Original Research
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Designing a tool allowing for a standardized assessment of resistance to drug diversion 1.
Introduction
2.
Materials and methods
3.
Designing a scale
4.
Results
5.
Discussion
6.
Conclusion
Caroline Victorri-Vigneau†, Cedric Collin, Catherine Messina-Gourlot, Christel Raffournier, Michel Mallaret, Je´roˆme Besse, Marie-Anne Courne, Nathalie Richard, Ve´ronique Se´bille, Philippe Arnaud & participants of expert group of the study* *Collaborators: Nolwen Forbin, Denis Wouessidjewe, Anne-Marie PenserLhe´ritier, Alf Lamprecht, Roger Leverge †
Nantes University Hospital, Institut de Biologie, Centre d’Evaluation et d’Information sur la Pharmacode´pendance, Clinical Pharmacology department, Service de Pharmacologie Clinique, Nantes, France
Objectives: Drug diversion is a growing problem in numerous countries. Some laboratories have developed tamper-resistant formulations. The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion for administration by another mode and intended mode. It would be helpful to have a pertinent panel of in vitro tests allowing assessment of how a formulation may be altered, both for healthcare authorities and for laboratories, so as to implement adequate sanitary measures. We designed a methodology/tool allowing assessment, in a standardized manner, of the formulation’s resistance to drug diversion. We present the various steps leading to the construction of the scale and to its first use. Methods: Creating a Steering Committee -- Choosing assays or parameters -standardized by a monograph of the European Pharmacopoeia and pragmatic assays related to users’ behaviors -- for the assessment of formulation resistance to drug diversion. Designing a scale: i) applying all these tests to a panel of formulations; ii) applying a score by drug and by test; and iii) attribution of weighting per test and calculating the total score for a drug. Results: Eight tests or parameters and 14 drugs (diverted drugs and controls) were chosen. Buprenorphine Subutex had the lowest score and flunitrazepam Rohypnol the highest. Conclusions: Our tool allowed classification of the various drugs selected. This classification correlated with results of postmarketing authorization assessment. Rohypnol, which was the object of many measures, including formulation changes, obtained the highest score in our study. Keywords: abuse, assessment tool, diversion, drug formulation, tampering Expert Opin. Drug Deliv. (2014) 11(7):995-1004
1.
Introduction
New drugs are developed to answer therapeutic goals. Nevertheless, once on the market, the drug product may be used outside of indications mentioned in the summary of product characteristics (French acronym RCP), for abuse [1]. Indeed, two types of diversion were described recently as follows. The first, drug abuse, can be defined as ‘the intentional self-administration of a medication for a nonmedical purpose such as altering one’s state of consciousness, e.g., getting high’ [2-4]. Abusers commonly tamper with drug products prior to administration. Tampering is defined as a chemical or physical manipulation that 10.1517/17425247.2014.901307 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
995
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
C. Victorri-Vigneau et al.
alters or damages the integrity of a dosage form, with the intention to enhance its pharmacological effect and to increase the onset of drug actions and the blood level of the active substance [5,6]. Tampering is typically done to enhance euphoria and to make the drug product suitable by alternative routes of administration (intravenous, nasal). Drug abuse with tampering (drug diversion) is a growing problem in many countries [7-9]. This problem has most often been reported with opioids [3,5,10-13]. The second, chemical submission, was identified as a specific mode of diversion. [14,15]. Chemical submission consists in administrating a substance to victims without knowledge for criminal or wrongful purposes. This type of diversion and drug product diversion shares the same operating mode: indeed, whether for chemical submission or for diversion of administration by another mode and intended mode, users alter the oral presentation by crushing tablets (indispensable step before sniffing, injecting or chemical submission) and dissolving them (injection, chemical submission). In this context, strategies have been developed to try to prevent drug abuse with specific formulations. Some laboratories developed tamper-resistant formulations to try to avoid these problems of drug product diversion, [3,16-27], (offering some type of physical resistance to crushing, chewing, snorting) [28-30] or abuse deterrent formulations (formulations that have added excipient to reduce the attractiveness of the product for abusers) [2,31-33]. Nevertheless, tamper-resistant dosage forms do not avoid these problems; and more specifically, they cannot prevent the ingestion of high doses required to obtain some effects. The problem of drug product diversion is a major concern for French healthcare authorities. The French National Agency for Medicines and Health Products Safety (French acronym ANSM) manages a network of 13 centers for the evaluation and information of pharmacodependence (French acronym CEIP). One of the CEIP’s main missions is to collect data and assess the potential of abuse and/or dependence of psychoactive drugs [34]. Furthermore, since 1 July 2003, the ANSM has implemented a prospective and permanent surveillance system to collect all recorded cases of chemical submission, with identification and dosage of the substances used. Thus, dependence and drug abuse cases, and cases of chemical submission, are reported to the ANSM Narcotics Committee (Commission des Stupe´fiants et des Psychotropes [CSP]), which recommends what sanitary measures to take to decrease the risks of abuse and dependence [34,35]. The CSP is regularly confronted to this drug product diversion problem, on the one hand, during evaluation of investigational drugs in late-stage clinical development and, on the other hand, during evaluation of approved drugs. The CSP has already asked for drug formulation modifications to deter abuse liability and diversion. As well, it has also already emitted an unfavorable opinion for the approval of drugs because of formulations that could encourage diversion. 996
The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion of administration mode and/or chemical submission so as to determine to what extent these risks are limited [2,3,7,13,16,18-20,22,25,27,36-47]. Recently, the FDA published a draft guidance for industry for the evaluation and labeling of abuse deterrent opioids. This draft guidance specifically explains the FDA’s current opinion on in vitro studies that should be conducted to demonstrate that a given formulation has or does not have tamper-resistant properties. Moreover, it specifies that the first part of evaluation of the potential for diversion related to the formulation is the analysis of laboratory-based in vitro manipulation and extraction studies. Thus, the goal of these laboratory-based studies should be to evaluate the ease with which the potentially tamper-resistant properties of a formulation can be defeated or compromised. This need of in vitro data was already mentioned in the 2010 guidance [4]. As well, the 2007 orientation in Canada was to study what physical and chemical characteristics of the product could increase the risk of injectable or pulmonary abuse; the experts recommended in vitro studies and clinical trials in humans [48]. But there are no specific recommendations in Europe. There are currently only great principles whatever the country concerned. There is no detailed guidance on how these assessments should be designed and conducted. Consequently, it would be helpful to have a pertinent panel of in vitro tests allowing assessing how a formulation may be altered, both for healthcare authorities and for laboratories. These tests could be an important tool to assess the abuse potential of drugs. Beyond the evaluation of a given drug, it would be essential to be able to ‘classify’ the various pharmaceutical presentations of drugs according to the potential for diversion of the formulation so as to implement adequate sanitary measures according to the classification score. The ANSM, in this context, sponsored a study, the objective of which was to design a scale allowing assessing in a standardized manner the formulation’s resistance to drug diversion. We present the various steps leading to the scale construction and the resulting classification obtained for selected drug formulations. 2.
Materials and methods
Creating a group of experts (Steering Committee) The study was monitored by a group of experts, including pharmacologists, members of the ANSM Department of Narcotics and Psychotropic drugs, members of the ANSM Department of Evaluation and of Pharmaceutical Quality, the President of the Narcotics Committee, the President of the ANSM work group ‘Recommendations for formulation and prevention of drug diversion’, university formulation specialists, industrial formulation specialists, and biostatisticians. This Steering Committee held a meeting at every step of the study and validated all decisions and results. 2.1
Expert Opin. Drug Deliv. (2014) 11(7)
Designing a tool allowing for a standardized assessment of resistance to drug diversion
Determining relevant tests or parameters to design a tool for the assessment of formulation resistance to drug diversion
all recorded cases with identification and dosage of drugs used on 1 July 2003 [55].
2.2
The group of experts chose the tests by first searching for all tests mentioned in the literature or suggested by guidelines. The group documented the following three properties for each test or parameter: . representativeness of the test or parameter compared
with actual diversion . importance of the test or parameter studied for drug Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
diversion . importance of the test or parameter studied for
The drugs for which a specific formulation may prevent diversion are drugs marketed in France and monitored by the CSP. Manipulations Designs of laboratory protocols conform to those described in the EP for a part of the tests. For the other tests, the design was as close as possible to the one used by individuals who tamper with the pharmaceutical presentation. 3.1.2
Analysis of results obtained and applying a score by drug and assay
3.2
chemical submission. The group of experts referred to methods described in the European Pharmacopeia (EP), whenever possible [49]. The EP is a unique reference for quality control of drugs in countries having signed the convention for its implementation. The official standards published are a legal and scientific basis for quality control during the development, production, and marketing processes. They concern the qualitative and quantitative composition and tests for drugs and raw materials used in their production, and on processing agents. The pertinence of each test or parameter was then estimated according to the validity of the method used (test issued or not from the EP), and according to the answer to the three previous described properties.
3.
Designing a scale
3.1
Applying all these tests to a panel of drugs Determining the drugs to be tested
3.1.1
The selected drug products were either drug products identified as diversion drugs in France or drug products for which efforts in formulation were made to limit their potential for diversion. The CEIP network identified diversion drugs in France. Indeed, these centers have developed epidemiological tools [35], and two of these specifically allow identifying the various types of diversion:
The following is the method used globally: for each test, the study of results obtained for all drugs allowed defining categories based on the distribution of results in percentiles (25, 50, 75 and 100%). Each of these classes was then given a score (more often from 0 to 3). The higher the score was, the more the drug had characteristics making diversion difficult. Once this step was performed, the score obtained by a drug for a given test was divided by the highest possible score for the test so as to normalize results/test. Attribution of weighting per test: evaluation of relative pertinence for each test
3.3
A weighting coefficient for each test was calculated after the pertinence analysis of each test made by the Steering Committee (c.f. Section 2) by combining evaluation of (i) the representativeness of the test or parameter compared with actual diversion, (ii) the importance of the test or parameter studied for drug diversion, (iii) the importance of the test or parameter studied for chemical submission, and (iv) the standardization of the method (presented in EP or not). Calculating the total score for a drug product For a given drug product, the normalized score for each test was multiplied by the weighting coefficient attributed to the test. The total score for a drug was calculated by adding all these scores. Total score for a drug product = S test scores 3.4
. The OPPIDUM survey (OPPIDUM for abuse of lawful
4.
and unlawful psychotropic drugs, ‘Observation des Produits Psychotropes Illicites ou De´tourne´s de leur Utilisation Me´dicamenteuse’ in French) is an annual survey of drug users managed in specialized care centers. Its aim is the survey of products used by drug addicts who call physicians in dedicated care centers [15,50-54]. . The surveillance of cases of chemical submission. The French Health Authorities implemented a prospective and permanent observation system allowing to collect
The Steering Committee monitoring each step of the study included 16 individuals. The Steering Committee selected eight tests or parameters. Their answers to the three different properties are listed in Table 1. The tests or parameters are listed in Table 2. The Steering Committee selected 14 drugs according to the data provided by the OPPIDUM survey and a national survey on chemical submission.
Results
Expert Opin. Drug Deliv. (2014) 11(7)
997
C. Victorri-Vigneau et al.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Table 1. Pertinence of parameters or tests estimated by the experts. Assay
European Pharmacopoeia or validated method
Representativeness of the test compared with the actual diversion
Importance of the parameter studied for drug diversion
Importance of the parameter studied for chemical submission
Pertinence of the test = test weighting coefficient
Tensile strength Active principle/mass ratio Disintegration time Fineness of dispersion Visual aspect (limpidity, opalescence, coloration) In vitro dissolution Extractability Syringability Total
1 NA 1 1 1
0 NA 1 1 1
1 2 2 2 1
1 0 2 2 2
3 2 6 6 5
1 0 0
0 1 1
2 2 2
2 1 0
5 4 3 34
Scores range from 0 to 2; the weighting coefficient of each test is calculated by adding the line scores. NA: Nonapplicable.
Table 2. Chosen tests and results obtained. Rational The hardness of a drug tablet make diversion more difficult
The tablets the most easily diverted are those with the least excipients( [61]) A slow disintegration may have a negative impact for injection and for chemical submission
The size of particles is important for injection as larger particles could make it more difficult, and for chemical submission as the presence of a particle could alert the victim The visual aspect of a solution may have an impact on chemical submission as the victim may be alerted by a visual characteristic (supernatant, deposits, color, etc.), but also on injection as
Choice of the test or parameter Tensile strength (2 hardness/ (p diameter thickness)) Hardness (EP, monograph 20908) compared to the tablet’s size AP/mass ratio
Disintegration time (EP, monograph 20901)
Fineness of dispersion
Limpidity
Opalescence
Conditions of application Whole tablets
Score obtained for a drug/maximal test score
Calculation of active principle mass in 1 unit/total mass of unit
Score obtained for an drug/score maximal of the test Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media
Tested solutions representatives of medium used for injection and chemical submission: aqueous and hydro alcoholic medium include variations of pH (to simulate disintegration in orange juice and Coca Cola), and temperature (to simulate disintegration in hot drinks such as coffee) 6 media tested, 3 chosen: water at 25 C, water at 60 C, and pH2 buffer at 25 C (EP, monograph 51701) This test was performed with water at 25 and 60 C (EP, monograph 0478). The solutions were then filtered to determine 3 classes: presence de particles > 1000 µm (visible), presence of particles > 710 µm, and < 1000 µm or absence of particles > 710 µm Presence of supernatants and/or particles in suspension and/or deposit in 3 different caramel colored media (water at 25 C, water at 60 C, and hydro alcoholic solution at 45% v/v) Opalescence of 3 solutions compared with controls (EP, monograph 20201)
EU: European Pharmacopeia.
998
Standardized score per test
Expert Opin. Drug Deliv. (2014) 11(7)
Sum of scores obtained for each of the 2 media/sum of maximum scores for each of the 2 media
A total visual aspect score was made by adding the standardized results of these 3 series of tests/3
Designing a tool allowing for a standardized assessment of resistance to drug diversion
Table 2. Chosen tests and results obtained (continued).
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Rational
Choice of the test or parameter
the visual aspect of the solution may be dissuasive (coloration, etc.)
Variation of coloration
An profile of rapid active principle liberation encourages diversion
In vitro dissolution (EP, monograph 20903)
An active principle extractible in a very small volume of fluid encourages diversion
Extractability
An solution of the drug in a very small volume of fluid easily syringable encourages diversion
Syringability Volume of fluid sampled
Conditions of application Variation of coloration of the same caramel colored solutions and of an orange colored medium (aqueous or hydro alcoholic at 45% v/v). (The orange juice-based drinks were nonlimpid products, the observation of limpidity and of opalescence could not be performed for these media) Assess if the use of standardized media simulating the solutions used for diversions may accelerate active principal liberation. Statistic analysis of ‘media’ and ‘drugs’ effects: 3 chosen media, water, hydro alcoholic medium at 45% v/v, and pH2 buffer Assess the extractability of the active principle in a very small volume of fluid (1 ml, corresponding to the volume of the stericup used by injected drug users) and assess if an extended release tablet will act as immediate release after being crushed 3 media were selected: purified water at 25 C, purified water at to 60 C and a pH2 buffer Assess the easiness if sampling with a syringe, without filtration of the solution obtained after crushing of a drug tablet in 1 ml. 2 tested conditions: with or without prior crushing The Steering Committee estimated that this test had to be related to the results of the extractability test. Indeed if the extractability is weak in a small volume, or null, syringable drugs should not be penalized. They decided to multiply the extractability and syringability score to obtain the final score of this test.
Standardized score per test
Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media
Sum of scores obtained for each of the 2 media/sum of maximum scores for each of the 2 media
EU: European Pharmacopeia.
The OPPIDUM survey allowed identifying drug products with a diverted mode of administration [56]. The selected drug products are listed in Table 3. These were first high-dose buprenorphine (Subutex 8 mg (buprenorphine) and generic buprenorphine 8 mg) and Skenan 100 mg (morphine sulfate). Benzodiazepines and related drugs were also mentioned as being taken by another route than per os: Rivotril 2 mg (clonazepam), Temesta 2.5 mg (lorazepam), Valium 10 mg (diazepam), Stilnox 10 mg (zolpidem), Lexomil 6 mg (bromazepam), and Rohypnol 1 mg (flunitrazepam). Ritaline 40 mg (methylphenidate) has also been increasingly diverted by nasal intake and intravenously. The most frequently identified substances every year are benzodiazepines and related drugs, according to a survey on chemical submission. Thus, lorazepam, clonazepam, diazepam, zolpidem, and bromazepam are in the list (Table 3). Doxylamine succinate 15 mg (Donormyl) has also been used for chemical submission [56].
Hydrocodone, oxycodone and hydromorphone for immediate and extended release formulations were not chosen for the initial tests because they were not listed among the most diverted drugs in France. The Steering Committee also select, as controls, three drug products available in France for which a formulation measure was developed by manufacturers to reduce diversion: methadone chlorhydrate 40 mg capsule, Concerta LP54 mg (methylphenidate chlorhydrate), and Rohypnol (flunitrazepam). It also decided to add Moscontin LP 100 mg (morphine sulfate) a control for Skenan as, contrary to the latter, it is an opioid drug nonreported in cases of diversion in France [57]. The score for each drug product was calculated, after performing the tests, by adding normalized results for each test multiplied by the weighting coefficient of the test (Table 1). This weighting coefficient was calculated according to answers
Expert Opin. Drug Deliv. (2014) 11(7)
999
C. Victorri-Vigneau et al.
Table 3. Drug scores and ranks. Drug
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Buprenorphine Subutex Buprenorphine Generic Lorazepam Temesta Doxylamine succinate Donormyl Clonazepam Rivotril Diazepam Valium Methylphenidate Ritaline Morphine sulfate Skenan Methadone Zolpidem Stilnox Bromazepam Lexomil Morphine sulfate Moscontin Methylphenidate chlorhydrate Concerta Flunitrazepam Rohypnol
Score/34
Rank
5 5 7 11 11 11 13 17 18 20 20 22 26 27
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Rounded scores make it possible to distinguish four classes corresponding to the level of resistance to drug diversion. Lower scores correspond to the less resisting drugs (5-7); at the opposite higher scores (26-27) correspond to the most resisting drugs; others drugs belong to two intermediate classes (11-13; 17-22).
to the experts’ opinion on the properties of the tests. The drug scores and their rank are listed in Table 3. 5.
Discussion
Drug diversion is an issue today in many countries. Efforts have been made by manufacturers to the find formulations that will make drug diversion more difficult. These formulations should be assessed and especially compared with other drug products. This study deals with in vitro evaluation. This will of course never replace in vivo evaluation, or drug surveillance, but it is a necessary preliminary and complementary step. First, concerning the selection of the tests, the aim was to find a good compromise between representativeness of diversion and reproducibility of the chosen tests. Consequently, our tool includes some tests the implementation of which is standardized by a monograph of the pharmacopoeia and pragmatic tests related to users’ behaviors. The two nonstandardized tests are nevertheless indispensable; they are used to assess the possibility of injecting the drug (extractability into a small volume then syringability). Most tests are based on official and acknowledged monographs that allow reproducing these tests industrially when developing the drug. The second point that should be underlined is that our tool meets the requirements mentioned in the literature and in the latest 2013 FDA guidance ‘abuse-deterrent opioids, evaluation and labeling’ [58]. This guidance, focusing partly on laboratory manipulation and extraction studies, specifies the need for various tests. Syringability, which is assessed in our tool, is also mentioned. The ability to crush is taken into account in our tool by the tensile strength. The extractability and the solubility are also some of the main tests included of tool. Many authors had already stressed the assessing 1000
solubility evaluation in various solvents [18]. The FDA also mentioned the fact that various solvents in various conditions (pH, temperature) should be used. Our tool meets these requirements. Some authors attempted to standardize the evaluation of extractability of active principles from pharmaceutics presentations [59]. These authors referred to opioids, but these studies were based on an interesting method. In this case, extraction was characterized by its easiness, the purity of the extracted substance, the efficiency of extraction (percentage extracted), and the power of extraction (number of doses in an extract). The techniques of extraction are classified into four categories: extraction by simple physical manipulations, extraction by a single chemical stage, extraction requiring several chemical stages, and extraction by complex techniques. A score is attributed according to the probability of abuse for every mode of intake after having performed a series of extractability tests on the active principle in various solvents and having determined the characteristics of the obtained extracts. This score ranges from 1 (highly unlikely) to 5 (very likely). This technique is certainly quite complete, but it is not powerful enough to assess the diversion potential of a drug. A more global scale is needed by simplifying the tests it includes. The FDA mentions the particular attention given to particle size distribution following manipulation. Our tool assesses this aspect with a fineness of dispersion test. Our tool, using these five tests (extractability, syringability, solubility, fineness of dispersion, and tensile strength), allows assessing the tamper-resistant techniques of drugs as they were described by Mastropietro [3], such as attempts at making drugs insoluble or leading to the formation of a gel. It in no case assesses the abuse-deterrent characteristics of drugs. Moreover, our tool allows the assessment of another type of possible diversion, chemical submission, by specifically investigating the time for disintegration and the visual aspect of solutions (opalescence, limpidity, and coloration). This aspect of drug diversion had already been studied. Olsen et al. [60] assessed the concentration, taste, and aspect of nine sedative drugs introduced without mixing in Coca-Cola or alcohol. These authors suggested the possibility to anticipate the risk of criminal use of drugs by checking the alert potential for the victim. It investigates a visual aspect but in a less standardized manner than our tool. It also raises the following important issue: Who would test the modifications of taste so as to assess detectability? Thus, even if the final score is global and allows classifying drugs for their resistance to diversion in a global manner, our tool allows specifying the evaluation for various risks (chemical submission or diversion of administration mode) by selecting some tests. This possible weighting according to the identified type of risk may help decision making in public healthcare. Concerning already existing scale in literature, some authors have mentioned scales aiming at assessing resistance to drug
Expert Opin. Drug Deliv. (2014) 11(7)
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Designing a tool allowing for a standardized assessment of resistance to drug diversion
diversion. Wright and colleagues [47] wrote down the great principles of a scale allowing classifying the pharmaceutical presentations according to the potential of diversion. This scale of resistance to drug misuse classifies the pharmaceutical presentations in seven levels ranging from no preparation needed for abuse to resistant to re-manufacture. Butler and colleagues [61] developed and validated a scale allowing assessing the attractiveness of various opioid pharmaceutical presentations for users. The 17 items of this scale were selected in collaboration with users. The authors claimed that this scale could be used to assess the attractiveness of new pharmaceutical presentations, not marketed yet. However, the two abovementioned scales do not allow global assessment of several diversion axes in vitro. Indeed, the issue of chemical submission should be raised when considering drug diversion. The ANSM, as well on the national and international levels, has strongly participated in discussions on chemical submission. In September 2008, during the French Presidency of the European Union, the ANSM organized a conference to present recent data on chemical submission and measures for the management victims and for prevention to experts dealing with this issue on the European level. In 2009, France and Argentina pushed the UNO Commission on narcotic drugs to adopt a resolution dealing with the use of pharmaceutical techniques to prevent sexual assault facilitated by drugs. In 2010, the UNO Commission on narcotic drugs adopted a second resolution, initiated by the ANSM and presented by the European Union, concerning international cooperation to prevent the administration of psychoactive substances to unaware victims for criminal purposes. This setup included the member countries taking into account recommendations made to the pharmaceutical industry for pharmaceutical presentations to prevent drug diversion. In July 2010, in accordance with the resolution objectives, the International Narcotics Control Board (INCB, French acronym OICS) sent a questionnaire to all the Member Countries to collect data on chemical submission and, when this was the case, actions were implemented. The ANSM sent to the INCB and the United Nations Office on Drugs and Crime the results of surveys on chemical submission and the survey protocol, as well as the recommendations for formulations relative to chemical submission drafted by the work group ‘Recommendations for formulations and prevention of diversion’ validated at the national level by ANSM and LEEM (French drug companies’ trade association). The global evaluation of drug diversion, but also the evaluation of presentation, should not be limited either to a drug family or to a type of diversion. Last but not the least, our tool allowed classifying the various drugs selected. This classification correlated with results of postmarketing authorization assessment performed by the CEIP in France. The most easily diverted drug according to the scale was buprenorphine. In France, buprenorphine
injections are a real public healthcare problem. The OPPIDUM survey results showed that 16% of individuals used buprenorphine intravenously and 46% sniffed it [56]. Rivotril was also listed in the less well-classified drugs. This drug has been the subject of an official enquiry by addictovigilance and continuously monitored since 2006 because cases of abuse, dependence, and diversion had been reported with the oral presentation. The results of this monitoring confirmed a great proportion of prescriptions were made outside of marketing authorization definition and the diverted use by drug addicts or for chemical submission. Given all these elements, a Risk Management Plan was implemented in 2008 by the laboratory to answer the request made by the ANSM. An update of the addictovigilance enquiry was made in 2010, and then in 2011. Given the persistence of a great proportion of prescriptions made outside of the marketing authorization definition, cases of abuse and dependence, and the important trafficking of prescriptions, the maximum duration of Rivotril prescription was decreased to 12 weeks. Furthermore, as of September 2011, the prescription of Rivotril per os for ambulatory patients had to be made with figures written out in letters and on a secure prescription. Finally, as of 15 March 2012, only neurologists and pediatricians could write out the initial prescription and the yearly renewal. It should be underlined that, although Rivotril and Buprenorphine have lowest scores, the drug products for which a new formulation had been developed were all given scores above 18. This result was particularly interesting because it proved the pertinence of our tool to assess resistance to diversion. Furthermore, a real difference was noted between the score of two methylphenidate formulations: Ritalin (score of 13) and Concerta (score of 26). This difference noted by our tool correlates with surveillance data as no diversion had been reported for Concerta. Another difference should be noted, between Skenan (score of 17) and Moscontin (score of 22); once again, there was a real difference when grading these drugs. No diversion had been reported for Moscontin. Skenan is a frequently diverted and injected drug in France; nevertheless, it was given a score of 17 by our tool, and indeed before injection, a preliminary preparation is necessary, frequently described on users’ forums. If we have a look at the extremes, the results obtained for Subutex and Concerta are interesting because these are two opposite formulations. Indeed, formulation measures were developed by Concerta, manufacturer to reduce diversion, which was not the case for Subutex. Subutex is known to be diverted in France (abusers inject it after dissolving in a small volume of water), whereas Concerta was not mentioned in the French tools assessing diversion. This was correlated by the results obtained with our tool. Subutex was indeed the most diverted drug among those tested with a score of 5/34, whereas Concerta was twice less diverted with a score > 25/34. The last example is Rohypnol, which was the object of many measures, including formulation changes, and had the
Expert Opin. Drug Deliv. (2014) 11(7)
1001
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
C. Victorri-Vigneau et al.
highest score in our study. This psychotropic drug presents a risk for abuse and diversion by drug addicts, and a potential implication in chemical submission. Indeed, these various risks were indeed demonstrated by the CEIP network in the 1990s. Thus, several measures were progressively taken to limit these risks: restriction of therapeutic indications to ‘severe sleep disorders’ and withdrawal of the 2 mg presentation (1996), withdrawal of the 20 tablet boxes (1999), modification in 2001 of the rules concerning the conditions of prescription and delivery (prescription on secure forms limited to 14 days and partial delivery at 7 days), and inclusion in the list of drugs concerned by 1 April 2008 decree (name of the pharmacist on the prescription and protocol of care in case of misuse). The adjunction of a blue-coloring agent in 1998 also had for aim to limit the risks of use for chemical submission.
delivery rules, the implementation of a risk management plan, etc. If the formulation properties are reassuring and are able to limit the potential for diversion, the drug could be more broadly prescribed. As a first perspective, it is crucial to continue this study by applying our method to other drugs, especially for opioids. A further perspective would be to propose a technical harmonized approach of evaluation of drug formulation concerning their diversion potential. This harmonized approach could be materialized in a EP monography summarizing our methodology in order to support the industries in their formulation development and to help health authorities in their evaluation.
Declaration of interest 6.
Conclusion
Identifying a potential for diversion should allow justifying the implementation of complementary measures to prevent this risk. For example, a limitation of prescription or stricter
The authors state no conflict of interest and have received no payment in preparation of this manuscript. Funding for this study was provided by the French National Agency for Medicines and Health Products Safety (French acronym ANSM).
Bibliography 1.
2.
Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend 2006;83(Suppl 1):S4-7 Katz NP, Adams EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain 2007;23(8):648-60
3.
Mastropietro DJ, Omidian H. Current approaches in tamper-resistant and abusedeterrent formulations. Drug Dev Ind Pharm 2013;39(5):611-24
4.
FDA dgfi. Assessment of Abuse Potential of Drugs. 2010. Available from: http://wwwfdagov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM198650pdf
5.
Courty P. High dosage buprenorphine and injection practices. A study of 303 patients. Ann Med Interne (Paris) 2003;154(Spec No 1):S35-45
6.
7.
1002
Victorri-Vigneau C, Dailly E, Veyrac G, et al. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol 2007;64(2):198-209 Schuster CR, Henningfield J. Conference on abuse liability assessment of CNS
medical use? Expert Opin Drug Deliv 2013;10(2):229-40
drugs. Drug Alcohol Depend 2003;70(3 Suppl):S1-4 8.
Sellers EM, Schuller R, Romach MK, et al. Relative abuse potential of opioid formulations in Canada: a structured field study. J Opioid Manag 2006;2(4):219-27
9.
Tharp AM, Winecker RE, Winston DC. Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches. Am J Forensic Med Pathol 2004;25(2):178-81
10.
Davis WR, Johnson BD. Prescription opioid use, misuse, and diversion among street drug users in New York City. Drug Alcohol Depend 2008;92(1-3):267-76
11.
12.
13.
Marquardt KA, Tharratt RS, Musallam NA. Fentanyl remaining in a transdermal system following three days of continuous use. Ann Pharmacother 1995;29(10):969-71 Correas Lauffer J, Braquehais Conesa D, Barbudo Del Cura E, et al. Abuse, tolerance and dependence of zolpidem: three case reports. Actas Esp Psiquiatr 2002;30(4):259-62 Lourenco LM, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-
Expert Opin. Drug Deliv. (2014) 11(7)
14.
Gaulier JM, Fonteau F, Jouanel E, et al. Rape drugs: pharmalogical and analytical aspects. Ann Biol Clin (Paris) 2004;62(5):529-38
15.
Thirion X, Barrau K, Micallef J, et al. [Maintenance treatment for opioid dependence in care centers: the OPPIDUM program of the Evaluation and Information Centers for Drug Addiction]. Ann Med Interne (Paris) 2000;151(Suppl A):A10-17
16.
Schuster CR. History and current perspectives on the use of drug formulations to decrease the abuse of prescription drugs. Drug Alcohol Depend 2006;83(Suppl 1):S8-14
17.
Hamed E, Moe D. Development of tamper deterrent formulations: state of the pharmaceutical industry. Curr Drug Abuse Rev 2010;3(3):139-46
18.
Mansbach RS, Moore RA Jr. Formulation considerations for the development of medications with abuse potential. Drug Alcohol Depend 2006;83(Suppl 1):S15-22
19.
Raffa RB, Pergolizzi JV Jr. Opioid formulations designed to resist/deter abuse. Drugs 2010;70(13):1657-75
Designing a tool allowing for a standardized assessment of resistance to drug diversion
20.
21.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
22.
23.
Sapienza FL. Abuse deterrent formulations and the Controlled Substances Act (CSA). Drug Alcohol Depend 2006;83(Suppl 1):S23-30 Seed SM, Dunican KC, Lynch AM, et al. An update in options for the treatment of pain: a review of new opioid formulations. Hosp Pract (1995) 2012;40(1):166-75 Stanos SP, Bruckenthal P, Barkin RL. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc 2012;87(7):683-94 Vosburg SK, Jones JD, Manubay JM, et al. A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin(R) (non-TRF) in prescription opioid abusers. Addiction 2013;108(6):1095-106
24.
Webster L. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations. Pain Med 2009;10(Suppl 2):S124-33
25.
Webster LR, Bath B, Medve RA. Opioid formulations in development designed to curtail abuse: who is the target? Expert Opin Investig Drugs 2009;18(3):255-63
first year. J Opioid Manag 2012;8(2):115-25 32.
33.
Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphinemaintained intravenous heroin abusers. Addiction 2010;105(4):709-18 Ruan X. Sustained-release morphine sulfate with sequestered naltrexone for moderate to severe pain: a new opioid analgesic formulation and beyond. Expert Opin Pharmacother 2011;12(7):999-1001
34.
Baumevieille M, Miremont G, Haramburu F, et al. [The French system of evaluation of dependence: establishment in a legal system]. Therapie 2001;56(1):15-22
35.
Micaleff J, Jolliet P, Victorri-Vigneau C, et al. First meeting of the French CEIP (centres d’evaluation et d’information sur la pharmacodependance). Assessment of the abuse and pharmacodependence potential during drug development. Therapie 2008;63(1):55-65
36.
Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 2003;70(Suppl 3):S13-40
43.
McColl S, Sellers EM. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend 2006;83(Suppl 1):S52-62
44.
McCormick CG. Regulatory challenges for new formulations of controlled substances in today’s environment. Drug Alcohol Depend 2006;83(Suppl 1):S63-7
45.
Parasrampuria DA, Schoedel KA, Schuller R, et al. Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. J Clin Psychopharmacol 2007;27(5):459-67
46.
Schneider JP, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse? CNS Drugs 2010;24(10):805-10
47.
Wright CT, Kramer ED, Zalman MA, et al. Risk identification, risk assessment, and risk management of abusable drug formulations. Drug Alcohol Depend 2006;83(Suppl 1):S68-76
48.
Canada S. Clinical Assessment of Abuse Liability for Drugs with Central Nervous System Activity 2007. Available from: http://wwwhcscgcca/dhp-mps/prodpharma/applicdemande/guide-ld/abus/abuse_ liability_abusif_usage_clin-fraphp
26.
Webster LR, Fine PG. Approaches to improve pain relief while minimizing opioid abuse liability. J Pain 2010;11(7):602-11
37.
Bannwarth B. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? Drugs 2012;72(13):1713-23
27.
Wick JY. Drug-abuse deterrent formulations. Consult Pharm 2009;24(5):356-62; 365
38.
49.
28.
Chai LY, Khare CB, Chua A, et al. Buprenorphine diversion: a possible reason for increased incidence of infective endocarditis among injection drug users? The Singapore experience. Clin Infect Dis 2008;46(6):953-5; author reply 5-6
Butler SF, Black R, Grimes Serrano JM, et al. Estimating attractiveness for abuse of a not-yet-marketed "abuse-deterrent" prescription opioid formulation. Pain Med 2010;11(1):81-91
Licata SC, Mashhoon Y, Maclean RR, et al. Modest abuse-related subjective effects of zolpidem in drug-naive volunteers. Behav Pharmacol 2011;22(2):160-6
39.
Butler SF, Fernandez KC, Chang A, et al. Measuring attractiveness for abuse of prescription opioids. Pain Med 2010;11(1):67-80
50.
40.
Coleman JJ, Bensinger PB, Gold MS, et al. Can drug design inhibit abuse? J Psychoactive Drugs 2005;37(4):343-62
Thirion X, Micallef J, Barrau K, et al. Observation of psychoactive substance consumption: methods and results of the French OPPIDUM programme. Eur Addict Res 2001;7(1):32-6
51.
Thirion X, Micallef J, Guet F, et al. [Dependence on psychotropic drugs and substitution treatment: recent trends. The OPPIDUM study of the Centers for Evaluation and Information on Drug Dependence (CEIP), October 1997]. Therapie 1999;54(2):243-9
52.
San Marco JL, Jouglard J, Thirion X, et al. [Observation of illicit or misused psychotropic drugs (O.P.P.I.D.U.M.): five years of surveillance of products consumed by drug addicts at Marseille]. Therapie 1996;51(5):586-98
29.
Chevalley AE, Besson J, Croquette-Krokar M, et al. Prevalence of methadone injection in three Swiss cities. Presse Med 2005;34(11):776-80
30.
Fudala PJ, Johnson RE. Development of opioid formulations with limited diversion and abuse potential. Drug Alcohol Depend 2006;83(Suppl 1):S40-7
31.
Badalamenti VC, Buckley JW, Smith ET. Safety of EMBEda (morphine sulfate and naltrexone hydrochloride) extended-release capsules: review of postmarketing adverse events during the
41.
42.
Grudzinskas C, Balster RL, Gorodetzky CW, et al. Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report. Drug Alcohol Depend 2006;83(Suppl 1):S77-82 Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep 2008;10(1):11-18
Expert Opin. Drug Deliv. (2014) 11(7)
1003
C. Victorri-Vigneau et al.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
53.
Pauly V, Frauger E, Rouby F, et al. Analysis of addictive behaviours among new prisoners in France using the OPPIDUM program. Encephale 2010;36(2):122-31
54.
Moracchini C, Frauger E, Pauly V, et al. Harm reduction centers (“CAARUD”): privileged places for warning signal detection in addictovigilance. Therapie 2012;67(5):437-45
55.
Djezzar S, Questel F, Burin E, et al. Chemical submission: results of 4-year French inquiry. Int J Legal Med 2009;123(3):213-19
56.
ANSM. Assesment tools 2009. Available from: http://ansmsantefr/ Activites/PharmacodependanceAddictovigilance/Outils-de-surveillanceet-d-evaluation-Resultats-d-enquetes/ (offset)/3
57.
Eiden C, Leglise Y, Bertomeu L, et al. New formulation of methadone for opioid dependence in France: acceptability and diversion/misuse liability. Therapie 2013;68(2):107-11
58.
FDA dgfi. Abuse-Deterrent Opioids, Evaluation and Labeling 2013. Available from: http://wwwfdagov/ downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM334743.pdf
59.
Katz NP, Buse DC, Budman SH, et al. Development and preliminary experience with an ease of extractability rating system for prescription opioids. Drug Dev Ind Pharm 2006;32(6):727-46
60.
Barnard EA, Skolnick P, Olsen RW, et al. International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 1998;50(2):291-313
61.
Butler SF, Benoit C, Budman SH, et al. Development and validation of an Opioid attractiveness scale: a novel measure of the attractiveness of opioid products to potential abusers. Harm Reduct J 2006;3:5
1004
Affiliation
Caroline Victorri-Vigneau†1,2, Cedric Collin3, Catherine Messina-Gourlot4, Christel Raffournier5, Michel Mallaret6, Je´roˆme Besse7, Marie-Anne Courne4, Nathalie Richard4, Ve´ronique Se´bille2,8, Philippe Arnaud9 & participants of expert group of the study* *Collaborators: Nolwen Forbin, Denis Wouessidjewe, Anne-Marie Penser-Lhe´ritier, Alf Lamprecht, Roger Leverge † Author for correspondence 1 Nantes University Hospital, Institut de Biologie, Centre d’Evaluation et d’Information sur la Pharmacode´pendance, Clinical Pharmacology Department, Service de Pharmacologie Clinique, 9 quai Moncousu, 44093 Nantes cedex 1, France Tel: +33 240084096; Fax: +33 240084097; E-mail: [email protected] 2 Nantes University, EA 4275 Biostatistic, Pharmacoepidemiology and Subjective Measures in Health Science, 44093 Nantes Cedex, France 3 French Health Products Safety Agency, Pharmacoepidemiology Department, 93285 Saint Denis Cedex, France 4 French Health Products Safety Agency, Narcotic Department, 93285 Saint Denis Cedex, France 5 French Health Products Safety Agency, Pharmaceutical Quality Department, 93285 Saint Denis Cedex, France 6 President of National Narcotics Committee, French Health Products Safety Agency, 93285 Saint Denis Cedex, France 7 Galenix Innovations, Alle´e des Palanques, 33127 Saint Jean d’Illac, France 8 Nantes University Hospital, Biometric Platform, Nantes, France 9 Faculty of Pharmaceutical Sciences, Universite´ Paris Descartes, Pharmaceutical Technology Department, 4 avenue de l’Observatoire, 75006 Paris, France
Expert Opin. Drug Deliv. (2014) 11(7)
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Designing a tool allowing for a standardized assessment of resistance to drug diversion 1.
Introduction
2.
Materials and methods
3.
Designing a scale
4.
Results
5.
Discussion
6.
Conclusion
Caroline Victorri-Vigneau†, Cedric Collin, Catherine Messina-Gourlot, Christel Raffournier, Michel Mallaret, Je´roˆme Besse, Marie-Anne Courne, Nathalie Richard, Ve´ronique Se´bille, Philippe Arnaud & participants of expert group of the study* *Collaborators: Nolwen Forbin, Denis Wouessidjewe, Anne-Marie PenserLhe´ritier, Alf Lamprecht, Roger Leverge †
Nantes University Hospital, Institut de Biologie, Centre d’Evaluation et d’Information sur la Pharmacode´pendance, Clinical Pharmacology department, Service de Pharmacologie Clinique, Nantes, France
Objectives: Drug diversion is a growing problem in numerous countries. Some laboratories have developed tamper-resistant formulations. The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion for administration by another mode and intended mode. It would be helpful to have a pertinent panel of in vitro tests allowing assessment of how a formulation may be altered, both for healthcare authorities and for laboratories, so as to implement adequate sanitary measures. We designed a methodology/tool allowing assessment, in a standardized manner, of the formulation’s resistance to drug diversion. We present the various steps leading to the construction of the scale and to its first use. Methods: Creating a Steering Committee -- Choosing assays or parameters -standardized by a monograph of the European Pharmacopoeia and pragmatic assays related to users’ behaviors -- for the assessment of formulation resistance to drug diversion. Designing a scale: i) applying all these tests to a panel of formulations; ii) applying a score by drug and by test; and iii) attribution of weighting per test and calculating the total score for a drug. Results: Eight tests or parameters and 14 drugs (diverted drugs and controls) were chosen. Buprenorphine Subutex had the lowest score and flunitrazepam Rohypnol the highest. Conclusions: Our tool allowed classification of the various drugs selected. This classification correlated with results of postmarketing authorization assessment. Rohypnol, which was the object of many measures, including formulation changes, obtained the highest score in our study. Keywords: abuse, assessment tool, diversion, drug formulation, tampering Expert Opin. Drug Deliv. (2014) 11(7):995-1004
1.
Introduction
New drugs are developed to answer therapeutic goals. Nevertheless, once on the market, the drug product may be used outside of indications mentioned in the summary of product characteristics (French acronym RCP), for abuse [1]. Indeed, two types of diversion were described recently as follows. The first, drug abuse, can be defined as ‘the intentional self-administration of a medication for a nonmedical purpose such as altering one’s state of consciousness, e.g., getting high’ [2-4]. Abusers commonly tamper with drug products prior to administration. Tampering is defined as a chemical or physical manipulation that 10.1517/17425247.2014.901307 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
995
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
C. Victorri-Vigneau et al.
alters or damages the integrity of a dosage form, with the intention to enhance its pharmacological effect and to increase the onset of drug actions and the blood level of the active substance [5,6]. Tampering is typically done to enhance euphoria and to make the drug product suitable by alternative routes of administration (intravenous, nasal). Drug abuse with tampering (drug diversion) is a growing problem in many countries [7-9]. This problem has most often been reported with opioids [3,5,10-13]. The second, chemical submission, was identified as a specific mode of diversion. [14,15]. Chemical submission consists in administrating a substance to victims without knowledge for criminal or wrongful purposes. This type of diversion and drug product diversion shares the same operating mode: indeed, whether for chemical submission or for diversion of administration by another mode and intended mode, users alter the oral presentation by crushing tablets (indispensable step before sniffing, injecting or chemical submission) and dissolving them (injection, chemical submission). In this context, strategies have been developed to try to prevent drug abuse with specific formulations. Some laboratories developed tamper-resistant formulations to try to avoid these problems of drug product diversion, [3,16-27], (offering some type of physical resistance to crushing, chewing, snorting) [28-30] or abuse deterrent formulations (formulations that have added excipient to reduce the attractiveness of the product for abusers) [2,31-33]. Nevertheless, tamper-resistant dosage forms do not avoid these problems; and more specifically, they cannot prevent the ingestion of high doses required to obtain some effects. The problem of drug product diversion is a major concern for French healthcare authorities. The French National Agency for Medicines and Health Products Safety (French acronym ANSM) manages a network of 13 centers for the evaluation and information of pharmacodependence (French acronym CEIP). One of the CEIP’s main missions is to collect data and assess the potential of abuse and/or dependence of psychoactive drugs [34]. Furthermore, since 1 July 2003, the ANSM has implemented a prospective and permanent surveillance system to collect all recorded cases of chemical submission, with identification and dosage of the substances used. Thus, dependence and drug abuse cases, and cases of chemical submission, are reported to the ANSM Narcotics Committee (Commission des Stupe´fiants et des Psychotropes [CSP]), which recommends what sanitary measures to take to decrease the risks of abuse and dependence [34,35]. The CSP is regularly confronted to this drug product diversion problem, on the one hand, during evaluation of investigational drugs in late-stage clinical development and, on the other hand, during evaluation of approved drugs. The CSP has already asked for drug formulation modifications to deter abuse liability and diversion. As well, it has also already emitted an unfavorable opinion for the approval of drugs because of formulations that could encourage diversion. 996
The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion of administration mode and/or chemical submission so as to determine to what extent these risks are limited [2,3,7,13,16,18-20,22,25,27,36-47]. Recently, the FDA published a draft guidance for industry for the evaluation and labeling of abuse deterrent opioids. This draft guidance specifically explains the FDA’s current opinion on in vitro studies that should be conducted to demonstrate that a given formulation has or does not have tamper-resistant properties. Moreover, it specifies that the first part of evaluation of the potential for diversion related to the formulation is the analysis of laboratory-based in vitro manipulation and extraction studies. Thus, the goal of these laboratory-based studies should be to evaluate the ease with which the potentially tamper-resistant properties of a formulation can be defeated or compromised. This need of in vitro data was already mentioned in the 2010 guidance [4]. As well, the 2007 orientation in Canada was to study what physical and chemical characteristics of the product could increase the risk of injectable or pulmonary abuse; the experts recommended in vitro studies and clinical trials in humans [48]. But there are no specific recommendations in Europe. There are currently only great principles whatever the country concerned. There is no detailed guidance on how these assessments should be designed and conducted. Consequently, it would be helpful to have a pertinent panel of in vitro tests allowing assessing how a formulation may be altered, both for healthcare authorities and for laboratories. These tests could be an important tool to assess the abuse potential of drugs. Beyond the evaluation of a given drug, it would be essential to be able to ‘classify’ the various pharmaceutical presentations of drugs according to the potential for diversion of the formulation so as to implement adequate sanitary measures according to the classification score. The ANSM, in this context, sponsored a study, the objective of which was to design a scale allowing assessing in a standardized manner the formulation’s resistance to drug diversion. We present the various steps leading to the scale construction and the resulting classification obtained for selected drug formulations. 2.
Materials and methods
Creating a group of experts (Steering Committee) The study was monitored by a group of experts, including pharmacologists, members of the ANSM Department of Narcotics and Psychotropic drugs, members of the ANSM Department of Evaluation and of Pharmaceutical Quality, the President of the Narcotics Committee, the President of the ANSM work group ‘Recommendations for formulation and prevention of drug diversion’, university formulation specialists, industrial formulation specialists, and biostatisticians. This Steering Committee held a meeting at every step of the study and validated all decisions and results. 2.1
Expert Opin. Drug Deliv. (2014) 11(7)
Designing a tool allowing for a standardized assessment of resistance to drug diversion
Determining relevant tests or parameters to design a tool for the assessment of formulation resistance to drug diversion
all recorded cases with identification and dosage of drugs used on 1 July 2003 [55].
2.2
The group of experts chose the tests by first searching for all tests mentioned in the literature or suggested by guidelines. The group documented the following three properties for each test or parameter: . representativeness of the test or parameter compared
with actual diversion . importance of the test or parameter studied for drug Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
diversion . importance of the test or parameter studied for
The drugs for which a specific formulation may prevent diversion are drugs marketed in France and monitored by the CSP. Manipulations Designs of laboratory protocols conform to those described in the EP for a part of the tests. For the other tests, the design was as close as possible to the one used by individuals who tamper with the pharmaceutical presentation. 3.1.2
Analysis of results obtained and applying a score by drug and assay
3.2
chemical submission. The group of experts referred to methods described in the European Pharmacopeia (EP), whenever possible [49]. The EP is a unique reference for quality control of drugs in countries having signed the convention for its implementation. The official standards published are a legal and scientific basis for quality control during the development, production, and marketing processes. They concern the qualitative and quantitative composition and tests for drugs and raw materials used in their production, and on processing agents. The pertinence of each test or parameter was then estimated according to the validity of the method used (test issued or not from the EP), and according to the answer to the three previous described properties.
3.
Designing a scale
3.1
Applying all these tests to a panel of drugs Determining the drugs to be tested
3.1.1
The selected drug products were either drug products identified as diversion drugs in France or drug products for which efforts in formulation were made to limit their potential for diversion. The CEIP network identified diversion drugs in France. Indeed, these centers have developed epidemiological tools [35], and two of these specifically allow identifying the various types of diversion:
The following is the method used globally: for each test, the study of results obtained for all drugs allowed defining categories based on the distribution of results in percentiles (25, 50, 75 and 100%). Each of these classes was then given a score (more often from 0 to 3). The higher the score was, the more the drug had characteristics making diversion difficult. Once this step was performed, the score obtained by a drug for a given test was divided by the highest possible score for the test so as to normalize results/test. Attribution of weighting per test: evaluation of relative pertinence for each test
3.3
A weighting coefficient for each test was calculated after the pertinence analysis of each test made by the Steering Committee (c.f. Section 2) by combining evaluation of (i) the representativeness of the test or parameter compared with actual diversion, (ii) the importance of the test or parameter studied for drug diversion, (iii) the importance of the test or parameter studied for chemical submission, and (iv) the standardization of the method (presented in EP or not). Calculating the total score for a drug product For a given drug product, the normalized score for each test was multiplied by the weighting coefficient attributed to the test. The total score for a drug was calculated by adding all these scores. Total score for a drug product = S test scores 3.4
. The OPPIDUM survey (OPPIDUM for abuse of lawful
4.
and unlawful psychotropic drugs, ‘Observation des Produits Psychotropes Illicites ou De´tourne´s de leur Utilisation Me´dicamenteuse’ in French) is an annual survey of drug users managed in specialized care centers. Its aim is the survey of products used by drug addicts who call physicians in dedicated care centers [15,50-54]. . The surveillance of cases of chemical submission. The French Health Authorities implemented a prospective and permanent observation system allowing to collect
The Steering Committee monitoring each step of the study included 16 individuals. The Steering Committee selected eight tests or parameters. Their answers to the three different properties are listed in Table 1. The tests or parameters are listed in Table 2. The Steering Committee selected 14 drugs according to the data provided by the OPPIDUM survey and a national survey on chemical submission.
Results
Expert Opin. Drug Deliv. (2014) 11(7)
997
C. Victorri-Vigneau et al.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Table 1. Pertinence of parameters or tests estimated by the experts. Assay
European Pharmacopoeia or validated method
Representativeness of the test compared with the actual diversion
Importance of the parameter studied for drug diversion
Importance of the parameter studied for chemical submission
Pertinence of the test = test weighting coefficient
Tensile strength Active principle/mass ratio Disintegration time Fineness of dispersion Visual aspect (limpidity, opalescence, coloration) In vitro dissolution Extractability Syringability Total
1 NA 1 1 1
0 NA 1 1 1
1 2 2 2 1
1 0 2 2 2
3 2 6 6 5
1 0 0
0 1 1
2 2 2
2 1 0
5 4 3 34
Scores range from 0 to 2; the weighting coefficient of each test is calculated by adding the line scores. NA: Nonapplicable.
Table 2. Chosen tests and results obtained. Rational The hardness of a drug tablet make diversion more difficult
The tablets the most easily diverted are those with the least excipients( [61]) A slow disintegration may have a negative impact for injection and for chemical submission
The size of particles is important for injection as larger particles could make it more difficult, and for chemical submission as the presence of a particle could alert the victim The visual aspect of a solution may have an impact on chemical submission as the victim may be alerted by a visual characteristic (supernatant, deposits, color, etc.), but also on injection as
Choice of the test or parameter Tensile strength (2 hardness/ (p diameter thickness)) Hardness (EP, monograph 20908) compared to the tablet’s size AP/mass ratio
Disintegration time (EP, monograph 20901)
Fineness of dispersion
Limpidity
Opalescence
Conditions of application Whole tablets
Score obtained for a drug/maximal test score
Calculation of active principle mass in 1 unit/total mass of unit
Score obtained for an drug/score maximal of the test Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media
Tested solutions representatives of medium used for injection and chemical submission: aqueous and hydro alcoholic medium include variations of pH (to simulate disintegration in orange juice and Coca Cola), and temperature (to simulate disintegration in hot drinks such as coffee) 6 media tested, 3 chosen: water at 25 C, water at 60 C, and pH2 buffer at 25 C (EP, monograph 51701) This test was performed with water at 25 and 60 C (EP, monograph 0478). The solutions were then filtered to determine 3 classes: presence de particles > 1000 µm (visible), presence of particles > 710 µm, and < 1000 µm or absence of particles > 710 µm Presence of supernatants and/or particles in suspension and/or deposit in 3 different caramel colored media (water at 25 C, water at 60 C, and hydro alcoholic solution at 45% v/v) Opalescence of 3 solutions compared with controls (EP, monograph 20201)
EU: European Pharmacopeia.
998
Standardized score per test
Expert Opin. Drug Deliv. (2014) 11(7)
Sum of scores obtained for each of the 2 media/sum of maximum scores for each of the 2 media
A total visual aspect score was made by adding the standardized results of these 3 series of tests/3
Designing a tool allowing for a standardized assessment of resistance to drug diversion
Table 2. Chosen tests and results obtained (continued).
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Rational
Choice of the test or parameter
the visual aspect of the solution may be dissuasive (coloration, etc.)
Variation of coloration
An profile of rapid active principle liberation encourages diversion
In vitro dissolution (EP, monograph 20903)
An active principle extractible in a very small volume of fluid encourages diversion
Extractability
An solution of the drug in a very small volume of fluid easily syringable encourages diversion
Syringability Volume of fluid sampled
Conditions of application Variation of coloration of the same caramel colored solutions and of an orange colored medium (aqueous or hydro alcoholic at 45% v/v). (The orange juice-based drinks were nonlimpid products, the observation of limpidity and of opalescence could not be performed for these media) Assess if the use of standardized media simulating the solutions used for diversions may accelerate active principal liberation. Statistic analysis of ‘media’ and ‘drugs’ effects: 3 chosen media, water, hydro alcoholic medium at 45% v/v, and pH2 buffer Assess the extractability of the active principle in a very small volume of fluid (1 ml, corresponding to the volume of the stericup used by injected drug users) and assess if an extended release tablet will act as immediate release after being crushed 3 media were selected: purified water at 25 C, purified water at to 60 C and a pH2 buffer Assess the easiness if sampling with a syringe, without filtration of the solution obtained after crushing of a drug tablet in 1 ml. 2 tested conditions: with or without prior crushing The Steering Committee estimated that this test had to be related to the results of the extractability test. Indeed if the extractability is weak in a small volume, or null, syringable drugs should not be penalized. They decided to multiply the extractability and syringability score to obtain the final score of this test.
Standardized score per test
Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media Sum of scores obtained for each of the 3 media/sum of maximum scores for each of the 3 media
Sum of scores obtained for each of the 2 media/sum of maximum scores for each of the 2 media
EU: European Pharmacopeia.
The OPPIDUM survey allowed identifying drug products with a diverted mode of administration [56]. The selected drug products are listed in Table 3. These were first high-dose buprenorphine (Subutex 8 mg (buprenorphine) and generic buprenorphine 8 mg) and Skenan 100 mg (morphine sulfate). Benzodiazepines and related drugs were also mentioned as being taken by another route than per os: Rivotril 2 mg (clonazepam), Temesta 2.5 mg (lorazepam), Valium 10 mg (diazepam), Stilnox 10 mg (zolpidem), Lexomil 6 mg (bromazepam), and Rohypnol 1 mg (flunitrazepam). Ritaline 40 mg (methylphenidate) has also been increasingly diverted by nasal intake and intravenously. The most frequently identified substances every year are benzodiazepines and related drugs, according to a survey on chemical submission. Thus, lorazepam, clonazepam, diazepam, zolpidem, and bromazepam are in the list (Table 3). Doxylamine succinate 15 mg (Donormyl) has also been used for chemical submission [56].
Hydrocodone, oxycodone and hydromorphone for immediate and extended release formulations were not chosen for the initial tests because they were not listed among the most diverted drugs in France. The Steering Committee also select, as controls, three drug products available in France for which a formulation measure was developed by manufacturers to reduce diversion: methadone chlorhydrate 40 mg capsule, Concerta LP54 mg (methylphenidate chlorhydrate), and Rohypnol (flunitrazepam). It also decided to add Moscontin LP 100 mg (morphine sulfate) a control for Skenan as, contrary to the latter, it is an opioid drug nonreported in cases of diversion in France [57]. The score for each drug product was calculated, after performing the tests, by adding normalized results for each test multiplied by the weighting coefficient of the test (Table 1). This weighting coefficient was calculated according to answers
Expert Opin. Drug Deliv. (2014) 11(7)
999
C. Victorri-Vigneau et al.
Table 3. Drug scores and ranks. Drug
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Buprenorphine Subutex Buprenorphine Generic Lorazepam Temesta Doxylamine succinate Donormyl Clonazepam Rivotril Diazepam Valium Methylphenidate Ritaline Morphine sulfate Skenan Methadone Zolpidem Stilnox Bromazepam Lexomil Morphine sulfate Moscontin Methylphenidate chlorhydrate Concerta Flunitrazepam Rohypnol
Score/34
Rank
5 5 7 11 11 11 13 17 18 20 20 22 26 27
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Rounded scores make it possible to distinguish four classes corresponding to the level of resistance to drug diversion. Lower scores correspond to the less resisting drugs (5-7); at the opposite higher scores (26-27) correspond to the most resisting drugs; others drugs belong to two intermediate classes (11-13; 17-22).
to the experts’ opinion on the properties of the tests. The drug scores and their rank are listed in Table 3. 5.
Discussion
Drug diversion is an issue today in many countries. Efforts have been made by manufacturers to the find formulations that will make drug diversion more difficult. These formulations should be assessed and especially compared with other drug products. This study deals with in vitro evaluation. This will of course never replace in vivo evaluation, or drug surveillance, but it is a necessary preliminary and complementary step. First, concerning the selection of the tests, the aim was to find a good compromise between representativeness of diversion and reproducibility of the chosen tests. Consequently, our tool includes some tests the implementation of which is standardized by a monograph of the pharmacopoeia and pragmatic tests related to users’ behaviors. The two nonstandardized tests are nevertheless indispensable; they are used to assess the possibility of injecting the drug (extractability into a small volume then syringability). Most tests are based on official and acknowledged monographs that allow reproducing these tests industrially when developing the drug. The second point that should be underlined is that our tool meets the requirements mentioned in the literature and in the latest 2013 FDA guidance ‘abuse-deterrent opioids, evaluation and labeling’ [58]. This guidance, focusing partly on laboratory manipulation and extraction studies, specifies the need for various tests. Syringability, which is assessed in our tool, is also mentioned. The ability to crush is taken into account in our tool by the tensile strength. The extractability and the solubility are also some of the main tests included of tool. Many authors had already stressed the assessing 1000
solubility evaluation in various solvents [18]. The FDA also mentioned the fact that various solvents in various conditions (pH, temperature) should be used. Our tool meets these requirements. Some authors attempted to standardize the evaluation of extractability of active principles from pharmaceutics presentations [59]. These authors referred to opioids, but these studies were based on an interesting method. In this case, extraction was characterized by its easiness, the purity of the extracted substance, the efficiency of extraction (percentage extracted), and the power of extraction (number of doses in an extract). The techniques of extraction are classified into four categories: extraction by simple physical manipulations, extraction by a single chemical stage, extraction requiring several chemical stages, and extraction by complex techniques. A score is attributed according to the probability of abuse for every mode of intake after having performed a series of extractability tests on the active principle in various solvents and having determined the characteristics of the obtained extracts. This score ranges from 1 (highly unlikely) to 5 (very likely). This technique is certainly quite complete, but it is not powerful enough to assess the diversion potential of a drug. A more global scale is needed by simplifying the tests it includes. The FDA mentions the particular attention given to particle size distribution following manipulation. Our tool assesses this aspect with a fineness of dispersion test. Our tool, using these five tests (extractability, syringability, solubility, fineness of dispersion, and tensile strength), allows assessing the tamper-resistant techniques of drugs as they were described by Mastropietro [3], such as attempts at making drugs insoluble or leading to the formation of a gel. It in no case assesses the abuse-deterrent characteristics of drugs. Moreover, our tool allows the assessment of another type of possible diversion, chemical submission, by specifically investigating the time for disintegration and the visual aspect of solutions (opalescence, limpidity, and coloration). This aspect of drug diversion had already been studied. Olsen et al. [60] assessed the concentration, taste, and aspect of nine sedative drugs introduced without mixing in Coca-Cola or alcohol. These authors suggested the possibility to anticipate the risk of criminal use of drugs by checking the alert potential for the victim. It investigates a visual aspect but in a less standardized manner than our tool. It also raises the following important issue: Who would test the modifications of taste so as to assess detectability? Thus, even if the final score is global and allows classifying drugs for their resistance to diversion in a global manner, our tool allows specifying the evaluation for various risks (chemical submission or diversion of administration mode) by selecting some tests. This possible weighting according to the identified type of risk may help decision making in public healthcare. Concerning already existing scale in literature, some authors have mentioned scales aiming at assessing resistance to drug
Expert Opin. Drug Deliv. (2014) 11(7)
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
Designing a tool allowing for a standardized assessment of resistance to drug diversion
diversion. Wright and colleagues [47] wrote down the great principles of a scale allowing classifying the pharmaceutical presentations according to the potential of diversion. This scale of resistance to drug misuse classifies the pharmaceutical presentations in seven levels ranging from no preparation needed for abuse to resistant to re-manufacture. Butler and colleagues [61] developed and validated a scale allowing assessing the attractiveness of various opioid pharmaceutical presentations for users. The 17 items of this scale were selected in collaboration with users. The authors claimed that this scale could be used to assess the attractiveness of new pharmaceutical presentations, not marketed yet. However, the two abovementioned scales do not allow global assessment of several diversion axes in vitro. Indeed, the issue of chemical submission should be raised when considering drug diversion. The ANSM, as well on the national and international levels, has strongly participated in discussions on chemical submission. In September 2008, during the French Presidency of the European Union, the ANSM organized a conference to present recent data on chemical submission and measures for the management victims and for prevention to experts dealing with this issue on the European level. In 2009, France and Argentina pushed the UNO Commission on narcotic drugs to adopt a resolution dealing with the use of pharmaceutical techniques to prevent sexual assault facilitated by drugs. In 2010, the UNO Commission on narcotic drugs adopted a second resolution, initiated by the ANSM and presented by the European Union, concerning international cooperation to prevent the administration of psychoactive substances to unaware victims for criminal purposes. This setup included the member countries taking into account recommendations made to the pharmaceutical industry for pharmaceutical presentations to prevent drug diversion. In July 2010, in accordance with the resolution objectives, the International Narcotics Control Board (INCB, French acronym OICS) sent a questionnaire to all the Member Countries to collect data on chemical submission and, when this was the case, actions were implemented. The ANSM sent to the INCB and the United Nations Office on Drugs and Crime the results of surveys on chemical submission and the survey protocol, as well as the recommendations for formulations relative to chemical submission drafted by the work group ‘Recommendations for formulations and prevention of diversion’ validated at the national level by ANSM and LEEM (French drug companies’ trade association). The global evaluation of drug diversion, but also the evaluation of presentation, should not be limited either to a drug family or to a type of diversion. Last but not the least, our tool allowed classifying the various drugs selected. This classification correlated with results of postmarketing authorization assessment performed by the CEIP in France. The most easily diverted drug according to the scale was buprenorphine. In France, buprenorphine
injections are a real public healthcare problem. The OPPIDUM survey results showed that 16% of individuals used buprenorphine intravenously and 46% sniffed it [56]. Rivotril was also listed in the less well-classified drugs. This drug has been the subject of an official enquiry by addictovigilance and continuously monitored since 2006 because cases of abuse, dependence, and diversion had been reported with the oral presentation. The results of this monitoring confirmed a great proportion of prescriptions were made outside of marketing authorization definition and the diverted use by drug addicts or for chemical submission. Given all these elements, a Risk Management Plan was implemented in 2008 by the laboratory to answer the request made by the ANSM. An update of the addictovigilance enquiry was made in 2010, and then in 2011. Given the persistence of a great proportion of prescriptions made outside of the marketing authorization definition, cases of abuse and dependence, and the important trafficking of prescriptions, the maximum duration of Rivotril prescription was decreased to 12 weeks. Furthermore, as of September 2011, the prescription of Rivotril per os for ambulatory patients had to be made with figures written out in letters and on a secure prescription. Finally, as of 15 March 2012, only neurologists and pediatricians could write out the initial prescription and the yearly renewal. It should be underlined that, although Rivotril and Buprenorphine have lowest scores, the drug products for which a new formulation had been developed were all given scores above 18. This result was particularly interesting because it proved the pertinence of our tool to assess resistance to diversion. Furthermore, a real difference was noted between the score of two methylphenidate formulations: Ritalin (score of 13) and Concerta (score of 26). This difference noted by our tool correlates with surveillance data as no diversion had been reported for Concerta. Another difference should be noted, between Skenan (score of 17) and Moscontin (score of 22); once again, there was a real difference when grading these drugs. No diversion had been reported for Moscontin. Skenan is a frequently diverted and injected drug in France; nevertheless, it was given a score of 17 by our tool, and indeed before injection, a preliminary preparation is necessary, frequently described on users’ forums. If we have a look at the extremes, the results obtained for Subutex and Concerta are interesting because these are two opposite formulations. Indeed, formulation measures were developed by Concerta, manufacturer to reduce diversion, which was not the case for Subutex. Subutex is known to be diverted in France (abusers inject it after dissolving in a small volume of water), whereas Concerta was not mentioned in the French tools assessing diversion. This was correlated by the results obtained with our tool. Subutex was indeed the most diverted drug among those tested with a score of 5/34, whereas Concerta was twice less diverted with a score > 25/34. The last example is Rohypnol, which was the object of many measures, including formulation changes, and had the
Expert Opin. Drug Deliv. (2014) 11(7)
1001
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
C. Victorri-Vigneau et al.
highest score in our study. This psychotropic drug presents a risk for abuse and diversion by drug addicts, and a potential implication in chemical submission. Indeed, these various risks were indeed demonstrated by the CEIP network in the 1990s. Thus, several measures were progressively taken to limit these risks: restriction of therapeutic indications to ‘severe sleep disorders’ and withdrawal of the 2 mg presentation (1996), withdrawal of the 20 tablet boxes (1999), modification in 2001 of the rules concerning the conditions of prescription and delivery (prescription on secure forms limited to 14 days and partial delivery at 7 days), and inclusion in the list of drugs concerned by 1 April 2008 decree (name of the pharmacist on the prescription and protocol of care in case of misuse). The adjunction of a blue-coloring agent in 1998 also had for aim to limit the risks of use for chemical submission.
delivery rules, the implementation of a risk management plan, etc. If the formulation properties are reassuring and are able to limit the potential for diversion, the drug could be more broadly prescribed. As a first perspective, it is crucial to continue this study by applying our method to other drugs, especially for opioids. A further perspective would be to propose a technical harmonized approach of evaluation of drug formulation concerning their diversion potential. This harmonized approach could be materialized in a EP monography summarizing our methodology in order to support the industries in their formulation development and to help health authorities in their evaluation.
Declaration of interest 6.
Conclusion
Identifying a potential for diversion should allow justifying the implementation of complementary measures to prevent this risk. For example, a limitation of prescription or stricter
The authors state no conflict of interest and have received no payment in preparation of this manuscript. Funding for this study was provided by the French National Agency for Medicines and Health Products Safety (French acronym ANSM).
Bibliography 1.
2.
Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend 2006;83(Suppl 1):S4-7 Katz NP, Adams EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain 2007;23(8):648-60
3.
Mastropietro DJ, Omidian H. Current approaches in tamper-resistant and abusedeterrent formulations. Drug Dev Ind Pharm 2013;39(5):611-24
4.
FDA dgfi. Assessment of Abuse Potential of Drugs. 2010. Available from: http://wwwfdagov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM198650pdf
5.
Courty P. High dosage buprenorphine and injection practices. A study of 303 patients. Ann Med Interne (Paris) 2003;154(Spec No 1):S35-45
6.
7.
1002
Victorri-Vigneau C, Dailly E, Veyrac G, et al. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol 2007;64(2):198-209 Schuster CR, Henningfield J. Conference on abuse liability assessment of CNS
medical use? Expert Opin Drug Deliv 2013;10(2):229-40
drugs. Drug Alcohol Depend 2003;70(3 Suppl):S1-4 8.
Sellers EM, Schuller R, Romach MK, et al. Relative abuse potential of opioid formulations in Canada: a structured field study. J Opioid Manag 2006;2(4):219-27
9.
Tharp AM, Winecker RE, Winston DC. Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches. Am J Forensic Med Pathol 2004;25(2):178-81
10.
Davis WR, Johnson BD. Prescription opioid use, misuse, and diversion among street drug users in New York City. Drug Alcohol Depend 2008;92(1-3):267-76
11.
12.
13.
Marquardt KA, Tharratt RS, Musallam NA. Fentanyl remaining in a transdermal system following three days of continuous use. Ann Pharmacother 1995;29(10):969-71 Correas Lauffer J, Braquehais Conesa D, Barbudo Del Cura E, et al. Abuse, tolerance and dependence of zolpidem: three case reports. Actas Esp Psiquiatr 2002;30(4):259-62 Lourenco LM, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-
Expert Opin. Drug Deliv. (2014) 11(7)
14.
Gaulier JM, Fonteau F, Jouanel E, et al. Rape drugs: pharmalogical and analytical aspects. Ann Biol Clin (Paris) 2004;62(5):529-38
15.
Thirion X, Barrau K, Micallef J, et al. [Maintenance treatment for opioid dependence in care centers: the OPPIDUM program of the Evaluation and Information Centers for Drug Addiction]. Ann Med Interne (Paris) 2000;151(Suppl A):A10-17
16.
Schuster CR. History and current perspectives on the use of drug formulations to decrease the abuse of prescription drugs. Drug Alcohol Depend 2006;83(Suppl 1):S8-14
17.
Hamed E, Moe D. Development of tamper deterrent formulations: state of the pharmaceutical industry. Curr Drug Abuse Rev 2010;3(3):139-46
18.
Mansbach RS, Moore RA Jr. Formulation considerations for the development of medications with abuse potential. Drug Alcohol Depend 2006;83(Suppl 1):S15-22
19.
Raffa RB, Pergolizzi JV Jr. Opioid formulations designed to resist/deter abuse. Drugs 2010;70(13):1657-75
Designing a tool allowing for a standardized assessment of resistance to drug diversion
20.
21.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
22.
23.
Sapienza FL. Abuse deterrent formulations and the Controlled Substances Act (CSA). Drug Alcohol Depend 2006;83(Suppl 1):S23-30 Seed SM, Dunican KC, Lynch AM, et al. An update in options for the treatment of pain: a review of new opioid formulations. Hosp Pract (1995) 2012;40(1):166-75 Stanos SP, Bruckenthal P, Barkin RL. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc 2012;87(7):683-94 Vosburg SK, Jones JD, Manubay JM, et al. A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin(R) (non-TRF) in prescription opioid abusers. Addiction 2013;108(6):1095-106
24.
Webster L. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations. Pain Med 2009;10(Suppl 2):S124-33
25.
Webster LR, Bath B, Medve RA. Opioid formulations in development designed to curtail abuse: who is the target? Expert Opin Investig Drugs 2009;18(3):255-63
first year. J Opioid Manag 2012;8(2):115-25 32.
33.
Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphinemaintained intravenous heroin abusers. Addiction 2010;105(4):709-18 Ruan X. Sustained-release morphine sulfate with sequestered naltrexone for moderate to severe pain: a new opioid analgesic formulation and beyond. Expert Opin Pharmacother 2011;12(7):999-1001
34.
Baumevieille M, Miremont G, Haramburu F, et al. [The French system of evaluation of dependence: establishment in a legal system]. Therapie 2001;56(1):15-22
35.
Micaleff J, Jolliet P, Victorri-Vigneau C, et al. First meeting of the French CEIP (centres d’evaluation et d’information sur la pharmacodependance). Assessment of the abuse and pharmacodependence potential during drug development. Therapie 2008;63(1):55-65
36.
Balster RL, Bigelow GE. Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 2003;70(Suppl 3):S13-40
43.
McColl S, Sellers EM. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend 2006;83(Suppl 1):S52-62
44.
McCormick CG. Regulatory challenges for new formulations of controlled substances in today’s environment. Drug Alcohol Depend 2006;83(Suppl 1):S63-7
45.
Parasrampuria DA, Schoedel KA, Schuller R, et al. Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. J Clin Psychopharmacol 2007;27(5):459-67
46.
Schneider JP, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse? CNS Drugs 2010;24(10):805-10
47.
Wright CT, Kramer ED, Zalman MA, et al. Risk identification, risk assessment, and risk management of abusable drug formulations. Drug Alcohol Depend 2006;83(Suppl 1):S68-76
48.
Canada S. Clinical Assessment of Abuse Liability for Drugs with Central Nervous System Activity 2007. Available from: http://wwwhcscgcca/dhp-mps/prodpharma/applicdemande/guide-ld/abus/abuse_ liability_abusif_usage_clin-fraphp
26.
Webster LR, Fine PG. Approaches to improve pain relief while minimizing opioid abuse liability. J Pain 2010;11(7):602-11
37.
Bannwarth B. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? Drugs 2012;72(13):1713-23
27.
Wick JY. Drug-abuse deterrent formulations. Consult Pharm 2009;24(5):356-62; 365
38.
49.
28.
Chai LY, Khare CB, Chua A, et al. Buprenorphine diversion: a possible reason for increased incidence of infective endocarditis among injection drug users? The Singapore experience. Clin Infect Dis 2008;46(6):953-5; author reply 5-6
Butler SF, Black R, Grimes Serrano JM, et al. Estimating attractiveness for abuse of a not-yet-marketed "abuse-deterrent" prescription opioid formulation. Pain Med 2010;11(1):81-91
Licata SC, Mashhoon Y, Maclean RR, et al. Modest abuse-related subjective effects of zolpidem in drug-naive volunteers. Behav Pharmacol 2011;22(2):160-6
39.
Butler SF, Fernandez KC, Chang A, et al. Measuring attractiveness for abuse of prescription opioids. Pain Med 2010;11(1):67-80
50.
40.
Coleman JJ, Bensinger PB, Gold MS, et al. Can drug design inhibit abuse? J Psychoactive Drugs 2005;37(4):343-62
Thirion X, Micallef J, Barrau K, et al. Observation of psychoactive substance consumption: methods and results of the French OPPIDUM programme. Eur Addict Res 2001;7(1):32-6
51.
Thirion X, Micallef J, Guet F, et al. [Dependence on psychotropic drugs and substitution treatment: recent trends. The OPPIDUM study of the Centers for Evaluation and Information on Drug Dependence (CEIP), October 1997]. Therapie 1999;54(2):243-9
52.
San Marco JL, Jouglard J, Thirion X, et al. [Observation of illicit or misused psychotropic drugs (O.P.P.I.D.U.M.): five years of surveillance of products consumed by drug addicts at Marseille]. Therapie 1996;51(5):586-98
29.
Chevalley AE, Besson J, Croquette-Krokar M, et al. Prevalence of methadone injection in three Swiss cities. Presse Med 2005;34(11):776-80
30.
Fudala PJ, Johnson RE. Development of opioid formulations with limited diversion and abuse potential. Drug Alcohol Depend 2006;83(Suppl 1):S40-7
31.
Badalamenti VC, Buckley JW, Smith ET. Safety of EMBEda (morphine sulfate and naltrexone hydrochloride) extended-release capsules: review of postmarketing adverse events during the
41.
42.
Grudzinskas C, Balster RL, Gorodetzky CW, et al. Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report. Drug Alcohol Depend 2006;83(Suppl 1):S77-82 Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep 2008;10(1):11-18
Expert Opin. Drug Deliv. (2014) 11(7)
1003
C. Victorri-Vigneau et al.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 05/17/15 For personal use only.
53.
Pauly V, Frauger E, Rouby F, et al. Analysis of addictive behaviours among new prisoners in France using the OPPIDUM program. Encephale 2010;36(2):122-31
54.
Moracchini C, Frauger E, Pauly V, et al. Harm reduction centers (“CAARUD”): privileged places for warning signal detection in addictovigilance. Therapie 2012;67(5):437-45
55.
Djezzar S, Questel F, Burin E, et al. Chemical submission: results of 4-year French inquiry. Int J Legal Med 2009;123(3):213-19
56.
ANSM. Assesment tools 2009. Available from: http://ansmsantefr/ Activites/PharmacodependanceAddictovigilance/Outils-de-surveillanceet-d-evaluation-Resultats-d-enquetes/ (offset)/3
57.
Eiden C, Leglise Y, Bertomeu L, et al. New formulation of methadone for opioid dependence in France: acceptability and diversion/misuse liability. Therapie 2013;68(2):107-11
58.
FDA dgfi. Abuse-Deterrent Opioids, Evaluation and Labeling 2013. Available from: http://wwwfdagov/ downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM334743.pdf
59.
Katz NP, Buse DC, Budman SH, et al. Development and preliminary experience with an ease of extractability rating system for prescription opioids. Drug Dev Ind Pharm 2006;32(6):727-46
60.
Barnard EA, Skolnick P, Olsen RW, et al. International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 1998;50(2):291-313
61.
Butler SF, Benoit C, Budman SH, et al. Development and validation of an Opioid attractiveness scale: a novel measure of the attractiveness of opioid products to potential abusers. Harm Reduct J 2006;3:5
1004
Affiliation
Caroline Victorri-Vigneau†1,2, Cedric Collin3, Catherine Messina-Gourlot4, Christel Raffournier5, Michel Mallaret6, Je´roˆme Besse7, Marie-Anne Courne4, Nathalie Richard4, Ve´ronique Se´bille2,8, Philippe Arnaud9 & participants of expert group of the study* *Collaborators: Nolwen Forbin, Denis Wouessidjewe, Anne-Marie Penser-Lhe´ritier, Alf Lamprecht, Roger Leverge † Author for correspondence 1 Nantes University Hospital, Institut de Biologie, Centre d’Evaluation et d’Information sur la Pharmacode´pendance, Clinical Pharmacology Department, Service de Pharmacologie Clinique, 9 quai Moncousu, 44093 Nantes cedex 1, France Tel: +33 240084096; Fax: +33 240084097; E-mail: [email protected] 2 Nantes University, EA 4275 Biostatistic, Pharmacoepidemiology and Subjective Measures in Health Science, 44093 Nantes Cedex, France 3 French Health Products Safety Agency, Pharmacoepidemiology Department, 93285 Saint Denis Cedex, France 4 French Health Products Safety Agency, Narcotic Department, 93285 Saint Denis Cedex, France 5 French Health Products Safety Agency, Pharmaceutical Quality Department, 93285 Saint Denis Cedex, France 6 President of National Narcotics Committee, French Health Products Safety Agency, 93285 Saint Denis Cedex, France 7 Galenix Innovations, Alle´e des Palanques, 33127 Saint Jean d’Illac, France 8 Nantes University Hospital, Biometric Platform, Nantes, France 9 Faculty of Pharmaceutical Sciences, Universite´ Paris Descartes, Pharmaceutical Technology Department, 4 avenue de l’Observatoire, 75006 Paris, France
Expert Opin. Drug Deliv. (2014) 11(7)
