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Reducing the Abuse Potential of Controlled Substances

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Abstract

Prescription drugs, principally opioid analgesics, now account for more fatal drug overdoses in the US than heroin and cocaine. Experts offer several theories for this, including the introduction within the past decade of high dosage, extended-release drug formulations that have proven easy to manipulate for abuse purposes. At the same time, the prescribing of immediate- and extended-release pain relievers — the most highly abused category of prescription drugs — has increased significantly. Regulatory agencies, in turn, have increased their oversight of prescribers, dispensers and manufacturers of controlled substances. For its part, the pharmaceutical industry has shown a modest but growing interest in developing abuse-deterrent drugs. In this article, we review the progress being made through the use of technology and design in mitigating the abuse potential of currently marketed and newly approved drugs, as well as several pipeline candidates. We discuss obstacles facing the future of this novel approach to reducing prescription drug abuse and conclude with policy recommendations intended to encourage the development of abuse-deterrent drugs.

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Notes

  1. The word ‘poisoning’ is often used to denote accidental drug overdoses. This is consistent with standards of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) for reporting ‘nondependent abuse of drugs’ and ‘dependent abuse of drugs’, the latter being further defined as ‘unintentional’, ‘suicide’, ‘undetermined’ and ‘homicide’.

  2. Defined as “use without a prescription of the individual’s own or simply for the experience or feeling the drugs caused.”[3]

  3. In accordance with federal law, specifically Title 21, United States Code 801, et seq., drugs and other substances having abuse potential may be ‘scheduled’ or classified according to an assessment of their abuse liability. Scheduled drugs and classification procedures are discussed later in this article (see footnote 5). Scheduled drugs also may be referred to in this article as ‘controlled substances’.

  4. 4 The literature contains several published papers comparing prescribing volumes and hospital emergency department drug mentions, but their findings appear to be inconsistent. Dasgupta and colleagues[6] performed a tedious exercise of converting kilograms of prescription drugs prescribed annually to their morphine equivalents and then calculated hospital emergency department drug mentions for each of ten opioids based on their equivalence to morphine. Others, including Joranson,[7] Zacny et al.,[8] Gilson et al.[9] and Novak et al.,[10] reported similar analyses comparing hospital emergency department drug mentions with some other metric such as prescribing volumes and/or bulk drug distribution volumes from the Drug Enforcement Administration’s Automated Records and Consolidated Orders System (ARCOS). There are unavoidable limitations to using prescribing data for these types of analyses, in as much as the vast majority (∼90%) of non-medical use of pain relievers and stimulants, according to the government survey cited above, occurs with persons who have not been prescribed the abused drugs.[3] Despite this limitation, most agree in principle with the suggestion of Dasgupta et al.[6] that “as legitimate use of an opioid medication increases, the prevalence of non-medical use and its consequences increase as well.”

  5. Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970 also known as The Controlled Substances Act (CSA), established five ‘schedules’ or ‘classes’ for categorizing controlled substances according to their abuse potential, accepted medical use in the US and designation by international treaties to which the US is a signatory. The law requires lawfully manufactured controlled substances to display on their labels a capital letter C along with a Roman numeral from II to V and corresponding to the schedule of the drug.[21] C-I (Schedule I) drugs are not approved for medical use in the US. C-II to C-V drugs are approved for medical use and classified in accordance with their relative abuse potential (i.e. C-II = highest abuse potential; C-V = lowest abuse potential).[22]

  6. The Bureau of Social Hygiene was founded in 1913 in New York City, and included a Committee on Drug Addiction that in 1928 engaged the National Research Council (NRC) to conduct research on narcotic drugs. As mentioned, the plan included finding and developing a non-habit-forming opioid. This research theory was based on a model presented by cocaine, whose abuse at the time had waned considerably following the introduction of procaine. In its first decade, the NRC developed nearly 500 compounds, many of which were new chemical entities. Some still are used to treat pain. In 1976, following changes in the government’s drug research agenda, the NRC project was taken over by its primary sponsor, which, by then, had become known as the College on Problems of Drug Dependence (CPDD), an independent society of scientists that, like the NRC, traced its origin to the Bureau of Social Hygiene.[26] In addition to its other work, the CPDD has continued to support the search for the elusive non-habit-forming opioid. On the first day of its 2005 annual conference, for example, 11 of 22 guest speakers gave presentations that focused on topics related in some way to abuse-deterrent drug formulations.[27]

  7. The expressions ‘abuse-deterrence’ and ‘abuse-resistant’ often are used interchangeably in the literature. Although one article studied for this review seemed to draw a distinction between formulations that ‘resist’ abuse and those that ‘deter’ abuse, the practical implications of these terms remain similar. In this article, we try to stay consistent with the use of ‘abuse-deterrence’, but we use the two expressions together occasionally to show that within the context of their use their meanings are quite similar.

  8. A reformulated version of OxyContin® that its sponsor claims will be “potentially less attractive for abuse” is in development.[34]

  9. This is based on actual or unweighted reports filed with the Drug Abuse Warning Network (DAWN). For the same 7-year period, the weighted or national estimates of Duragesic® mentions in DAWN averaged 81.1 per year. By comparison, in a 6-year period between 1995 and 2000 the entire category of ‘narcotic analgesics/combinations’ averaged an estimated 59440 mentions per year in the DAWN published data.[61]

  10. See, for example, www.erowid.org.

  11. This difference did not affect bioequivalence or pharmacokinetics.[65]

  12. Although these figures suggest a relationship between the introduction of generic fentanyl patches and a sudden rise in the abuse of fentanyl, it should be noted that the hospital emergency department data cited do not differentiate between pharmaceutical and nonpharmaceutical fentanyl, the latter being clandestinely produced fentanyl analogues. Moreover, despite the large increase in fentanyl mentions by hospital emergency departments for the period in question, two published studies (by the same team of researchers) using poison control centre data concluded that the introduction of generic fentanyl patches did not increase the abuse of fentanyl.[68,69] We also should mention that a serious outbreak of nonpharmaceutical fentanyl abuse in 2005–7 claimed over 1000 confirmed overdose deaths in the US.[70] Lastly, we have no way of determining how many, if any, of the hospital emergency department admissions for fentanyl-related causes reported above involved nonpharmaceutical forms of the drug. In addition, during the period in question (2004–8), besides the nonpharmaceutical forms of fentanyl, and the transdermal pharmaceutical form, fentanyl also was available by prescription as an immediate-release lozenge (Actiq™, Cephalon, Frazer, PA, USA) and, after September 2006, as a buccal tablet (Cephalon). Fentanyl also has been available since before January 1982 for inpatient use as an injectable drug.[71]

  13. Durect has licensed Remoxy®, a modified-release form of oxycodone that uses ORADUR™ technology, and three other ORADUR™-based opioids to Pain Therapeutics, which in turn has licensed commercialization rights to King Pharmaceuticals. Remoxy® has completed clinical trials and is awaiting FDA approval, expected in mid 2010 according to company forecasts.[41]

  14. In November 2008, the FDA conducted tests on claims made by Durect that Remoxy® was less abusable because of information similar to what appeared in the company’s promotional materials. The FDA’s extensive analysis of features described above as barriers to abuse did not support the sponsor’s claims. In summarizing the results, a senior clinical pharmacologist for the FDA stated: “The extended-release characteristics appeared to be compromised when Remoxy was subjected to crushing and extraction with ethanol, mastication, and buccal absorption.”[79] Durect has indicated that it will address the FDA’s concerns and re-submit Remoxy® for approval sometime in mid 2010.[80]

  15. The prescribing information (PI) for Embeda™ describes two controlled clinical trials in which test subjects were given immediate-release morphine whole, crushed and intravenously for comparison with Embeda™ and placebo used in the same way. Relatively large reductions in liking (87.5%) and euphoria (69%) were reported by those receiving Embeda™. With respect to these results, the PI states: “The clinical significance of the degree of reduction in drug liking and euphoria reported in these studies has not yet been established. There is no evidence that the naltrexone in EMBEDA reduces the abuse liability of EMBEDA.”[85]

  16. 21 CFR 1308.31 permits the DEA Administrator to exempt from all or part of the CSA certain non-narcotic prescription drugs upon application by their sponsors. However, this regulation does not state that exemption will be based on the drug’s concentration, preparation, mixture or delivery system as is the case with 21 CFR 1308.33, the provision pertaining to exemption of certain anabolic steroids.

  17. As a result of this provision, dozens of anabolic steroid preparations were removed from scheduling entirely because their sponsors were able to demonstrate that because of their formulations and/or delivery systems, they had no significant potential for abuse.

  18. This differed from patent protection, which was not afforded to orphan drugs. Under the Act, the FDA was prevented from approving a new or generic drug application for the same drug or for the same rare disease indication. The FDA could, however, approve a subsequent application for the same drug for a different indication.[90]

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Acknowledgements

The authors declare that this article represents an original work by them and was not paid for, inspired, reviewed or edited by a commercial sponsor. In addition, the authors declare the following consultancy relationships: John J. Coleman, PhD: provided consultancy services for Novartis; Meda; J&J (McNeil Consumer & Specialty Pharmaceuticals/ Ortho-McNeil Janssen Scientific Affairs, LLC. Supporting McNeil Pediatrics/Janssen Pharmaceutica, L.P.; Shire). Robert L. DuPont, MD: provided consultancy services for Novartis; J&J (McNeil Consumer & Specialty Pharmaceuticals/Ortho-McNeil Janssen Scientific Affairs, LLC. Supporting McNeil Pediatrics/Janssen Pharmaceutica, L.P.). Charles R. Schuster, PhD: provided consultancy services for Reckitt Benckiser Pharmaceutical Co; Takeda; AstraZeneca; Orexo; Organon; Merck; Shire; CoLucid; Apreva; Schering-Plough; Consumer Healthcare Products; Institute for Behavior and Health, Inc.

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Authors and Affiliations

  1. Prescription Drug Research Center, Fairfax, Virginia, USA

    John J. Coleman

  2. Wayne State University School of Medicine, Detroit, Michigan, USA

    Charles R. Schuster

  3. CRS Associates, LLC, Chicago, Illinois, USA

    Charles R. Schuster

  4. Institute for Behavior and Health, Inc., 6191 Executive Boulevard, Rockville, MD, 20852, USA

    Robert L. DuPont

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  1. John J. Coleman
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  2. Charles R. Schuster
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  3. Robert L. DuPont
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Correspondence to Robert L. DuPont.

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Coleman, J.J., Schuster, C.R. & DuPont, R.L. Reducing the Abuse Potential of Controlled Substances. Pharm Med 24, 21–36 (2010). https://doi.org/10.1007/BF03256795

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