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Diversion Literature

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Diversion Literature

    Prescription Drug Diversion Literature

    This is a summary of the results of a search for the terms diversion‘, ‗drug‘, and/or ‗illicit‘

    in PubMed. The purpose of this summary is to prepare for research or articles relating to the diversion of drugs from their intended purpose to illicit use. This is a general review, no specific project is in mind.

     Three primary areas of interest are found in the literature; background, including definition and extent of problem, control methods, and discussions of specific drugs or drug classes. We address each of these below. Following the review sections are listings of the abstracts cited.

    Background

    The background section contains information about articles that address definitions, extent/prevalence, why drugs are diverted and who is involved. The latest article presented deals with a related topic: sharing.

Definition

    Many similar definitions are found in the literature. We find the one used by Inciardi et al. to be the most complete. ―Prescription drug diversion involves the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit marketplace, and can occur along all points in the drug delivery process, from the original manufacturing site to the wholesale distributor, the physician's office, the retail pharmacy, or the patient.[1]

    Extent

    Data from recent national surveys and other published reports in a 2008 article indicate that the lifetime prevalence of non-medical prescription drugs use/abuse in the United States is approximately 20% (48 million persons aged >/= 12 years). Public health concern is further heightened by a significant increase in past-month use among adolescents (3.3% of 12-17 year olds) and young adults (6.4% of 18-25 year olds) and the vulnerability of a growing elderly population.[2] In 1978 Goldman and Thistel reported on applicants to two metropolitan drug abuse programs and found a significant percentage of applicants had used illicit methadone prior to seeking treatment and that for the most part they were using ―program methadone‖ presumable diverted from take-

    home medication from patients active in treatment programs.[3] In 1982 Piklis found that

    pentazocine/tripelennamine combination is available to the illicit trade through theft or diversion from legitimate sources.[4] Smith and Woody report the nonmedical use of scheduled medications commonly prescribed for pain, pain-related symptoms, and psychiatric disorders began rising in the mid-1190s.[5] In 2004, Brushwood and Kimberline noted ―Leaks of controlled substances from the

    closed system of distribution seem to be increasing as rapidly through theft and loss as through inappropriate prescribing and dispensing.[6] Barrett et al. reported on methylphenidate misuse in a

    university student sample. One finding was that ―Most of those who reported their source of

    methylphenidate obtained it from an acquaintance with a prescription.[7] Also in 2005 Cicero et al. studied abuse of Oxycontin in the United States. They noted ―Over the past 5 years, there have

    been reports, frequently anecdotal, that opioid analgesic abuse has evolved into a national epidemic. In this study, we report systematic data to indicate that opioid analgesic abuse has in fact increased among street and recreational drug users, with OxyContin and hydrocodone products the most frequently abused.[8] Coleman et al. found a recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use.[9] McCabe and Boyd investigate the sources of prescription drugs for illicit use and stated ―The majority of respondents who were illicit users obtained their prescription drugs from peer sources.‖[10] In

    another article on that study, McCabe found the leading sources of prescription stimulants for illicit use were friends and peers.[11] In a third article regarding that study, McCabe et al. found ―The

    prevalence rate for illicit use within the past year was highest for pain medication, followed by stimulant medication, sedative or anxiety medication, and sleeping mediation.‖[12] Other

    statements regarding the extent of drug diversion include

    ; 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.[13]

    ; Designer drugs and high content modified release formulations have been exploited both in

    casual recreational drug abuse as well as, on a much larger scale, by the criminal diversion

    of these products for profit.[14]

    ; However, because these are attractive, addicting drugs, diversion from sources such as

    physicians and pharmacists can lead to serious health problems. Of importance is that

    addiction to opiate medications can interfere with treatment of the original pain condition,

    and can lead to life threatening states because of poor judgment and depressed mood in the

    users.[15]

    ; data on this population's mechanisms of access to prescription opioids clearly suggest that

    there is an active black market for these drugs.[16]

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    ; Sources of abused prescription drugs cited by focus group participants were extremely

    diverse, including their physicians and pharmacists; parents and relatives; "doctor shopping";

    leftover supplies following an illness or injury; personal visits to Mexico, South America

    and the Caribbean; prescriptions intended for the treatment of mental illness; direct sales on

    the street and in nightclubs; pharmacy and hospital theft; through friends or acquaintances;

    under-the-door apartment flyers advertising telephone numbers to call; and "stealing from

    grandma's medicine cabinet[1]

    ; While antipsychotic medications are not typically thought of as drugs with an abuse

    potential, reports of the use and diversion of intranasal quetiapine among prison inmates, i.v.

    quetiapine abuse, and this case report indicate otherwise[17]

    Why drugs are abused and diversion occurs

    The reasons for using diverted drugs were not addressed in the medical literature until recently. Motives were studied by McCabe et al. in 2007. The three most common motives associated with the nonmedical use of prescription opioids were to relieve pain, get high, and experiment.[18] In a study of attention-deficit-hyperactivity disorder (ADHD) drugs, Arria et al. found among 225 nonmedical users, nonmedical use was infrequent and mainly associated with studying, although 35 (15.6%) used prescription stimulants to party or to get high.[19] Who is diverting drugs?

    There is no specific class or type of people who can be blamed for the rise of diversion. The literature, however, has reported extensively on abusers, students and health care workers. Research, primarily descriptive, initiated with drugs abusers included nine articles.[1, 16, 20-27] Studies of student misuse of drugs were reported in ten research studies.[7, 10-12, 18, 28-32] The author responsible for most of these is Sean McCabe and others at the Substance Abuse Research Center, University of Michigan, Ann Arbor. A third focus of research studies in the literature is health care workers which accounted for fifteen articles.[33-47] In addition to these major groups, research includes a literature search for ADHD diversion. [48] A random-digit dialed telephone survey combined with the National Survey on Drug Use and Health [49] also focused on ADHD. In 2007 Boeuf and Lapryere-Mestre analysis 1,710 abnormal prescription forms to describe patterns of drug diversion.[50]

    Sharing

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    Goldsworthy et al. discuss a relatively new topic: prescription-medication sharing.[51] They note that sharing may be associated with two distinct and not mutually exclusive classes of consequences: those that arise from abuse and illegal use and those that arise from loss of warnings and instructions. Their survey revealed 22.9% reported having loaned their medications to someone else and 26.9% reported having borrowed someone else's prescription

    Control

    A major topic in the literature is control of drugs to prevent diversion. In 1983 Feldman et al. conducted a survey of 100 randomly selected Massachusetts hospital pharmacies and found, similar to the findings of a nationwide study, many respondents reported selective inclusion of those Schedule III, IV, and V drugs possessing an increased risk of illicit diversion into a more controlled distribution system.[22] In 1990 Angarola discussed success of national and international regulation of opioid drugs in preventing diversion and noted a reduction of opioid abuse and related illegal activities. However, this may have limited availability to those who the drugs.[52] For more on this concern see Double Edge section below.

    In 1991, Weissman and Johnson propose that existing multiple prescription regulations are effective in reducing drug abuse and diversion.[53] In 1992, Klein et al. found that hospitals with surgical satellite pharmacies had better accountability than in hospitals without them.[54] In 1993, Schmidt and Schlesinger describe a system that involves participation by anesthesiologists, operating room nurses, and pharmacists to accurately record amount and type of drugs dispensed, used, wasted, and returned. Periodic, random, qualitative, and quantitative analyses of drugs returned for wastage are performed. In the first 6 months in which the system was used, 6,336 patients were treated and no cases of drug diversion were discovered or suspected.[41] In 1994 NcNutt et al. report on a system that required all benzodiazepines prescriptions in New York State to be reported. They found reduced prescriptions for this class of drug among elderly patients. In 2001 Forgione et al. describe various ways prescription drugs are diverted to the black markets, some monitoring programs employed by the states, and guidelines that doctors, pharmacists, and other providers can use to protect themselves against possible liabilities arising from the diversion of prescription drugs.[55]

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    Specific control systems are described in the literature. Smiledge and Davern report an anesthesia controlled substance dispensing system in 1984. Drug kits are dispensed by the pharmacy to the operating room and then to individual anesthetists. The system limits quantities of drugs available at one time and provides for clear individual account for drugs and the rapid detection nod reconciliation of discrepancies.[36] A similar method was described by Maltby et al. in 1994.[56] They reported one case of drug diversion by a staff anesthetist in seven years. In 1993, Dodd describes OSTAR Oklahoma Schedule II abuse reduction; an electronic point of sale

    diversion control system.[57] Also in 1993, Mirro et al. describe the Indiana system of multiple copy prescriptions that allow information to be gathered in a central location to track illicit drug use.[58] As part of their requirements for accreditation, the Joint Commission for Accreditation of Hospital Organization (JCAHO) includes include counting, checking and locking a methods to avoid diversion.[59] In 2001, Simoni-Wastila and Tomplins compare two specific control programs: multiple copy prescriptions and electronic data transfer systems.[60] In 2002 Manchikant and Singh discuss the National All Schedules Prescription Electronic Reporting Act (NASPER) as proposed by the American Society of Interventional Pain Physicians. Cicero et al. in 1005, describe a method to review use of Tramadol (Ultram, Ultracet).[8] Degenhardt et al. describe the Drug Monitoring System (DRUMS) run by the Australian Government and the Australian Illicit Drug Reporting System (IDRS) which were analyzed (2001-2004).[27]

    The Xyrem Success Program (Xyrem Risk Management Program) is described by Fuller and Hornfeldt in 2003.[61] This program control distribution of sodium oxybate (Xyrem), a drug for the treatment of narcolepsy, which has a potential for being a substance of abuse. All prescriptions must be written through a web site operated by Express Scripts. Details of the program are also discussed by them in a 2004 article.[61] The development of opioid formulations with limited diversion and abuse potential are discussed by Fudala and Johnsoni 2006.[62] The Food and Drug Administration (FDA) required Othto-McNeil Pharmaceutical to monitor abuse and of their tramadol drugs.[63]. The Researched Abuse, Diversion and Addiction-related Surveillance (RADARS) system was developed to assess the abuse and diversion of OxyContin along with other opioids.[64] In 2007, the FDA was petitioned by citizens to require pharmaceutical companies manufacturing controlled substances to demonstrate and certify in their application materials for FDA approval of new drugs that they have made every effort to formulate the drug in such a way that avoids or at least minimizes the drug's potential for both intentional and unintentional abuse

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    without compromising its therapeutic effectiveness and (2) Requiring pharmaceutical companies to include proactive risk management plans in all new applications for controlled drugs, demonstrating strong evidence of a prescription drug's safety, as well as concrete steps that will be taken to prevent the abuse of the drug while maintaining its maximum therapeutic effectiveness.[65]

    A few articles have discussed the use of lab tests to determine if diversion has occurred, especially with unused portions returned to the pharmacy. In 1995 Kingsbury et al. describe a method for quantitative analysis of fentanyl[66]; a drug also focused on by Holth et al. in 2002 who propose methodology to detect drugs in discarded syringes. In 2002, Cone and Preston focus on lab tests for methodone[67]; as do Gonzalez et al.[68] In 2004 Kurashima et al. describe the determination of origin of ephegrine used as precursor for illicit methamphetamine.[69] In 2005, Wolf and Pilkis describe a rapid high-performance liquid chromatographic (HPLC) procedure for analysis of analgesic pharmaceutical mixtures for quality assurance and drug diversion testing.[70] They note the method ―has been applied to detect not only errors in the preparation of solutions of

    scheduled drugs, but also to uncover illegal diversion of drugs of abuse by medical personnel.‖

    A general problem of control systems was suggested by Hellawell in 1995. ―Despite increasing collaboration between law enforcement authorities in different countries, illicit drug problems appear likely to increase in the future because of the vast profits available, continuing (and increasing) demand and more permissive attitudes concerning drugs among young people.‖ He suggest greater emphasis must be place3d on diversion schemes involving close links between police and drug treatment services.[71]. Another problem is related by Coleman it al. in 2005. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. [9]

    A general solution is proposed by Griffiths et al. in 2003. They describe initial abuse liability testing of a new compound; the classic acute dose-effect comparison study in volunteers with histories of drug abuse. This trial is most appropriate for predicting the likelihood of use by abusers and for predicting the extent of drug diversion and illicit street sales of the novel compound.[72] An additional solution is the use of combinations. In 2006, Robinson reported on a sublingual formulation combining naloxone with Buprenorphine that is effective in both

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    maintenance therapy and detoxification of individuals addicted to opioids.[73] The introduction of a sublingual formulation combining naloxone with buprenorphine further reduces the risk of diversion to illicit intravenous use. A similar advance in formulations is the extended-release treatment for ADHD (Vyvance) that tends to reduce euphoric qualities of immediate-release drugs.[74]

    Success of control systems has also been reported. In 1996, four men one an associate

    hospital pharmacy directorwere indicted on charges relating to the theft and resale of more than $3 million in prescription cancer drugs from two Syracuse hospitals over an eight-year period.[43] Double Edge

    There is a double-edged problem with controlling drug diversion. On one hand, the drugs may be needed for legitimate treatment. On the other hand, availability of the drugs may lead to illegal activities. In 1989, discussing anabolic steroids, Phillips reports the Arkansas Department of Health seeks cooperation and assistance in helping combat the illegal diversion by physicians and pharmacies of these hazardous drugs and to ensure that these drugs are available to patients only through legitimate channels.[38]. In 1992, Schwartz commented on the affect to prescribing practices; ‗Several reports indicate a significant increase in the prescribing of benzodiazepine substitutes that are less safe and effective, along with increased overdoses of some substitute drugs. Changes in physicians' legitimate prescribing practices may reflect their fears of the damage to career and peace of mind that follows investigations by regulatory agencies.‖[75] In 1994, Shapiro

    wrote ―Governments throughout the world have struggled for decades to ensure the availability of narcotic analgesics for legitimate medical and scientific purposes while controlling the abuse and illegal diversion of such substances. While the international drug-control system has effectively limited illicit trafficking of opioids, concerns remain about its effectiveness in ensuring the availability of these drugs for legitimate purposes.‖[76] In a discussion of substitution treatment for

    heroin addiction in 2002, Bell et al. noted ―The first key issue concerns the balance between

    making treatment accessible and attractive, and minimizing the diversion to the black market.‘[77]

    Regarding pain treatment, Manchikanti et al. put it this way: ―In the United States, physicians are faced with two opposing dilemmas in the treatment of pain the potential for drug abuse and

    diversion, and the possible under treatment of pain‘[78] Similar thoughts were written by Smith

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and Woody[5], Hertz and Knight[79], and in 2006 Passik et al. wrote ―Physicians and patients have

    been singled out as the main players in the societal problem of diversion of prescription drugs. In fact, the problem can only be overcome when not only physicians and patients but also healthcare practitioners, third-party payers, law enforcement agencies and regulators, the pharmaceutical industry, and the media finally work together to prevent it, instead of fingering any one party for the blame.‖[80]

    Specific Drugs

    Another way to look at diversion literature is to focus on specific drug classes. One topic is drugs used to treat addiction. One treatment method is maintenance with a less potent form of an addictive drug. The longest use of this technique is with methadone (Dolophine, Methadose, Physeptone) which is an opiate agonist. In addition to being an opiate detoxification adjunct, methadone is also an analgesic. This drug has been available since at least 1973. The first illicit use was reported in 1978.[3] Two studies of fatal use were reported in 1999.[21, 81] The risk-benefit of a drug that is both effective and dangerous has been studied as well as pharmacology and other matters related to the methadone and other replacement drugs.[1, 3, 8, 21, 24, 25, 27, 33, 67, 77, 81-92]

    Nonmedical use and diversion of specific drugs are mentioned in:

    ; ADHD treatments [11, 19, 29, 31, 32, 48, 49, 74, 93-96]

    ; Anesthetics [23, 36, 40-42, 46, 54, 56, 70, 97-101]

    ; Antipsychotics [17]

    ; Benzodiazepines [35, 47, 50, 75, 79, 84, 85, 88, 102-104]

    ; fentenyl [8, 42, 46, 56, 66, 70, 97, 105, 106]

    ; ketomine [23, 46, 66, 84]

    ; Methadone [1, 3, 8, 21, 24, 25, 27, 33, 67, 77, 81-92]

    ; Opioids [1, 5, 16, 18, 30, 33, 35, 44, 46, 47, 50, 52, 64, 73, 76, 79, 80, 84, 87, 88, 92, 99,

    107, 108]

    ; Tramadol [63, 109], steroids[38, 39, 110]

    ; Xyrem [61, 111]

    Legal aspects of diversion

    Diversion is the topic of many articles related to the laws, regulation, and recommended practice of drug manufacture, transportation, prescribing and use of drugs that may be

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    misused/abused, In 1983 Bayer mentions the Single Convention on Narcotic Drugs, 1961, and discusses the provision of the 1971 Convention on Psychotropic Substances.[112] In 1983, Murdoch mentions the same meetings.[113] Phillips discusses the Anabolic Steroid Legislation Act 249 of 1989 [Arkansas].[38] In 1990 the Maryland Committee on Drugs addressed specific issues including diversion.[114] In 1994, Shapiro discusses the legal bases for the control of analgesic drugs.[76] An article by Hill in 1996 focuses on government regulatory influences on opioid prescribing.[107] The Implementation of the Comprehensive methamphetamine Control Act of 1996; final rule of the Drug Enforcement Agency (DEA), was published in 2002. [115] DEA regulations concerning methadone were discussed by Jaffe and O‘Keefe in 2003.[87]. The Drug

    Addiction Treatment Act of 2000 used by the DEA as authority for practitioners to dispense or prescribe approved narcotic controlled substances for maintenance or detoxification treatment was published in 2005. [116]

    Full abstracts of all literature found, whether cited above or not

    The first mention of diversion in medical literature was found in 1973 in the Proceedings. National Conference on Methadone Treatment by T M Wochok, The title was Drugs, Diversion and Crime. [83] Neither the full text nor abstract could be located. We present below summaries of articles found in the search, in chronological order. We exclude only those citations that do not include an abstract.

1978: F. R. Goldman and C. I. Thistel published ‗Diversion of methadone: illicit methadone use

    among applicants to two metropolitan drug abuse programs‘. Interview of newly admitted patients

    from two comprehensive drug abuse programs in the Baltimore area were conducted concerning frequency of illicit methadone use and availability of illicit methadone for a 3-month period prior to their admission. The results showed that a significant percentage of applicants had used illicit methadone prior to seeking treatment, and that for the most part they were using "program methadone" presumably diverted from take-home medication from patients active in treatment programs in the Maryland area.[3]

    1982 Poklis reports on a five year study (1977 to 1981) in St Louis, Missouri, on the intravenous use of a pentazocine/tripelennamine combination (T's and Blues) which has become a major drug abuse problem. There has been a continuous increase in the involvement of these drugs in (a) sudden and violent deaths (62 homicides, 7 fatal intoxications), (b) emergency room visits (137 in 1980), (c) admissions to drug treatment programs (7.7% in 1978 up to 64% in 1981), and (d) police laboratory cases (100 in 1977 - 78 up to 700 in 1981). Initial popularity of the drugs was related to the decline in the quality of street heroin (2.5% in 1977 reduced to 0.5% by 1979) and the lack of strict legal controls. Serious adverse reactions include clonic-tonic seizures and pulmonary foreign body granulomatosis. Ethanol and diazepam were present in 53% and 10% of T's and Blues

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    medical examiner's cases, respectively (n = 70). Addicts are usually black males, 20 - 30 years old, from impoverished areas of the city. The drugs are available to the illicit trade through theft or

    diversion from legitimate sources.[4]

    1983 Bayer reports the establishment of international control of opiates has been an important achievement of the international community; this is substantiated by the fact that, at the beginning of this century, legally manufactured morphine and heroin were the principal sources of illicit supply, whereas at present the illicit traffic in these drugs is supplied from illicit sources. The poppy straw process has helped to promote measures to control opium poppy cultivation in a number of European countries; Turkey has been a successful example of such control. The present large-scale illicit traffic in cannabis resin and cocaine is the consequence of the lack of the implementation of provisions of the Single Convention on Narcotic Drugs, 1961, to control the cannabis plant and the coca bush at the national level. The provisions of the 1971 Convention on

    Psychotropic Substances, being largely a result of international compromise, are not designed in the best possible way to prevent the diversion of psychotropic substances from legal sources to illicit channels. There are no appropriate provisions for the control and monitoring of international transactions. There is a discrepancy between the rather limited scope of international control of substances listed in schedules III and IV of the 1971 Convention and the much larger scope of control of hypnotics, sedatives and tranquillizers at national levels. The provisions of the 1971 Convention, however, constitute a legal basis for bilateral and multilateral actions for the detection of suspected diversion cases, and offer possibilities of promoting the prevention of diversion of psychotropic substances. At present, the relationship between the control of psychotropic drugs, including the prevention of diversion and the organization of the national drug supply system, as well as the efficacy of national control over pharmaceutical products, has not been fully recognized by the international community.[112]

    1983: Feldman et al. present results of a survey questionnaire concerning the procedures used to distribute controlled substances that was mailed to 100 randomly selected Massachusetts hospital pharmacies. The tabulated results were compared to a similar study surveying 285 short-term medical and surgical hospitals nationwide. Of the 58 responding hospitals, 47 (81%) reported controlling either all or some Schedule III Controlled Substances in a manner similar to that used for the distribution and accountability of Schedule II drugs. A total of 42 (72%) reported maintaining the same systems for Schedule IV agents. In contrast, only 24 (42%) of those respondents reported controlling Schedule V drugs in a manner similar to Schedule II Controlled Substances. Similar to the findings of a nationwide study, many of the responding Massachusetts hospitals reported selective inclusion of those Schedule III, IV, and V drugs possessing an increased risk of illicit diversion into a more controlled distribution system. Many

    Massachusetts hospitals distribute and account for controlled substances in a manner similar to that used nationwide.[22]

    1983 Murdoch describes a computerized monitoring system which records the movements throughout Australia of selected legal drugs with abuse potential. The Drugs of Dependence

    Monitoring System is designed to prevent diversion to the illicit market. From the moment of

    import or manufacture, every movement of the selected drug is monitored until the drug reaches the

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