1 National Academy of Medicine Session 4 Opioid Analgesics with Abuse- Deterrent Properties: Current Data and Future Opportunities Richard C. Dart, MD, PhD Director, Rocky Mountain Poison and Drug Center Executive Director, RADARS System Professor, University of Colorado
Opioids with Abuse Deterrent Properties: Current Data and Future Opportunities 2 Oxycodone ER fulfills the Hill criteria for causation Plausibility Consistency Temporality Specificity Effect Size Alternative explanations Questions and Issues National Academy of Science US Food and Drug Administration International Society of Pharmacoepidemiology, August 26, 2015
3 Hill Criteria: Plausibility A plausible mechanism between cause and effect is helpful (but understanding of the mechanism is limited by current knowledge) Hill AB. Proc Royal Soc Med 1965;58:295-300.
Scientific Basis of Abuse-Deterrent Opioids 4 Prescription drug abuse is like other drug abuse, except with an additional route of abuse: Oral = intact + chewed or crushed Intranasal Intravenous Importance of manipulating drug Crucial transition Changes perception of heroin use 1 Risk of acute (overdose, death) and chronic events (addiction, infections, death) higher after intranasal or IV abuse than oral abuse 1. Vosburg. J Child Adol Subst Abuse 2016.
5 Biological Plausibility Person in Pain Filling the Balloon Susceptible Person Intact Chewed Crushed Outcomes Addiction Recreational Abuser Overdose Death Dart RC, Iwanicki JL. Can J Diag 2015;32:10.
6 Intervening in Prescription Drug Abuse Person in Pain Emptying the Balloon Guidelines Susceptible Person P D M P Intact A D F Chewed A D F Crushed Outcomes Addiction Recreational Abuser A D F Overdose Death A D F Dart RC, Iwanicki JL. Can J Diag 2015;32:10.
7 Hill Criteria: Temporality Effect has to occur after the cause (including a delay, if expected) Minimal delay expected for oxycodone ER All drug shipped after August 9, 2010 was reformulated version Pharmacy turnover of opioids is rapid Only oxycodone ER has adequate data to evaluate effectiveness Hill AB. Proc Royal Soc Med 1965;58:295-300.
Oxycodone ER Prescriptions Dispensed Decreased Promptly After Reformulation 8 30% % Change in Prescriptions Dispensed 20% 10% 0% -10% -20% -30% Other Opioids Oxycodone ER -40% -50% Reformulation of Oxycodone ER 2011 2012 2013 2014 2015 2016 IMS, 2015 Other Opioids = Oral dosage forms of opioid analgesics: hydrocodone, hydromorphone, morphine, oxymorphone, tramadol, tapentadol, and IR oxycodone
RADARS System Surveillance of Prescription Drug Abuse 9 Independent postmarketing surveillance program focusing solely on prescription drug abuse Most manufacturers of prescription opioids are subscribers Limited to use for regulatory and risk-management use Acute Health Events Drug Transactions Entering Treatment Entering Treatment New Initiates Web Monitoring Illicit Market Price
10 Why Adjust for Population? Population-adjusted Rate = # Events in Geographic Area Population in same Geographic Area Accounts for obtaining drug (reduction in doctor shopping) Abuse after prescription is dispensed What if we had a perfect ADF? doctor shopping, pill mill activity high risk abuse after Rx
Temporality: 3 Phases of Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010 2016Q2 11
12 Hill Criteria: Effect Size A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. Hill AB. Proc Royal Soc Med 1965;58:295-300.
Effect Size: Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010-2016 13
14 Hill Criteria: Consistency Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect
Consistency: Oxycodone ER Associated with Lower Rates Across Many Data Sources 15 Outcome Misuse Abuse Source RADARS (Poison Centers) RADARS (Poison Centers) NPDS (Poison Centers) NAVIPPRO (Treatment Centers) RADARS SKIP (Treatment Centers) Pre vs. Post % Change [95% CI] Since Reformulation ER Oxycodone Other Opioids RADARS OTP (Treatment Centers) Opioid Use Disorder Database of Opioid Users (Marketscan) Overdose Diversion Doctor Shopping Database of Opioid Users (Marketscan) RADARS (Drug Diversion) IMS Prescription Data Data adjusted for prescription volume Coplan et al. Clin Pharmacol Ther. 2016. -100% -50% 0% 50% 100% Decrease Increase
National Survey of Drug Use and Health, OxyContin Nonmedical Use 16 2 Introduction of Reformulated Oxycodone ER 1.6 # Cases of Past Year Nonmedical OxyContin Use (in millions) 1.2 0.8 0.4 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Rate per 100,000 population 20094 20102 20104 20112 20114 20122 20124 20132 20134 20142 17 Poison Center Cases: Response to Reformulation of Oxycodone ER and Oxymorphone ER Oxycodone ER Oxymorphone ER Other Opioids Reformulation of: OxyC ER OxyM ER Reformulation of: OxyC ER OxyM ER Reformulation of: OxyC ER OxyM ER 0.08 0.035 0.7 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.03 0.025 0.02 0.015 0.01 0.005 0.6 0.5 0.4 0.3 0.2 0.1 0 0 0
18 Hill Criteria: Specificity The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship 1 Results specific to oxycodone ER compared to other analgesic opioids FDA Concerns 2 1. Hill AB. Proc Royal Soc Med 1965;58:295-300. 2. International Society of Pharmacoepidemiology, August 26, 2015
For data streams that collect information on a variety of events (e.g., abuse, adverse reactions), changes should be limited to abuse-related categories 19 Abuse Misuse Suicide Suicide Unintentional Unintentional therapeutic error therapeutic error Unintentional general exposure Unintentional general exposure -100% -50% 0% 50% 100% Relative Change in Population Rate
20 For evaluation of ADFs, changes should be seen only in the routes of abuse expected to be affected Inhale or Inject Oral -100% -50% 0% 50% 100% Relative Change in Population Rate All routes of abuse should be low with an effective ADF
Per 100,000 Population Alternate Explanations Fail the Temporality and Specificity Criteria 21 0.8 0.6 0.4 0.2 Oxycodone ER All Other Opioids WA Rx Guidelines Natl Drug Take Back Reformulation FL TIRF REMS ER/LA REMS HC-APAP Tramadol NY/ACEP Rx Guidelines 0.12 0.1 0.08 0.06 0.04 Per 100,000 Population 0.02 0 20031 20041 20051 20061 20071 20081 20091 20101 20111 20121 20131 20141 20151 20161 0 PDMP Initiation
22 Other Issues Effect of ADFs on opioid related harm in the community FDA policies and procedures of review, approval, and monitoring Gaps in Research Immediate Release vs. Extended Release Formulations
Effect of Abuse Deterrent Opioids on Opioid-Related Harm in the Community 23 Extended release products have a small part of opioid market ER products account for small portion of total abuse Oxycodone ER can reduce its own abuse, not entire market
FDA Policies and Procedures Gaps in Research 24 Guidance was excellent beginning Definitions Meaningful reduction Addiction, Overdose Totality of the evidence no framework to address Comparator drugs IR/ER abuse usually starts on IR, but no special risk management
25 Conclusions and Implications Specificity, consistency and effect size indicate that abuse deterrent opioids are likely to be effective in reducing abuse and its outcomes Similar effects for crush-resistant oxymorphone ER Widespread use would reduce prices and reduce the crucial transition from intact swallowing to crushing Education, training, and other interventions needed as well
Backup Slides 26
Temporality: Oxycodone ER Abuse and Diversion, Dosage Units Dispensed, 2010-2016 27
Effect Size: Oxycodone ER Abuse and Diversion, Adjusted Dosing Units Dispensed, 2009-2016 28
Specificity of Reduction in Abuse of Oxycodone ER 29 Abuse Abuse Misuse Misuse Suicide Suicide Unintentional Unintentional therapeutic therapeutic error Unintentional general Unintentional general exposure -100% -50% 0% 50% 100% Relative change in dosing units dispensed rate
Specificity of Reduction in Abuse of Oxycodone ER by Route 30 Inhale or Inject Oral -100% -50% 0% 50% 100% Relative change in dosing units dispensed rate
31 ADFs Will Increase Opioid Use: ER Opioid Prescriptions Have Been Decreasing Over Last 5 Years 25 20 22.3 21.8 21.4 21.3 20.7 Dispensed ER Prescriptions (in millions) 15 10 5 IMS National Prescription Audit (2011-2015) 0 2011 2012 2013 2014 2015 Year
IV and Intranasal Opioid Abuse Associated With Higher Risk of Death or Major Effects 32 Route of Abuse Compared to Oral Ingestion Relative Risk of Death or Major Effect Relative Risk [95% CI] P-Value Intranasal 2.2 [1.7, 3.0] <0.0001 Intravenous 2.6 [2.0, 3.4] <0.0001 0.1 1 10 Lower Risk vs Oral Ingestion Greater Risk vs Oral Ingestion RADARS System Poison Center Program, 2015 Data on File
Reformulated Oxycodone ER Replaced Original Formulation Quickly 33
Did Introduction of Oxycodone ER Cause an Increase in Heroin Abuse? 34 Dart RC et al. NEJM 2015;372:241-8.
35 Approaches to Abuse Deterrence Physical / chemical barriers Hydrocodone (Hysingla, Vantrela ) Morphine (Arymo, Morphabond ) Oxycodone (OxyContin, Xtampza ) Agonist / antagonist Morphine (Embeda ) Oxycodone (Troxyca ER) Aversion Delivery System (incl. depot forms and implants) New molecular entities and prodrugs Combination Two or more methods combined Novel approaches
Abuse-Deterrent ER Oxycodone Reduces IV Abuse in Australia 36 4500 Introduction of Reformulated ER oxycodone 4000 3500 3000 Number of IV Cases 2500 2000 1500 1000 500 Non-abuse-deterrent oxycodone Reformulated ER oxycodone 0 Degenhardt et al. Drug Alc Dependence 2015;151:56-57.
Street Price of Reformulated Oxycodone ER 45% Lower Than Original Version 37 $3.00 Oxycodone ER Price, 2011 $2.50 Median Dollar per milligram $2.00 $1.50 $1.00 $0.50 $1.00 $0.55 $0.00 OxyContin, crushable OxyContin, reformulated StreetRx.com, 2016
Adjustment for Population or Dosing Units Provides Different Perspectives 38 Population # Events in Geographic Area Population in same Geographic Area = Accounts for obtaining drug (reduction in doctor shopping) Abuse after prescription is dispensed What if we had a perfect ADF? doctor shopping, pill mill activity high risk abuse after Rx Dosage Units Dispensed # Events in Geographic Area # Dosage Units Dispensed in same Geographic Area = Evaluates abuse after user has obtained the drug Does not include reduction in doctor shopping or prescribing behavior