because rate of onset is linked in practical ways to the route of administration, it is important to consider how the different routes of administration relate to reinforcement and addiction. Specifically, drugs ingested through injection, smoking and inhalation have much more rapid onset than the oral route. Thus, reinforcement and addictive potential is lower for orally administered drugs. That said, the oral route of administration can lead to behavioral reinforcement and addiction, especially if dosages are high (e.g. Volkow and Swanson, 2003). 2.3. Co-ingestion of multiple agents Co-ingestion of psychoactive substances with similar (e.g. sedatives and alcohol) or different pharmacological profiles (e.g. stimulants and nicotine) in some cases can result in additional reinforcement, thereby increasing the addictive potential. Illustrating this point are patients on daily methadone maintenance, in whom the subjective and physiologic opioid effects of methadone are enhanced by concurrent ingestion of benzodiazepines (Preston et al., 1984), despite the lack of demonstrated pharmacokinetic interactions (Preston et al., 1986). Patients may also co-abuse substances to assist with side effects (e.g. the use of sedatives to overcome insomnia from stimulants) or to decrease undesirable drug effects (e.g. using cocaine to reduce alcoholinduced sedation). Such combinations are clearly dangerous in their own right; concurrent use of cocaine and alcohol, for example, produces cocaethylene, a psychoactive metabolite that is more toxic than those resulting from either agent singly (Cami et al., 1998; Farre et al., 1997; Hearn et al., 1991). However, the relationship of multi-drug use to addiction is less clear. Finally, reinforcing effects of selected drugs can be reduced, as in the therapeutic use of naloxone–opioid combinations. This allows a blocking agent to be ingested simultaneously with an active agent, preventing the reinforcing effects of the opioid agent if the drug is injected.
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W.M. Compton, N.D. Volkow / Drug and Alcohol Dependence 83S (2006) S4–S7
2.4. Context Expectation of drug effects may be a key ingredient in the addictive potential of prescription drugs (e.g. Volkow and Swanson, 2003). A drug taken for a bona fide medical condition may be inherently less reinforcing than the same drug taken with the express purpose of intoxication or psychic enhancement. In youth, we hypothesize that there may also be a social learning aspect, based on young people observing the modeling of drug use by adults in their families and social networks. Medications may be taken by family members on a routine basis and may be used for a variety of conditions. The increases in marketing of medications through media (especially television) may be related to changed attitudes toward ingestion of psychotherapeutic agents. Moreover, the fact that these drugs are considered “medication” and are endorsed by physicians may give a false sense of safety. It should also be noted that a key difference of the prescription drugs from other drugs of abuse is the explicit or implicit medical context of administration. A final factor to consider in determining abuse and addictive potential is overall availability. A ubiquitous technology, the internet, may play a significant role in this regard by opening up a new source for access to these drugs, explaining a portion of the increase in their abuse (Forman, 2003; National Center on Addiction and Substance Abuse, 2004). Anyone with a credit card can now obtain access to prescription drugs, allowing these substances to be taken without the supervision of a physician. 3. Scientific questions Significant increases in the abuse of and addiction to prescription drugs make it imperative that we develop effective prevention and treatment approaches. An additional concern is that the ways that prescription drug abuse in the United States compare to such problems in other countries are not well established. Although many countries provide data concerning drug abuse, including prescription drug abuse, in their student and/or adult populations (e.g. Australian Institute of Health and Welfare, 2002; Hibell et al., 2001; Seblova et al., 2005; Turunen et al., 2005), how the rates of prescription drug use have changed over time has received minimal attention. Further, how these rates compare to those of the United States has not been extensively addressed. Is the situation in the United States a harbinger of problems likely to be seen in other locations? Are there crossnational differences that may help to illuminate the causes of increases in certain populations? More specific scientific questions relate to developmental neurobiology, the natural history of addiction to prescription drugs, and the relationship of abuse and addiction to the clinical management of patients who are prescribed these agents for bona fide medical conditions. It is crucial to determine the risk to brain development associated with acute and chronic prescription drug administration through advances in developmental neurobiology. How does use of these drugs at different stages of brain development impact future reinforcing properties of other substances? Is there a priming effect or, conversely, a diminished responsiveness?
A key question currently under investigation is whether early use of methylphenidate or amphetamine (such as for attention deficit hyperactivity disorder, ADHD) is related to future abuse or addiction to stimulants or other drugs (Glantz, 2002; National Institute on Drug Abuse, 2003). Although studies and analyses are needed beyond those previously done mostly in white males, there is evidence that stimulant therapy for ADHD in childhood is protective against substance use disorders (SUDs) in adolescence and adulthood (Biederman, 2003). Meta-analyses have demonstrated that exposure of youths to ADHD stimulant therapies does not increase the risk for developing subsequent SUD and that such therapies are associated with a reduction in risk, though adolescents at the time of analyses may not have yet passed through the full risk period for SUD development (Faraone and Wilens, 2003; Wilens et al., 2003). Moreover, because the sample sizes of non-treated ADHD subjects in these studies have been rather small, further investigations are warranted to better understand the effects of stimulant medications on the risk for future substance abuse. These types of questions highlight the need for research into the effects of prescription drugs on the developing brain, using both in vitro and in vivo models. The implications of this research would be far-reaching, even pertaining to prescribing practices with children and youth. Should the same practices currently used for adults be used for children and adolescents, or are there differences in vulnerability to addiction during the different developmental stages? An important question in the natural history of prescription drug abuse is the identification of who is at risk for addiction. Though it is recognized that individuals with a past history of drug abuse are vulnerable to addiction when treated with abusable prescription drugs, much less is known about the risk of those that have not abused drugs in the past (Simoni-Wastila and Strickler, 2004). There is a paucity of information relating to interactions between the conditions for which the abusable drugs may be prescribed and the development of addiction (e.g. whether pain protects against the neural adaptations that result in opiate addiction). Research that leads to procedures for early identification of problematic prescription drug use will help clinicians detect early symptoms of addiction before the syndrome is fully developed (e.g. Katz et al., 2003). Additional questions include: How are these agents abused? Are they injected or taken orally; are they taken alone or in combination with other drugs such as alcohol? What are the sources for obtaining these agents? There is major black market for these drugs—rivaling or exceeding that for cocaine and heroin. What are the sources? Where do users obtain their substances? How does the source vary according to the type of user? That is, do drug-na¨ıve youth have different sources than experienced adult drug users? What about the elderly? Are the pharmacological effects similar in the young and in the elderly? Recent preclinical studies have shown that old animals do not develop tolerance to analgesic effects of morphine as rapidly as young animals do (Wang et al., 2005). Do the elderly have reinforcing responses to opioid analgesics similar to those in young people? In the area of treatment development, are there replacement drugs for these abused prescription medications that do not have
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addictive potential? Recent work with drugs that act on cannabinoid 2 (CB2) receptors, which are constrained to peripheral sites, suggest that these agents could be beneficial for neuropathic pain as an alternative to opioid agents (Rice, 2001). Can combinations of medications be given which minimize the chances of addiction (Basile et al., 2002)? Are there formulations that can minimize the diversion of these medications, such as the buprenorphine–naloxone combination, or the extended-release formulations for stimulant medications such as Concerta? From the clinical perspective, how should physicians prescribe abusable medications to persons with a history of addiction or those who already exhibit signs of addiction? 4. Conclusion Despite the focus on the addictive potential of many agents in this commentary, prescription drugs with abuse potential have obvious health benefits. A better understanding of the pharmacological variables that minimize their reinforcing effects will decrease the risk of their diversion and abuse. In parallel, an investigation of factors that can predict vulnerability to addiction (social, genetic and developmental factors, and/or comorbidity with mental illnesses), strategies to help identify the early signs of addiction, and the best clinical practices for use of these agents will help minimize the likelihood of addiction. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Press, Washington, DC. Australian Institute of Health and Welfare, 2002. National drug strategy household survey: detailed findings, in: Media, Publishing Unit (Ed.), Drug Statistics Series. Australian Institute of Health and Welfare, Canberra. Basile, A.S., Fedorova, I., Zapata, A., Liu, X., Shippenberg, T., Duttaroy, A., Yamada, M., Wess, J., 2002. Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc. Natl. Acad. Sci. U.S.A. 99, 11452–11457. Biederman, J., 2003. Pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) decreases the risk for substance abuse: findings from a longitudinal follow-up of youths with and without ADHD. J. Clin. Psychiatry 64 (Suppl. 11), 3–8. Cami, J., Farre, M., Gonzalez, M.L., Segura, J., de la Torre, R., 1998. Cocaine metabolism in humans after use of alcohol. Clinical and research implications. Recent Dev. Alcohol 14, 437–455. Faraone, S.V., Wilens, T., 2003. Does stimulant treatment lead to substance use disorders? J. Clin. Psychiatry 64 (Suppl. 11), 9–13. Farre, M., de la Torre, R., Gonzalez, M.L., Teran, M.T., Roset, P.N., Menoyo, E., Cami, J., 1997. Cocaine and alcohol interactions in humans: neuroendocrine effects and cocaethylene metabolism. J. Pharmacol. Exp. Ther. 283, 164–176. Fischman, M.W., 1989. Testing for Abuse Liability of Drugs in Humans. NIDA Research Monographs. National Institute on Drug Abuse, Rockville, MD. Forman, R.F., 2003. Availability of opioids on the Internet. JAMA 290, 889. Glantz, M.D., 2002. Introduction to the special issue on the impact of childhood psychopathology interventions on subsequent substance abuse: pieces of the puzzle. J. Consult. Clin. Psychol. 70, 1203–1206.
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Hearn, W.L., Rose, S., Wagner, J., Ciarleglio, A., Mash, D.C., 1991. Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol. Biochem. Behav. 39, 531–533. Hibell, B., Andersson, B., Ahlstr¨om, S., Balakireva, O., Bjarnason, T., Kokkevi, B., Morgan, M.J., 2001. The 1999 ESPAD Report: alcohol and other drug use among students in 30 European countries, in: Co-operation Group to Combat Drug Abuse, Illicit Trafficking in Drugs (Pompidou Group) (Ed.). The Swedish Council for Information on Alcohol and Other Drugs, CAN Council of Europe, Stockholm. Johnston, L.D., O’Malley, P.M., Bachman, J.G., Schulenberg, J.E., 2005. Monitoring the Future National Survey Results on Drug Use, 1975–2004, vol. I: Secondary School Students (NIH Publication No. 05-5727). National Institute on Drug Abuse, Bethesda, MA, 680 pp. Katz, N.P., Sherburne, S., Beach, M., Rose, R.J., Vielguth, J., Bradley, J., Fanciullo, G.J., 2003. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth. Analg. 97, 1097–1102. National Center on Addiction and Substance Abuse, 2004. You’ve Got Drugs! Prescription Drug Pushers on the Internet. Columbia University, New York, p. 17. National Institute on Drug Abuse, 2003. The Impact of Child Psychopathology and Childhood Interventions on Subsequent Drug Abuse. Request for Application DA-03-007. U.S. Department of Health and Human Services, NIH. O’Brien, C.P., 2001. Drug addiction and drug abuse. In: Hardman, J.G. (Ed.), Goodman and Gilman’s Pharmacological Basis of Therapeutics. McGrawHill, New York, pp. 621–642. Preston, K.L., Griffiths, R.R., Stitzer, M.L., Bigelow, G.E., Liebson, I.A., 1984. Diazepam and methadone interactions in methadone maintenance. Clin. Pharmacol. Ther. 36, 534–541. Preston, K.L., Griffiths, R.R., Cone, E.J., Darwin, W.D., Gorodetzky, C.W., 1986. Diazepam and methadone blood levels following concurrent administration of diazepam and methadone. Drug Alcohol Depend. 18, 195–202. Rice, A.S., 2001. Cannabinoids and pain. Curr. Opin. Investig. Drugs 2, 399–414. Seblova, J., Polanecky, V., Sejda, J., Studnickova, B., 2005. Trends in substance abuse by teenagers in the Czech Republic. J. Emerg. Med. 28, 95–100. Simoni-Wastila, L., Strickler, G., 2004. Risk factors associated with problem use of prescription drugs. Am. J. Public Health 94, 266–268. Substance Abuse and Mental Health Services Administration, 2004. Overview of Findings from the 2003 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, MD. Turunen, J.H., Mantyselka, P.T., Kumpusalo, E.A., Ahonen, R.S., 2005. Frequent analgesic use at population level: prevalence and patterns of use. Pain 115, 374–381. Volkow, N.D., Swanson, J.M., 2003. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am. J. Psychiatry 160, 1909–1918. Wang, Y., Mitchell, J., Moriyama, K., Kim, K.J., Sharma, M., Xie, G.X., Palmer, P.P., 2005. Age-dependent morphine tolerance development in the rat. Anesth. Analg. 100, 1733–1739. Wilens, T.E., Faraone, S.V., Biederman, J., Gunawardene, S., 2003. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111, 179–185. Zacny, J., Bigelow, G., Compton, P., Foley, K., Iguchi, M., Sannerud, C., 2003. College on problems of drug dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 69, 215–232. Zacny, J.P., Gutierrez, S., 2003. Characterizing the subjective, psychomotor, and physiological effects of oral oxycodone in non-drug-abusing volunteers. Psychopharmacology (Berl.) 170, 242–254.
Abuse of prescription drugs and the risk of addiction夽 Wilson M. Compton ∗ , Nora D. Volkow National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 6001 Executive Blvd., Bethesda, MD 20892, USA Received 16 August 2005; received in revised form 6 October 2005; accepted 17 October 2005
Abstract Abuse of several categories of prescription drugs has increased markedly in the United States in the past decade and is now at alarming levels for certain agents, especially opioid analgesics and stimulants. Prescription drugs of abuse fit into the same pharmacological classes as their non-prescription counterparts. Thus, the potential factors associated with abuse or addiction versus safe therapeutic use of these agents relates to the expected variables: dose, route of administration, co-administration with other drugs, context of use, and expectations. Future scientific work on prescription drug abuse will include identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, and the development of clinically effective agents that minimize the risks for abuse. With the high rates of prescription drug abuse among teenagers in the United States, a particularly urgent priority is the investigation of best practices for effective prevention and treatment for adolescents, as well as the development of strategies to reduce diversion and abuse of medications intended for medical use. Published by Elsevier Ireland Ltd. Keywords: Prescription drug abuse; Drug dependence; Addiction; Opioid analgesic
1. Background/identification of the problem All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing a poison. Paracelsus 1493–1541. Pharmaceutical products have been abused throughout the ages, and the current epidemic of prescription drug abuse in the United States represents the newest wave of a long-standing problem. The extent of the problem is staggering, with national surveys showing that in 2003 approximately 15 million Americans, ages 12 and older used a psycho-therapeutic for a condition other than medical use (Substance Abuse and Mental Health Services Administration (SAMHSA), 2004). This includes non-medical use of opioid analgesics, sedatives/tranquilizers and stimulant medications. Prescription drug misuse was second, after marijuana, in terms of prevalence among the illicit substances among 12th graders, with prevalences between 2002 and 2004 ranging from 9 to 10% for Vicodin, 4 to 5% for 夽
This article is part of a supplemental issue of the journal devoted entirely to papers on how abuse liability of medications is affected by their formulation for medical use. ∗ Corresponding author. Tel.: +1 301 443 6504; fax: +1 301 443 2636. E-mail address: [email protected] (W.M. Compton). 0376-8716/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.drugalcdep.2005.10.020
OxyContin, 9 to 10% for amphetamine and 5 to 6% for Ritalin (Johnston et al., 2005). Particularly worrisome is that recent epidemiological data (Fig. 1) has shown that prescription drug abuse has increased significantly in the past decade. Notably, the incidence of analgesic abuse increased from 628,000 initiates in 1990 to 2.4 million initiates in 2001 (SAMHSA, 2004). A limitation to the interpretation of the existing research is that the terms “misuse”, “abuse”, “dependence” and “addiction” are applied in idiosyncratic ways. We propose that definitions be specified in each report, and for this paper, we define prescription drug abuse as any intentional use of a medication with intoxicating properties outside of a physician’s prescription for a bona fide medical condition, excluding accidental misuse. This definition of abuse includes use of medications prescribed for another user, even if for a physical condition, because this behavior can be risky. However, such misuse likely has a different pattern of social, familial and individual predictors than the typical abuse of prescription drugs for their intoxicating properties, and research to describe the different patterns of prescription drug abuse is needed. It should be noted that our use of the term “abuse” is distinct from the abuse diagnosis specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994). To avoid confusion with physical dependence, the term
W.M. Compton, N.D. Volkow / Drug and Alcohol Dependence 83S (2006) S4–S7
Fig. 1. Annual number of new abusers of psychotherapeutics in the United States: 1965–2002. (Source: National Survey on Drug Use and Health, Substance Abuse and Mental Health Services Administration, 2004).
addiction is used here instead of dependence, which is the clinical term favored by the DSM-IV. Physical dependence results in withdrawal symptoms when drugs such as benzodiazepines and opiates are discontinued, but the adaptations responsible for these effects are different from those that underlie addiction. Like other drug-related conditions, prescription drug abuse is mostly concentrated in adolescents and young adults (SAMHSA, 2004); yet, little is known about the effects of these drugs in adolescence. Rapid brain development during this developmental stage implies that early exposure to prescription drugs may result in neurobiological changes and behavioral consequences that differ from those we have seen in adults. Given these concerns, the purposes of this commentary are to: (1) review potential factors associated with abuse or addiction compared to safe therapeutic use of prescription drugs, and (2) review scientific questions related to research on prescription drug abuse and addiction. 2. Potential factors associated with prescription drug abuse and addiction From a pharmacological perspective, prescription drugs fit into the same drug classes as the usual illicit drugs. Methylphenidate and amphetamines fit into the stimulant category, like cocaine and methamphetamine, while hydrocodone and oxycodone fit into the category of opioids, like heroin. Thus, the same general pharmacological factors associated with abuse and addiction to non-prescription drugs apply to prescription drug abuse. Key variables that influence the abuse and addiction potential of these agents are: dose, route of administration, co-administration with other drugs, context and expectations (Volkow and Swanson, 2003). 2.1. Dose In general, doses utilized therapeutically are lower than doses that are abused. For example, the doses of methylphenidate used for attention deficit disorder are typically below the level
S5
expected to produce reinforcement (Volkow and Swanson, 2003). For opioid analgesics, this is not always the case. The doses required in some instances for adequate pain control can be identical to those taken by drug abusers (Fischman, 1989). In addition, non-drug abusing populations can experience unpleasant effects from doses of opioid analgesics reported to be highly reinforcing by persons addicted to these substances (Zacny et al., 2003; Zacny and Gutierrez, 2003), highlighting the relevance of individual differences in the sensitivity to the reinforcing effects of these drugs. Frequency of use is also likely to influence the risk for abuse and addiction. This is not just related to the total dose administered, but also to the intervals between doses that can either facilitate or minimize the chances for the neuroadaptations that result in addiction. In this way, even an oral route of administration can be reinforcing if high doses are administered frequently and at short intervals. 2.2. Rate of onset of action Reinforcement from drugs is inversely related to rate of onset of action (e.g. O’Brien, 2001). Because rate of onset is linked in practical ways to the route of administration, it is important to consider how the different routes of administration relate to reinforcement and addiction. Specifically, drugs ingested through injection, smoking and inhalation have much more rapid onset than the oral route. Thus, reinforcement and addictive potential is lower for orally administered drugs. That said, the oral route of administration can lead to behavioral reinforcement and addiction, especially if dosages are high (e.g. Volkow and Swanson, 2003). 2.3. Co-ingestion of multiple agents Co-ingestion of psychoactive substances with similar (e.g. sedatives and alcohol) or different pharmacological profiles (e.g. stimulants and nicotine) in some cases can result in additional reinforcement, thereby increasing the addictive potential. Illustrating this point are patients on daily methadone maintenance, in whom the subjective and physiologic opioid effects of methadone are enhanced by concurrent ingestion of benzodiazepines (Preston et al., 1984), despite the lack of demonstrated pharmacokinetic interactions (Preston et al., 1986). Patients may also co-abuse substances to assist with side effects (e.g. the use of sedatives to overcome insomnia from stimulants) or to decrease undesirable drug effects (e.g. using cocaine to reduce alcoholinduced sedation). Such combinations are clearly dangerous in their own right; concurrent use of cocaine and alcohol, for example, produces cocaethylene, a psychoactive metabolite that is more toxic than those resulting from either agent singly (Cami et al., 1998; Farre et al., 1997; Hearn et al., 1991). However, the relationship of multi-drug use to addiction is less clear. Finally, reinforcing effects of selected drugs can be reduced, as in the therapeutic use of naloxone–opioid combinations. This allows a blocking agent to be ingested simultaneously with an active agent, preventing the reinforcing effects of the opioid agent if the drug is injected.
S6
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2.4. Context Expectation of drug effects may be a key ingredient in the addictive potential of prescription drugs (e.g. Volkow and Swanson, 2003). A drug taken for a bona fide medical condition may be inherently less reinforcing than the same drug taken with the express purpose of intoxication or psychic enhancement. In youth, we hypothesize that there may also be a social learning aspect, based on young people observing the modeling of drug use by adults in their families and social networks. Medications may be taken by family members on a routine basis and may be used for a variety of conditions. The increases in marketing of medications through media (especially television) may be related to changed attitudes toward ingestion of psychotherapeutic agents. Moreover, the fact that these drugs are considered “medication” and are endorsed by physicians may give a false sense of safety. It should also be noted that a key difference of the prescription drugs from other drugs of abuse is the explicit or implicit medical context of administration. A final factor to consider in determining abuse and addictive potential is overall availability. A ubiquitous technology, the internet, may play a significant role in this regard by opening up a new source for access to these drugs, explaining a portion of the increase in their abuse (Forman, 2003; National Center on Addiction and Substance Abuse, 2004). Anyone with a credit card can now obtain access to prescription drugs, allowing these substances to be taken without the supervision of a physician. 3. Scientific questions Significant increases in the abuse of and addiction to prescription drugs make it imperative that we develop effective prevention and treatment approaches. An additional concern is that the ways that prescription drug abuse in the United States compare to such problems in other countries are not well established. Although many countries provide data concerning drug abuse, including prescription drug abuse, in their student and/or adult populations (e.g. Australian Institute of Health and Welfare, 2002; Hibell et al., 2001; Seblova et al., 2005; Turunen et al., 2005), how the rates of prescription drug use have changed over time has received minimal attention. Further, how these rates compare to those of the United States has not been extensively addressed. Is the situation in the United States a harbinger of problems likely to be seen in other locations? Are there crossnational differences that may help to illuminate the causes of increases in certain populations? More specific scientific questions relate to developmental neurobiology, the natural history of addiction to prescription drugs, and the relationship of abuse and addiction to the clinical management of patients who are prescribed these agents for bona fide medical conditions. It is crucial to determine the risk to brain development associated with acute and chronic prescription drug administration through advances in developmental neurobiology. How does use of these drugs at different stages of brain development impact future reinforcing properties of other substances? Is there a priming effect or, conversely, a diminished responsiveness?
A key question currently under investigation is whether early use of methylphenidate or amphetamine (such as for attention deficit hyperactivity disorder, ADHD) is related to future abuse or addiction to stimulants or other drugs (Glantz, 2002; National Institute on Drug Abuse, 2003). Although studies and analyses are needed beyond those previously done mostly in white males, there is evidence that stimulant therapy for ADHD in childhood is protective against substance use disorders (SUDs) in adolescence and adulthood (Biederman, 2003). Meta-analyses have demonstrated that exposure of youths to ADHD stimulant therapies does not increase the risk for developing subsequent SUD and that such therapies are associated with a reduction in risk, though adolescents at the time of analyses may not have yet passed through the full risk period for SUD development (Faraone and Wilens, 2003; Wilens et al., 2003). Moreover, because the sample sizes of non-treated ADHD subjects in these studies have been rather small, further investigations are warranted to better understand the effects of stimulant medications on the risk for future substance abuse. These types of questions highlight the need for research into the effects of prescription drugs on the developing brain, using both in vitro and in vivo models. The implications of this research would be far-reaching, even pertaining to prescribing practices with children and youth. Should the same practices currently used for adults be used for children and adolescents, or are there differences in vulnerability to addiction during the different developmental stages? An important question in the natural history of prescription drug abuse is the identification of who is at risk for addiction. Though it is recognized that individuals with a past history of drug abuse are vulnerable to addiction when treated with abusable prescription drugs, much less is known about the risk of those that have not abused drugs in the past (Simoni-Wastila and Strickler, 2004). There is a paucity of information relating to interactions between the conditions for which the abusable drugs may be prescribed and the development of addiction (e.g. whether pain protects against the neural adaptations that result in opiate addiction). Research that leads to procedures for early identification of problematic prescription drug use will help clinicians detect early symptoms of addiction before the syndrome is fully developed (e.g. Katz et al., 2003). Additional questions include: How are these agents abused? Are they injected or taken orally; are they taken alone or in combination with other drugs such as alcohol? What are the sources for obtaining these agents? There is major black market for these drugs—rivaling or exceeding that for cocaine and heroin. What are the sources? Where do users obtain their substances? How does the source vary according to the type of user? That is, do drug-na¨ıve youth have different sources than experienced adult drug users? What about the elderly? Are the pharmacological effects similar in the young and in the elderly? Recent preclinical studies have shown that old animals do not develop tolerance to analgesic effects of morphine as rapidly as young animals do (Wang et al., 2005). Do the elderly have reinforcing responses to opioid analgesics similar to those in young people? In the area of treatment development, are there replacement drugs for these abused prescription medications that do not have
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addictive potential? Recent work with drugs that act on cannabinoid 2 (CB2) receptors, which are constrained to peripheral sites, suggest that these agents could be beneficial for neuropathic pain as an alternative to opioid agents (Rice, 2001). Can combinations of medications be given which minimize the chances of addiction (Basile et al., 2002)? Are there formulations that can minimize the diversion of these medications, such as the buprenorphine–naloxone combination, or the extended-release formulations for stimulant medications such as Concerta? From the clinical perspective, how should physicians prescribe abusable medications to persons with a history of addiction or those who already exhibit signs of addiction? 4. Conclusion Despite the focus on the addictive potential of many agents in this commentary, prescription drugs with abuse potential have obvious health benefits. A better understanding of the pharmacological variables that minimize their reinforcing effects will decrease the risk of their diversion and abuse. In parallel, an investigation of factors that can predict vulnerability to addiction (social, genetic and developmental factors, and/or comorbidity with mental illnesses), strategies to help identify the early signs of addiction, and the best clinical practices for use of these agents will help minimize the likelihood of addiction. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Press, Washington, DC. Australian Institute of Health and Welfare, 2002. National drug strategy household survey: detailed findings, in: Media, Publishing Unit (Ed.), Drug Statistics Series. Australian Institute of Health and Welfare, Canberra. Basile, A.S., Fedorova, I., Zapata, A., Liu, X., Shippenberg, T., Duttaroy, A., Yamada, M., Wess, J., 2002. Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc. Natl. Acad. Sci. U.S.A. 99, 11452–11457. Biederman, J., 2003. Pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) decreases the risk for substance abuse: findings from a longitudinal follow-up of youths with and without ADHD. J. Clin. Psychiatry 64 (Suppl. 11), 3–8. Cami, J., Farre, M., Gonzalez, M.L., Segura, J., de la Torre, R., 1998. Cocaine metabolism in humans after use of alcohol. Clinical and research implications. Recent Dev. Alcohol 14, 437–455. Faraone, S.V., Wilens, T., 2003. Does stimulant treatment lead to substance use disorders? J. Clin. Psychiatry 64 (Suppl. 11), 9–13. Farre, M., de la Torre, R., Gonzalez, M.L., Teran, M.T., Roset, P.N., Menoyo, E., Cami, J., 1997. Cocaine and alcohol interactions in humans: neuroendocrine effects and cocaethylene metabolism. J. Pharmacol. Exp. Ther. 283, 164–176. Fischman, M.W., 1989. Testing for Abuse Liability of Drugs in Humans. NIDA Research Monographs. National Institute on Drug Abuse, Rockville, MD. Forman, R.F., 2003. Availability of opioids on the Internet. JAMA 290, 889. Glantz, M.D., 2002. Introduction to the special issue on the impact of childhood psychopathology interventions on subsequent substance abuse: pieces of the puzzle. J. Consult. Clin. Psychol. 70, 1203–1206.
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