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Current thinking on the premarketing evaluation of abuse-deterrent opioid formulations
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Abstracts / Drug and Alcohol Dependence 140 (2014) e2–e85
Client reasons for poor engagement early in substance abuse treatment John S. Cacciola 1,2 , A. Mericle 1 , Adam C. Brooks 1 , M. Ivey 2 , J. McKay 1,2 1 Treatment Research Institute, Philadelphia, PA, United States 2 University of Pennsylvania, Philadelphia, PA, United States
Aims: Numerous prediction studies have identified variables (e.g., substance use and psychiatric severity) associated with attrition from outpatient substance abuse treatment (SAT). Very few studies have examined factors associated with dropout from the client’s perspective. Those that have indicate that dissatisfaction with aspects of treatment as well as individual status factors are reported reasons for dropout. The present study rates clients’ selfreported reasons for early attrition from outpatient SAT. Methods: Clients (N = 106) recently admitted to two outpatient SAT programs, who irregularly attended treatment during the first 2–3 weeks, were contacted for a brief telephone motivational intervention. During this call they were queried about reasons for lack of attendance, which were then abstracted and coded. Results: Clients reported various and multiple reasons for poor early engagement in treatment that roughly paralleled those reported for dropping out of treatment by clients in previous studies. These reasons can be categorized as: Client Factors—particularly medical and psychological problems, and acute life stressors; Treatment Factors including issues with clients and staff, as well as the schedule and nature of the treatment itself; and Environmental or Logistical Factors such as transportation, finances, and competing employment demands. Conclusions: Client attributions for outpatient treatment attrition are not fully parallel with variables identified in prediction studies obtained via patient assessments. Further, clients identify many issues that appear to be actionable in some way, and that if prepared for or dealt with by the clinics at both the programmatic and individual client levels, could improve retention. Financial support: NIAAA 1-P01-AA016821-01A1 and NIDA 2P60-DA005186-21. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.086 Current thinking on the premarketing evaluation of abuse-deterrent opioid formulations Silvia N. Calderon, J.M. Tolliver, M. Klein Controlled Substance Staff, Food and Drug Administration, Silver Spring, MD, United States Aims: To provide an overview of the Food and Drug Administration (FDA) current thinking about the studies that should be conducted to demonstrate that a formulation has abuse deterrent (AD) properties. Methods: Abuse and misuse of prescription opioid analgesics is a serious and growing public health problem. Consequently, the development of AD formulations that are less prone to abuse or misuse is a public health priority. To that end, the Center for Drug Evaluation and Research at FDA is developing a guidance regarding the evaluation of AD opioid formulations. Results: A phased three tier approach for premarketing assessment has been proposed for formulations with potential AD features. The first tier consists of in-vitro manipulation and extraction studies, aimed to evaluate the ease with which AD features of a new formulation can be defeated or partially compromised under exper-
imental conditions. Pharmacokinetic/pharmacodynamic studies constitute the second tier. These studies are designed to understand the in-vivo properties of the new formulation by comparing the pharmacokinetic profiles of the “manipulated” formulation with the intact formulation and other comparator drugs through one or more routes of administration, and to collect pharmacodynamic outcomes such as adverse events associated with the administration of the manipulated formulation. The third tier consists on evaluating the relative abuse potential of the AD formulation to that of a positive control and placebo in human abuse potential studies. Conclusions: The development of formulations with abusedeterrent properties represents an evolving area of research. Abuse-deterrent technologies and the methodology for evaluating those technologies are rapidly evolving. Therefore, in addition to retaining a flexible, adaptive approach to the evaluation of AD formulations, there is considerable potential for additional scientific work to aid in the efforts to develop and assess AD formulations. Financial support: N/A. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.087 Methylphenidate self-administration increases the potency and reinforcing effects of releasers through a dopamine transporter mechanism Erin Calipari 1 , M.J. Ferris 1 , A. Salahpour 2 , M.G. Caron 3 , D.C. Roberts 1 , S.R. Jones 1 1 Wake Forest School of Medicine, Winston-Salem, NC, United States 2 University of Toronto, Toronto, ON, Canada 3 Duke University Medical Center, Durham, NC, United States
Aims: Intravenous abuse of methylphenidate (MPH) has become prevalent, which is alarming given the lack of research on its consequences. We examined the effects of MPH selfadministration (SA) on the nucleus accumbens core (NAcc) dopamine (DA) system, as changes can influence reward and reinforcement. The DA transporter (DAT) is the primary site of action of psychostimulants, thus we assessed the potency of compounds to inhibit the DAT following MPH SA. Further, we assessed the reinforcing efficacy of cocaine (COC), MPH, and amphetamine (AMPH). MPH SA resulted in increased DAT levels, thus we increased DAT levels by transgenic over-expression [DAT(tg)] to determine if it was sufficient to cause the MPH SA-induced effects. Methods: Rats underwent fixed ratio one (FR1) SA. Kinetics of stimulated DA signals were measured with in vitro voltammetry. COC, MPH and AMPH were applied to slices to assess potency. To assess reinforcing efficacy animals were switched to a threshold procedure (Oleson et al., 2012) for AMPH, COC, and MPH. For locomotor analysis mice were placed into locomotor chambers, injected with drug and monitored. Results: MPH SA increased uptake rates and DAT levels. MPH SA increased the potency and reinforcing efficacy of AMPH and MPH, with no effect on COC. We replicated the effects with DAT(tg) mice, demonstrating increased AMPH and MPH, but not cocaine, induced potency and locomotor activity, suggesting that increased DAT levels are the mechanism by which theses effects occur. Conclusions: MPH SA resulted in enhanced potency and reinforcing efficacy of AMPH and MPH but not COC. These effects are likely through DAT increases as increasing DAT levels [DAT(tg)] had the same effects. This has implications for MPH abusers as well as individuals with differential DAT levels at baseline (e.g. ADHD, drug abusers) as it suggests an enhanced susceptibility to the reinforcing properties of some psychostimulants.
Abstracts / Drug and Alcohol Dependence 140 (2014) e2–e85
Client reasons for poor engagement early in substance abuse treatment John S. Cacciola 1,2 , A. Mericle 1 , Adam C. Brooks 1 , M. Ivey 2 , J. McKay 1,2 1 Treatment Research Institute, Philadelphia, PA, United States 2 University of Pennsylvania, Philadelphia, PA, United States
Aims: Numerous prediction studies have identified variables (e.g., substance use and psychiatric severity) associated with attrition from outpatient substance abuse treatment (SAT). Very few studies have examined factors associated with dropout from the client’s perspective. Those that have indicate that dissatisfaction with aspects of treatment as well as individual status factors are reported reasons for dropout. The present study rates clients’ selfreported reasons for early attrition from outpatient SAT. Methods: Clients (N = 106) recently admitted to two outpatient SAT programs, who irregularly attended treatment during the first 2–3 weeks, were contacted for a brief telephone motivational intervention. During this call they were queried about reasons for lack of attendance, which were then abstracted and coded. Results: Clients reported various and multiple reasons for poor early engagement in treatment that roughly paralleled those reported for dropping out of treatment by clients in previous studies. These reasons can be categorized as: Client Factors—particularly medical and psychological problems, and acute life stressors; Treatment Factors including issues with clients and staff, as well as the schedule and nature of the treatment itself; and Environmental or Logistical Factors such as transportation, finances, and competing employment demands. Conclusions: Client attributions for outpatient treatment attrition are not fully parallel with variables identified in prediction studies obtained via patient assessments. Further, clients identify many issues that appear to be actionable in some way, and that if prepared for or dealt with by the clinics at both the programmatic and individual client levels, could improve retention. Financial support: NIAAA 1-P01-AA016821-01A1 and NIDA 2P60-DA005186-21. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.086 Current thinking on the premarketing evaluation of abuse-deterrent opioid formulations Silvia N. Calderon, J.M. Tolliver, M. Klein Controlled Substance Staff, Food and Drug Administration, Silver Spring, MD, United States Aims: To provide an overview of the Food and Drug Administration (FDA) current thinking about the studies that should be conducted to demonstrate that a formulation has abuse deterrent (AD) properties. Methods: Abuse and misuse of prescription opioid analgesics is a serious and growing public health problem. Consequently, the development of AD formulations that are less prone to abuse or misuse is a public health priority. To that end, the Center for Drug Evaluation and Research at FDA is developing a guidance regarding the evaluation of AD opioid formulations. Results: A phased three tier approach for premarketing assessment has been proposed for formulations with potential AD features. The first tier consists of in-vitro manipulation and extraction studies, aimed to evaluate the ease with which AD features of a new formulation can be defeated or partially compromised under exper-
imental conditions. Pharmacokinetic/pharmacodynamic studies constitute the second tier. These studies are designed to understand the in-vivo properties of the new formulation by comparing the pharmacokinetic profiles of the “manipulated” formulation with the intact formulation and other comparator drugs through one or more routes of administration, and to collect pharmacodynamic outcomes such as adverse events associated with the administration of the manipulated formulation. The third tier consists on evaluating the relative abuse potential of the AD formulation to that of a positive control and placebo in human abuse potential studies. Conclusions: The development of formulations with abusedeterrent properties represents an evolving area of research. Abuse-deterrent technologies and the methodology for evaluating those technologies are rapidly evolving. Therefore, in addition to retaining a flexible, adaptive approach to the evaluation of AD formulations, there is considerable potential for additional scientific work to aid in the efforts to develop and assess AD formulations. Financial support: N/A. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.087 Methylphenidate self-administration increases the potency and reinforcing effects of releasers through a dopamine transporter mechanism Erin Calipari 1 , M.J. Ferris 1 , A. Salahpour 2 , M.G. Caron 3 , D.C. Roberts 1 , S.R. Jones 1 1 Wake Forest School of Medicine, Winston-Salem, NC, United States 2 University of Toronto, Toronto, ON, Canada 3 Duke University Medical Center, Durham, NC, United States
Aims: Intravenous abuse of methylphenidate (MPH) has become prevalent, which is alarming given the lack of research on its consequences. We examined the effects of MPH selfadministration (SA) on the nucleus accumbens core (NAcc) dopamine (DA) system, as changes can influence reward and reinforcement. The DA transporter (DAT) is the primary site of action of psychostimulants, thus we assessed the potency of compounds to inhibit the DAT following MPH SA. Further, we assessed the reinforcing efficacy of cocaine (COC), MPH, and amphetamine (AMPH). MPH SA resulted in increased DAT levels, thus we increased DAT levels by transgenic over-expression [DAT(tg)] to determine if it was sufficient to cause the MPH SA-induced effects. Methods: Rats underwent fixed ratio one (FR1) SA. Kinetics of stimulated DA signals were measured with in vitro voltammetry. COC, MPH and AMPH were applied to slices to assess potency. To assess reinforcing efficacy animals were switched to a threshold procedure (Oleson et al., 2012) for AMPH, COC, and MPH. For locomotor analysis mice were placed into locomotor chambers, injected with drug and monitored. Results: MPH SA increased uptake rates and DAT levels. MPH SA increased the potency and reinforcing efficacy of AMPH and MPH, with no effect on COC. We replicated the effects with DAT(tg) mice, demonstrating increased AMPH and MPH, but not cocaine, induced potency and locomotor activity, suggesting that increased DAT levels are the mechanism by which theses effects occur. Conclusions: MPH SA resulted in enhanced potency and reinforcing efficacy of AMPH and MPH but not COC. These effects are likely through DAT increases as increasing DAT levels [DAT(tg)] had the same effects. This has implications for MPH abusers as well as individuals with differential DAT levels at baseline (e.g. ADHD, drug abusers) as it suggests an enhanced susceptibility to the reinforcing properties of some psychostimulants.