Prescription Opioid Abuse: Abuse-Deterrent Opioids as Part of a Multipronged Approach. For Pfizer Use Only

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1 Prescription Opioid Abuse: Abuse-Deterrent Opioids as Part of a Multipronged Approach

2 Table of Contents Chronic Pain and Prescription Opioids Source of Prescription Opioids and Patient Risk Assessment Routes of Prescription Opioid Abuse & Adverse Health Outcomes FDA Evaluation and Labeling of Abuse-Deterrent Opioids (ADOs) The Potential Role of Abuse-Deterrent Opioids (ADOs) in Helping to Deter Opioid Abuse 2

3 Chronic Pain: A Serious Public Health Issue Chronic pain is a major concern for individuals, families, and society, with an increasing prevalence, cost, and impact on quality of life Millions of Americans are affected by chronic pain 1 Estimated annual cost of $ billion 2 While the use of prescription opioids has been linked to abuse, misuse, diversion, these medications still serve as an efficacious treatment option for patients in the management of chronic pain 3-5 However, clinical guidelines for chronic pain recommend that opioids be considered only after an adequate trial of non-opioid options IOM. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; Gaskin DJ, Richard P. J Pain. 2012;13(8): Moore RA, McQuay HJ, Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic nonmalignant pain: systematic review of randomized trials of oral opioids. Arthr ResTher. 2005;7(5):R Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic noncancer pain: A systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage. 2008;35: Fine, PG. Opioid therapy as a component of chronic pain management: Pain experts weigh in on key principles to optimize treatment. Topics in Pain Management. 2008;23(10):1-8.) 5. Utah Department of Health. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain. Salt Lake City, UT: Utah Dept of Health; Manchikanti L et al. Pain Physician. 2012;15(3 suppl):s67-s Chou R et al. J Pain. 2009;10(2): US Department of Veterans Affairs, US Department of Defense. VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain. Version 2.0. Washington, DC: US Dept of Veterans Affairs, US Dept of Defense; Washington State Agency Medical Directors Group (AMDG). Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain: An Educational Aid to Improve Care and Safety With Opioid Therapy Update. Olympia, WA: Washington State 3 Agency Medical Directors Group; 2010

4 Opioids Are Frequently Used to Treat Pain, Even Though Guidelines Recommend Use Only After Other Therapies Opioid Prescriptions Dispensed by Retail Pharmacies (US, ) No. Prescriptions (in millions) Adapted f rom Volkow ND. America s Addiction to Opioids: Heroin and Prescription Drug Abuse. NIDA Web site. ities/testimony-to-congress/2015/americas-addiction-to-opioids-heroin-prescription-drug-abuse. Published May 14, Accessed February 9,

5 The Increase in Opioid Prescriptions Is Associated With Serious Health Consequences Prescription opioid overdose deaths quadrupled from ; emergency department (ED) visits increased by 183% from , , ,000 No. Prescription Opioid-related Deaths 15,000 12,000 9,000 6,000 3,000 4,030 Overdose Deaths 172,738 ED Visits 16, , , , ,000 0 No. Opioid-related ED Visits 53% to 80% of people who die from prescription opioid overdoses have a history of chronic pain CDC. MMWR Morb Mortal Wkly Rep. 2013;62(12): SAMHSA. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: SAMHSA; HHS Publication No. (SMA) , DAWN Series D Lanier WA et al. Presented at: Annual Epidemic Intelligence Service Conference; April 19-23, 2010; Atlanta, GA. 4. Paulozzi LJ et al. Addiction. 2009;104(9): HHS. Addressing Prescription Drug Abuse in the United States. Washington, DC: HHS; September Accessed July 10,

6 Opioid Deaths Are Only Part of the Story 10 The CDC estimates that for every opioid overdose death in 2010, there were: Abuse treatment admissions* 26 ED visits for misuse/abuse 108 who abused/were dependent Note: Compiled by CDC from separate 2010 databases *Treatment admissions are for primary use of opioids: Treatment Exposure Data Set. ED visits: Drug Abuse Warning Network (DAWN) Abuse/dependence and nonmedical use: National Survey on Drug Use and Health. 733 past-year nonmedical users CDC. Primary Care and Public Health Initiative. Prescription Drug Abuse and Overdose: Public Health Perspective. October 24, ww.cdc.gov/primarycare/materials/opoidabuse/docs/pda-phperspective-508.ppt. Accessed February 9,

7 Prescription Opioid Abuse: CDC Statistics Today, at least half of all U.S. opioid overdose deaths involve a prescription opioid. 1 Overdose deaths involving prescription opioids have quadrupled since From 1999 to 2014, more than 165,000 people have died in the U.S. from overdoses related to prescription opioids. 1 In 2014, more than 14,000 people died from overdoses involving prescription opioids. 1 In 2014, almost 2 million Americans abused or were dependent on prescription opioids. 2 1 CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; Available at onder.cdc.gov. 2 Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health,

8 The Increase in Opioid Prescriptions Has Been Associated With a Dramatic Rise in Overdose Deaths Age-Adjusted Opioid Overdose Death Rates 1 * Deaths per 100,000 Population 10 Drug overdose deaths involving opioids (total, including heroin) Natural and semisynthetic opioids (eg, morphine, oxycodone, hydrocodone) Synthetic opioids excluding methadone (eg, fentanyl, tramadol) 8 Methadone Heroin *Age-adjusted death rates calculated by applying age-specific death rates to the 2000 US standard population age distribution. Overdose deaths involving opioids identified using ICD-10 codes. Deaths might involve >1 drug. 1. Rudd RA et al. MMWR Morb Mortal Wkly Rep. 2016;64(50-51): Lanier WA et al. Presented at: Annual Epidemic Intelligence Service Conference; April 19-23, 2010; Atlanta, GA. 3. Paulozzi LJ et al. Addiction. 2009;104(9):

9 Source of Prescription Opioids and Patient Risk Assessment

10 Understanding the Terminology Term Misuse 1 Abuse 1 Diversion 2 Definition Intentional therapeutic use of a drug product in an inappropriate way Specifically excludes the definition of abuse Intentional, nontherapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect Intentional removal of a medication from legitimate distribution and dispensing channels Also involves the sharing or purchasing of drugs between family and friends, or individual theft from family and friends 1. FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; Webster L et al. J Opioid Manag. 2011;7(3): Webster L et al. J Opioid Manag. 2011;7(3):

11 According to a 2013 Survey, About 70% of Nonmedical Users of Prescription Pain Relievers Get Them From Friends or Relatives Sources Where Users Obtained Pain Relievers >1 Doctor, 2.6% Original Sources of Pain Relievers Obtained Free From Friend or Relative Other,* 4.3% Internet, 0.1% Drug Dealer or Stranger, 4.3% 1 Doctor, 21.2% Bought/Took From Friend or Relative, 14.6% Free From Friend or Relative, 53.0% 1 Doctor, 83.8% Other, 1.2%* >1 Doctor, 3.3% Free From Other Friend or Relative, 5.1% Bought/Took From Other Friend or Relative, 4.9% Drug Dealer or Stranger, 1.4% Internet, 0.3% Note: Due to rounding, percentages do not add up to 100%. *Other includes: Wrote Fake Prescription, Stole from Doctor s Office/Clinic/Hospital/Pharmacy, and Some Other Way. SAMHSA. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-48, HHS Publication No. (SMA) Rockville, MD: SAMHSA; September

12 Identifying Patients at High Risk for Opioid Misuse and Abuse Is Extremely Challenging 100% N=367 patients confirmed as at high risk for opioid misuse and abuse* Based on a Study of Primary Care Physicians PCP assignment of risk among these confirmed high-risk patients 20% Incorrectly identified as at low risk (n=73) 5% 74% Incorrectly identified as at moderate risk (n=275) Only 5% correctly identified as at high risk (n=18) Open-label, nonrandomized, noncomparative study in which PCPs were asked to identify patients at high risk for opioid misuse and abuse. *Confirmed using SOAPP -R (Screener and Opioid Assessment for Patients With Pain-Revised, a patient-completed 24-item questionnaire to identify risk for future misuse and/or abuse of opioids). For this study, SOAPP -R score 0-9 = low risk; = moderate risk; and 22 = high risk. Patients at high risk for opioid abuse (SOAPP -R score 22 at baseline). Due to rounding, percentages do not add up to 100%, and n s do not = Brow n J et al. J Opioid Manag. 2011;7(6):

13 Routes of Prescription Opioid Abuse & Adverse Health Outcomes

14 Prescription Opioids Can Be Misused and Abused by Different Routes Swallowed whole or chewed Examples of Abuse Methods 1,3 Crushed then swallowed, snorted or smoked Crushed, dissolved, then injected The most common form of abuse is swallowing a number of intact capsules or tablets to achieve a feeling of euphoria 1 Product manipulated in pursuit of more intense high resulting from rapid increase in opioid in the blood 2 Methods vary among products, based on pharmacokinetic properties, bioavailability via different routes, ease of tampering, nature of euphoria, and presence of dangerous excipients 2 1. FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; Katz N et al. Am J Drug Alcohol Abuse. 2011;37(4): Vietri J et al. Pain Med. 2014;15(12):

15 In a 2012 Survey, Half of People Abusing Prescription Opioids Reported Product Manipulation 1 Abuse Methods Involving Manipulation of the Product 2 Swallowed whole or chewed Crushed then swallowed, snorted or smoked Crushed, dissolved, then injected The most common form of abuse is swallowing a number of intact capsules or tablets to achieve a feeling of euphoria 1 Product manipulation is more common with extended-release opioids, due to a higher drug content, than with immediate-release opioids 3 1. Vietri J et al. Pain Med. 2014;15(12): FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; Katz N et al. Am J Drug Alcohol Abuse. 2011;37(4):

16 ER Opioids Are Tampered With for Purposes of Misuse and Abuse Abuse of ER Formulations of Prescription Opioid Medications by Route of Administration (June 1, 2009 to August 8, 2010*) 80 Percentage of Persons Abusing ER Oxycodone ER Oxymorphone ER Morphine Oral Snorting Smoking Injecting *Prior to introduction of reformulated ER oxycodone and ER oxymorphone. Note: Percentages for each drug do not add up to 100% because respondents could report multiple routes of administration. Adapted from Butler S et al. J Pain. 2013;14(4): Used with permission. 16

17 In One Study, Patients Admitted to an Abuse Treatment Center Reported Progression From Oral Ingestion to Snorting/Injection Initial Route of Administration (n = 112/187) Injecting, <1% Route of Administration at Treatment Admission (n = 133/187) Snorting, 16% Mean duration of prescription opioid use: 19.2 months* Oral, 14% Injecting, 26% Oral, 83% Snorting, 62% Study looked at route of administration of controlled-release oxycodone at initiation of use/misuse and admission to an addictiontreatment center (October 2000 to March 2002; N = 187). *Average time between first use/misuse and addiction-treatment admission. Hays LR. J Addict Dis. 2004;23(4):

18 Non-oral (vs Oral) Misuse and Abuse Is Associated With Up to a Twofold Higher Risk for Severe Health Consequences Proportion of Cases of Misuse/Abuse Inhaling, 5% Injecting, 3% Percentage of Cases Leading to Major Effect* or Death 16.5% Oral, 92% 8.6% 10.2% Oral Inhaling Injecting *Symptoms that were life-threatening or resulted in significant residual disability or disfigurement. Katz N et al. Am J Drug Alcohol Abuse. 2011;37(4):

19 FDA Evaluation and Labeling of Abuse-Deterrent Opioids (ADOs)

20 FDA Considers Development of Abuse-Deterrent Opioids To Be a High Public Health Priority Abuse-deterrent properties are defined as those shown to meaningfully deter abuse, even if they do not fully prevent it Abuse-deterrent technologies to date are intended to make: manipulation (crushing, chewing, dissolving, extracting) of the opioid more difficult, or the effect of the manipulated opioid less attractive or rewarding FDA guidance describes the studies to be conducted to demonstrate a given formulation has abuse-deterrent properties, how studies will be evaluated, and what labeling claims may be approved based on results. FDA remains supportive of ADO development. 2 FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; Califf, Robert M., Janet Woodcock, and Stephen Ostroff. "A Proactive Response to Prescription Opioid Abuse." New England Journal of Medicine (2016). FDA Guidance Issued April One potentially important step towards the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. FDA considers the development of these products a high public health priority. FDA Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling (April 2015) 20

21 Potential Abuse-Deterrent Opioid Product Categories (FDA Defined) Technology Physical/chemical barrier Agonist/antagonist combination Aversion Delivery system New molecular entities and prodrugs Combination Novel approaches Description Physical barriers can prevent/deter manipulation Chemical barriers can resist extraction of the opioid Physical and chemical barriers can change the physical form of an oral drug, rendering it less amenable to abuse Antagonist added to interfere with, reduce, or defeat euphoria associated with abuse Substances can be added to the product to produce an unpleasant effect if the dosage form is manipulated or is used at a higher dosage than directed Drug-release design or method of drug delivery (eg, depot injectable) offers resistance to abuse Properties could include the need for enzymatic activation, different receptorbinding profiles, slower penetration into the CNS, or other novel effects Prodrugs with abuse-deterrent properties could provide a chemical barrier to the in vitro conversion to the parent opioid, which may deter abuse of the parent opioid Two or more of the above methods Novel approaches or technologies not captured in the previous categories FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

22 2015 FDA Guidance: Premarketing and Postmarketing Studies of Abuse Deterrence Premarketing studies Category 1: Laboratory-based in vitro manipulation and extraction Category 2: Pharmacokinetic Purpose: evaluate in vitro the ease with which the abuse-deterrent properties can be defeated or compromised Purpose: understand the in vivo properties of the formulation by comparing PK profiles Category 3: Clinical abuse potential* Purpose: measure and collect subjective response data predictive of the likelihood of product abuse Category 4: Postmarketing studies Purpose: determine whether the marketing of a product with abuse-deterrent properties results in meaningful reductions in abuse *Also known as human abuse liability (HAL) studies. FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

23 Category 1: Laboratory-Based in vitro Manipulation and Extraction Studies Purpose: evaluate in vitro the ease with which the abuse-deterrent properties can be defeated or compromised Designed with knowledge of properties of formulation and abuse methods Should fully characterize abuse-deterrent properties and effort to defeat them Assess simple and sophisticated mechanical and chemical ways to manipulate: Defeating or compromising the controlled release of an opioid from an ER formulation Preparing an IR formulation for alternative routes of administration Separating opioid antagonist, if present, from opioid agonist Compare to appropriate non-ado formulations FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

24 Hypothetical Example of a Category 1 Extractability and Syringeability Study Extractability Amount of drug from new formulation and comparator that can be extracted after soaking for increasing lengths of time in various liquids Syringeability Whether the dissolved product can be drawn up into a syringe, based on the temperature, plunger speed, and needle size ADO Non-ADO ADO Non-ADO Cola 1% 91% Hot tea 6% 60% Vinegar 0% 90% Baking soda solution 1% 74% 18 gauge YES YES 21 gauge NO YES 25 gauge NO YES Drug composition may vary based on technology. Data for illustrative purposes only. 24

25 Category 2: Pharmacokinetic Studies Purpose: understand the in vivo properties of the formulation by comparing PK profiles Plasma Drug Concentration (ng/ml) Crushed ER Opioid (non-abuse-deterrent) Crushed ER Opioid (abuse deterrent) Chewed ER Opioid (abuse deterrent) Intact ER Opioid (abuse deterrent) Time (hours) Graph for illustrative purposes only. The rate of rise of drug concentration should be assessed when possible, because it is thought to contribute to differential abuse potential among drugs, formulations, and routes of administration. FDA Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling (April 2015) FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

26 Category 3: Clinical Abuse Potential* Studies Purpose: measure and collect subjective response data predictive of the likelihood of product abuse 1 Pharmacology assessments that provide unique information relevant to CNS-active drugs 1 Compare subjective responses to drug liking, drug high, and willingness to take drug again for each active agent and placebo 2 Study design principles 2 : Randomized, double-blind, placebo-controlled, positive comparator controlled, crossover Enrollment of an appropriate abusing population Prequalification phase Relevant routes of administration Preparation of samples with consideration of blinding Potential use of a proxy solution for IV injection Strong disliking Visual Analog Scale Do you like the drug effect that you are feeling now? Neither like nor dislike Strong liking *Also known as human abuse liability (HAL) studies. 1. FDA. Guidance for Industry: Assessment of Abuse Potential of Drugs [draft guidance]. Rockville, MD: FDA; January FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

27 Understanding Clinical Abuse Potential Study Data Strong drug liking E max (maximal response) Neutral Placebo Crushed non-ado Intact ADO Strong drug disliking Crushed ADO Time Graph for illustrative purposes only. FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

28 Category 4: Postmarketing Studies Purpose: determine whether the marketing of a product with abuse-deterrent properties results in meaningful reductions in abuse, misuse, and related adverse clinical outcomes Examples of abuse-related clinical outcomes Addiction data Overdoses/poisonings Deaths Given the changing landscape, a numerical threshold cannot define what would be considered a meaningful reduction. FDA Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling (April 2015) FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

29 Where to Find Abuse-Deterrent Data and Labeling Refer to prescribing information section 9: DRUG ABUSE AND DEPENDENCE Includes descriptions and data regarding the specific product s abusedeterrent studies (will vary by product) If such information does not appear in a product s labeling under section 9, that product is not an ADO, by FDA standards The pharmacokinetic data demonstrate that crushing [Tradename] results in the simultaneous release and rapid absorption of opioid and antagonist. These data along with the results from oral and intranasal clinical abuse potential studies and a clinical abuse potential study of intravenous opioid and antagonist to simulate crushed [Tradename] indicate that [Tradename] has properties that are expected to deter abuse via the oral, intranasal, and intravenous routes. However, abuse of [Tradename] by these routes is still possible. Example of potential labeling for an ADO with category 2 and 3 data FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA;

30 The Potential Role of Abuse-Deterrent Opioids in Helping to Deter Opioid Abuse

31 Progression of Opioid Abuse: A Multipronged Approach in Addressing Abuse Initial Opioid Treatment Suspected Abuse or Misuse Addiction Overdose Potential Strategies Patient Agreements Patient Education Safe storage & Disposal PDMP 1 ADOs Urine Tests Pill limits Medication- Assisted Treatment Programs Naloxone Addiction Counseling 1 Dow ell, Deborah, Tamara M. Haegerich, and Roger Chou. "CDC guideline for prescribing opioids for chronic pain United States, 2016." JAMA (2016). 2 Dart, Richard C., et al. Trends in opioid analgesic abuse and mortality in the United States. New England Journal of Medicine (2015): Coplan, Paul M., et al. Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended release oxycodone 31 w ith abuse deterrent characteristics. Pharmacoepidemiology and drug safety (2013):

32 Epidemiological Data From Actual Use Indicate That Abuse-Deterrent ER Oxycodone Reduced Its Abuse Among Patients Reporting Abuse of Prescription Opioids, Abuse* of ER Oxycodone Decreased 50% After Introduction of its Reformulation 25 Past-30-Day Abuse, % % June 1, 2009 August 8, % reduction in abuse of opioid (P<.0001) 12.1% August 9, 2010 March 31, Before Reformulation (n=2894/12,211) After Reformulation (n=1705/14,091) * In past 30 days. Using the Addiction Severity Index-Multimedia Version (ASI-MV), 140,496 subjects were assessed for substance use problems at 357 US centers, which were part of the NAVIPPRO surveillance system. Data collected during a 34-month period ( 11 quarters) from June 1, 2009 to March 31, Among total sample, 18.8% reported abuse of any prescription opioid. Butler S et al. J Pain. 2013;14(4):

33 Impact of a Tamper Resistant Opioid Formulation: NAVIPPRO Data Shows a Change in Frequency of Abuse The average number of days in the past 30 days abusing ER oxycodone and comparators before and after the introduction of ADO oxycodone ER Original Oxycodone ER (Days) Before period (6/09-8/8/10) After Reformulated ADO Oxycodone ER (Days) (8/9/12-3/31/12) Pre-Post Percentage Change ER oxycodone %* ER oxymorphone %* ER morphine % N=140,496 individuals assessed for substance abuse treatment at 357 U.S. centers *p<.0001, p= Butler, et al J. Pain, Vol.14, No.4 (April),

34 Summary of Observed Changes in ER Oxycodone Upon Introduction of ADO ER Oxycodone Observation Data Source Timeframe Change Self reported abuse Self reported abuse Self reported abuse Drug abuse related poison center exposures Drug diversion rates Drug price law enforcement NAVIPPRO Drug Treatment 1 1 year prior, 18 months post -41% (P<0.0001) RADARS Opioid 5.5 years prior, 3 years post Decreased Treatment Program 2 (% not reported) RADARS Survey of Key Informants years prior, 3 years post Decreased (% not reported) RADARS Poison 1 year prior, 2 years post -36% Center Exposures 3 (P<0.001) RADARS Drug Diversion 4 RADARS Drug Diversion 4 2 years prior, 18 months post Time of switch to 1 year post Self reported street price RADARS StreetRX 5 Single time period comparison post switch -53% (P<0.001) -22% (P=0.002) -37% 1. Butler, et al J. Pain, Vol.14, No.4 (April), 2013, 2. Dart et al. NEJM, 372; 3, January 2015; Coplan et al Pharmacoepidemiology and Drug Safety 2013; 22: ; 4. Severtson et al., J Pain, Vol 14, No 10 (October), 2013: pp , 5. RADARS System Technical Report, Q1, Data from StreetRx 34

35 Prescription Opioid Abuse: Consider ADOs as part of a Multipronged Approach Opioid abuse is a growing epidemic, as shown in overdose deaths, and all patients are at risk 1,2 Those who abuse often obtain opioids from legitimate prescriptions 4 Oral overconsumption is most common; non-oral misuse and abuse has a higher rate of severe consequences 5 ADO technologies are intended to make product manipulation more difficult or the effect of the manipulated product less rewarding 3 Consider ADOs as part of a multipronged approach to responsible opioid prescribing 6 1. SAMHSA, CBHSQ. The DAWN Report: Highlights of the 2011 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: SAMHSA; February 22, Rudd RA et al. MMWR Morb Mortal Wkly Rep. 2016;64(50-51): FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; SAMHSA. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-48, HHS Publication o. (SMA) Rockville, MD: SAMHSA; September Katz N et al. Am J Drug Alcohol Abuse. 2011;37(4): Webster LR, Fine PG. J Pain. 2010;11(7):