Real World Data: Do ADFs Change Behavior?
What Current Opioid Data Imply for Stimulants in the Future
Janetta L. Iwanicki, MD Scientific Director of Research and Surveillance RADARS, Rocky Mountain Poison & Drug Center 2 Roadmap
• Real-world data on ADF effectiveness
• Opana ER and its complicated history
• Effects of policy on behavior and trends
• Current prescription stimulant real-world data
• Lessons learned
References: 10 pt. Biological Plausibility
Person in Filling the Balloon Pain
Susceptible Outcomes Person Intact Chewed Crushed Addiction
Recreational Overdose Abuser
Death
Dart RC, Iwanicki JL. Can J Diag 2015;32:10. Intervening in Prescription Drug Abuse
Person in Emptying the Balloon Pain
Guidelines A A P D D Susceptible D F F Outcomes M Person Intact Chewed Crushed P Addiction
Recreational A Overdose D Abuser F
Death A D F
Dart RC, Iwanicki JL. Can J Diag 2015;32:10. Oxycodone ER Prescriptions Dispensed Decreased Promptly After Reformulation
30%
20% Other Opioids 10%
0% % Change in Prescriptions -10% Dispensed -20% Oxycodone ER -30%
-40% Reformulation of Oxycodone ER
-50% 2011 2012 2013 2014 2015 2016
Other Opioids = Oral dosage forms of opioid analgesics: hydrocodone, hydromorphone, morphine, oxymorphone, tramadol,
IMS, 2015 tapentadol, and IR oxycodone Temporality: 3 Phases of Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010 – 2016Q2 Effect Size: Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010-2016 Consistency: Oxycodone ER Associated with Lower Rates Across Many Data Sources
Pre vs. Post % Change [95% CI] Outcome Source Since Reformulation
Misuse RADARS (Poison Centers) ER Oxycodone Other Opioids RADARS (Poison Centers)
NPDS (Poison Centers)
NAVIPPRO (Treatment Centers) Abuse RADARS SKIP (Treatment Centers)
RADARS OTP (Treatment Centers)
Opioid Use Disorder Database of Opioid Users (Marketscan) Overdose Database of Opioid Users (Marketscan)
Diversion RADARS (Drug Diversion)
Doctor Shopping IMS Prescription Data
Data adjusted for prescription volume
Coplan et al. Clin Pharmacol Ther. 2016. Decrease Increase Poison Center Cases: Response to Reformulation of Oxycodone ER and Oxymorphone ER
Oxycodone ER Oxymorphone ER Other Opioids
Reformulation of: Reformulation of: Reformulation of: OxyC ER OxyM ER OxyC ER OxyM ER OxyC ER OxyM ER Rate per 100,000 population Rate Alternate Explanations Fail the Temporality and Specificity Criteria
Reformulation HC-APAP FL TIRF WA Rx REMS Tramadol Guidelines ER/LA Oxycodone ER Natl Drug REMS All Other Opioids Take Back
NY/ACEP Rx Guidelines
PDMP Initiation 11 Opana ER
• Extended-release oxymorphone
• Oxymorphone developed in Germany 1914
• Patented 1955
• Opana ER formulation Initially approved in 2006
• Indications: moderate to severe pain requiring around-the- clock treatment
• Geographic distribution
References: 10 pt. 12 Opana ER: Geographic distribution and heterogeneity
Drug: Opana ER Time: 2009q3 – 2016q4 Source: IQVIA N: 360,432,541 units dispensed Analysis unit: 3-digit ZIP Metric: cumulative population-adjusted rate
13 Oxymorphone
• Poor oral bioavailability – 10x more potent intravenously than orally
• Leads to unusual behaviors • Single 40mg pill = split into quarters • Each quarter = 2-4 users • Single pill leads to 8-16 doses intravenously • Each dose 50-75 MME
References: 10 pt. 14 Oxymorphone
• Poor oral bioavailability – 10x more potent intravenously than orally
• Leads to unusual behaviors – Drug sharing – Unsafe injection practices
• Complications – HIV – Hepatitis C – TTP
References: 10 pt. 15 Opana ER: Interventions and Policy Changes
• 2011: Reformulation approved – Released in 2012 – Tamper resistant, but did not achieve ADF labeling
• Concern for transition from intranasal to intravenous abuse
• Outbreaks associated with oxymorphone
References: 10 pt. 16 Opana ER: Interventions and Policy Changes
• March 2017: – FDA meeting – 18-8 vote, benefits no longer outweigh risks • June 2017: – Recommended to be removed from market • July 2017: – Opana ER removed – No change to generic forms or IR
References: 10 pt. Oxymorphone: Big picture Poison Center Program
0.25 Per 100,000 population 0.2 Oxycodone Fentanyl
0.15 Hydrocodone Hydromorphone Morphine
0.1 Oxymorphone Methadone Buprenorphine Tramadol 0.05 Tapentadol Oxymorphone
0
17 18 Opana ER: Effects of Policy on Behavior and Trends Poison Center Program, rate per population
All Oxymorphone
Opana ER
2012 2017
References: 10 pt. 19 Opana ER: Effects of Policy on Behavior and Trends Poison Center Program, rate per prescriptions
Oxymorphone IR
2012 2017 Opana ER
References: 10 pt. 20 Opana ER: Effects of Policy on Behavior and Trends Treatment Center Programs, rate per population
All Oxymorphone
Oxymorphone IR
2012 2017 Opana ER
References: 10 pt. 21 Opana ER: Effects of Policy on Behavior and Trends Treatment Center Programs, rate per prescriptions
Oxymorphone IR
2012 2017
Opana ER
References: 10 pt. 22 Opana ER: Effects of Policy on Behavior and Trends Drug Diversion Program, rate per population
All Oxymorphone
Opana ER 2012 2017
Oxymorphone IR
References: 10 pt. 23 Opana ER: Effects of Policy on Behavior and Trends Drug Diversion Program, rate per prescriptions
2012 2017
Oxymorphone IR
Opana ER
References: 10 pt. 24 Opana ER: Effects of Policy on Behavior and Trends Did injection behavior change?
References: 10 pt. 25 Opana ER: Effects of Policy on Behavior and Trends Did injection behavior change?
References: 10 pt. 26 Opana ER: Effects of Policy on Behavior and Trends Did injection behavior change? NMURx data
700000
600000 573092
500000 497964
400000
300000
200000 185358
106705 100000
Number of Adults in US 0 Total Oral Inhalation Injection
Route of Nonmedical Use
References: 10 pt. 27 Stimulants
• Used as single substance or polysubstance • Pharmaceutical ”speedball” effect • Highest rates in teenage and young adult population • Rates of intentional abuse stable, but diversion increasing
References: 9 pt. 28 Stimulants, RADARS Poison Centers
0.14
0.12
0.1
0.08
Methylphenidate
0.06 Amphetamine per 100,000 population
0.04
0.02
0 20073 20081 20083 20091 20093 20101 20103 20111 20113 20121 20123 20131 20133 20141 20143 20151 20153 20161 20163 20171 20173
References: RADARS PC 3Q2017, intentional abuse cases 29 Stimulants, RADARS Drug Diversion
0.4
0.35
0.3
0.25
0.2 Methylphenidate
Amphetamine
per 100,000 population 0.15
0.1
0.05
0 20073 20081 20083 20091 20093 20101 20103 20111 20113 20121 20123 20131 20133 20141 20143 20151 20153 20161 20163 20171 20173
References: 9 pt. 30 Prescription Stimulants: Prevalence of Nonmedical Use NMURx data
2.5
2.08 2
1.57 1.5
1
0.5 0.32 0.17 0.16 Prevalence Nonmedical Prevalence of Use 0 Total Amphetamine Atomextine Methylphenidate Modafinil
Route of Nonmedical Use
References: 10 pt. 31 Prescription Stimulants: Routes of Nonmedical Use NMURx data
90 85.1 80 70 60 50 40
Users 30 24.5 20.3 21.6 20 12.1 10 0 Proportion Nonmedical of Past Year
Route of Nonmedical Use
References: 10 pt. 32 Prescription Stimulants: Routes of Nonmedical Use NMURx data
100 90 87.8 83.3 80 70 63.1 60 Swallowed 50.2 50 Crushed/Chewed 40 37.9 32.9 Dissolved in Mouth Users 31.1 30 28.5 23.5 22.9 Inhaled 20 18.6 Injected 10 6.8 0
Proportion Nonmedical of Past Year Amphetamine Atomoxetine Methylphenidate Modafinil
Route of Nonmedical Use
References: 10 pt. 33 Conclusions
• ADF preparations do appear to decrease overall abuse – Biggest impact likely in those who are do not yet have severe opioid use disorder
• ADF preparations may impact route of abuse – Transition from IN to IV seen with oxymorphone
• Oxymorphone as a molecule lends itself to dangerous behaviors – Low oral bioavailablity, high intravenous potency – Sharing behaviors are common
References: 10 pt. 34 Conclusions and Discussion
• Rising prescription stimulant nonmedical use, abuse, diversion – Approx 5 million adults in US currently nonmedically use – Potential for early warning of issues to come
• Trajectories of stimulant use poorly understood – Will the balloon apply?
• Non-oral routes of stimulant abuse suggest potential for ADF utility – Will need to address both inhalation and injection – Beware unintended consequences
References: 10 pt. 35
Questions?
References: 10 pt.