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2017 ASHP MIDYEAR

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Educational Affairs
The Effectiveness and Safety of Various Abuse Deterrent Formulations of Oxycodone: A Systematic Review

by Alexander Heinz, PharmD Candidate, Roosevelt University College of Pharmacy; Julia Gilbert, PharmD Candidate, Roosevelt University College of Pharmacy; Gerald Cavanagh, PharmD Candidate, Roosevelt University College of Pharmacy; Abby A. Kahaleh, BPharm, MS, PhD, MPH, Associate Professor, Roosevelt University College of Pharmacy

Abstract 

Introduction:  Oxycodone is an opioid analgesic medication with a high risk for abuse.  This systematic review examined and compared the effect of various opioid-deterrent formulations of oxycodone on their ability to reduce opioid abuse.  Three types of abuse deterrent formulations (ADF) were studied: Technology-Based ADF’s, Opioid Antagonist ADF’s, and Aversive Excipient ADF’s. 

Methods:  Twelve randomized controlled trials that were published in English, conducted in North America within the past 5 years, and studied abuse deterrent formulations of oxycodone were included. Search methods for identification of studies were conducted through Pubmed and Cochrane Central Register of Controlled Trials (CENTRAL). The primary outcome was the effect of ADFs on oxycodone formulation manipulation and opioid abuse trends in  patients prescribed ADFs. The secondary outcomes were adverse events, quality of life, adherence (primarily being used as prescribed), and patient experience of euphoria. All reviewers performed all data abstraction and quality assessment individually. 

Results: Technology- based formulations were shown to be both effective in preventing opioid abuse and had a much lower incidence of adverse effects. 

Conclusion:  Although educating patients remains the most important step in reducing the epidemic of opioid abuse and overdose, studying additional ways to deter and reduce abuse can be extremely helpful in furthering the abuse potential.
  
Background 

Description of the problem 
Abuse of opioid analgesics is a major problem that has increased substantially in the United States throughout the past decade. In 2015, the total opiate-related overdose deaths was 33,091, which is nearly four-times the death rate in 1999.1 Opioid abuse is contributed to a reduced quality of life and an increased risk of death from overdose. Opioids are primarily prescribed for pain management.  However, they are easily accessible without a prescription. 
 
Patient experience, resources, education, access, and drug properties are among the factors that influence substance abuse.1 Opioid analgesics are a treatment option for moderate to severe pain that are prescribed to millions of patients annually. Although opioids can be abused through oral ingestion, the frequency of abuse by injection or inhalation increases as the duration and severity of abuse increases.2  Figure 1 illustrates the contributing factors to opioid abuse.

There is a critical need to reduce the abuse potential of opioid medications. Studies indicate that abuse with prescription opioids is a strong risk factor for heroin use.3,4 The incidence of heroin users is 19 times higher among those who use opioids for nonmedical reasons than those who report medical use.3 Another study found that 50% of persons ages 18 to 33 years who had recently began using heroin reported having abused opioids in the past.4
Figure 1: Contributing Factors to Opioid Abuse (2)




Description of the intervention
Research over the past decade has extensively examined drug structures to address the emerging opioid pandemic. Opioid analgesics with abuse-deterrent properties can help prevent abuse via various routes of administration that require cutting, crushing, or other ways of manipulating the formulations. There are three methods utilized to create abuse-deterrent formulations (ADFs) are described below: 
  1. Technology-Based ADF’s: One category of abuse deterrent formulations is technology-based. These formulations use proprietary manufacturing that utilizes unique polymers, inactive beads, and excipients to maintain the original pharmacokinetic properties or “gel” upon crushing or dissolving, which prevents abuse in all routes of administration except the oral route.1

  2. Opioid Antagonist ADF’s Another category utilized is the addition of opioid antagonists, either naloxone or naltrexone to the formulation. Opioid antagonists compete and displace opioids at opioid receptor sites and can be formulated in dosage forms to release when a medication in inappropriately utilized, such as crushing, or with a route of administration that favors the opioid over the antagonist.2

  3. Aversive Excipients ADF’s The third category of abuse deterrent formulations consists of opioids with a particular aversive excipient, such as niacin.3 This excipient gives the medication an unpleasant, unwanted side effect when used in excess and therefore, helps prevent abuse with the formulation.
Objectives
The primary objective of this study was to review the evidence for the safety and effectiveness of abuse deterrent formulations (ADF) of oxycodone. The secondary objective was to evaluate the potential of the ADF to prevent opioid abuse in American adults.

Methods
A systematic review method was utilized to conduct this research. The studies included in the systematic review were randomized controlled trials in adult participants who have a history of prescription and/or nonprescription opioid use. The interventions included the administration of various abuse deterrent oxycodone formulations compared to placebo and current non-abuse deterrent formulations. 

The primary outcome was the effect of ADFs on oxycodone formulation manipulation and opioid abuse trends in patients prescribed ADFs. The secondary outcomes were adverse events, quality of life, adherence (primarily being used as prescribed), and patient experience of euphoria. Search methods for identification of studies were conducted through Pubmed and Cochrane Central Register of Controlled Trials (CENTRAL). All reviewers performed all data abstraction and quality assessment individually.

The inclusion criteria for the systematic review was inclusion of the terms “oxycodone,” “abuse deterrent,” “opioid,” “abuse resistant,” and “randomized.” The studies were all published in English and conducted in North America. Exclusion criteria were studies not published in English, conducted outside of North America, not relevant to the safety and efficacy of abuse deterrent formulations, and not evaluating oxycodone.

Data Collection
Three review authors independently assessed all the titles and abstracts identified as a result of the search strategy. Twenty-seven articles were collected on the search, 12 fit inclusion/exclusion criteria. Thirteen articles were not relevant to the study subject, as they were found to later fit the exclusion criteria and 2 publications were found to be published presentations. Three types of ADFs were evaluated in the data collected: opioid antagonist formulations, technology-based formulations, and aversive excipient-based formulations.

The three abuse deterrent formulation categories were ranked on an efficacy scale of 1-to-3, with 1 meaning highly effective and 3 meaning least effective. The efficacy was evaluated based on patient reported feeling, adverse events, and potential adherence. Of the studies included, nine were categorized as technology-based formulations, two as opioid antagonist formulations, and one as aversive excipient-based formulations. The previous drug effects were compared with adverse events to indicate how effective treatments were. In the rare occasions that the researchers disagreed on the ranking of the articles, they discussed the discrepancies until a consensus was reached.

Results
The following three tables describe the articles that were included in the systematic review. All three categories had similar efficacy results and were shown to prevent abuse. However, their safety profiles and types of abuse they prevented differed slightly.
Table 1. Technology-Based ADFs (5-13) (view PDF)
Technology-based formulations such as DETERx (Table 1) are both safe and effective. These formulations have been found to statistically significantly prevent opioid abuse. When these medications are crushed, they have been found to maintain similar pharmacokinetics as when intact, thus lowering the likelihood of illicit use by crushing. This formulation also allows these medications to be available for patients who have trouble swallowing or require a G-tube for medication administration. These medications were also not found to have significantly different adverse effects than immediate release or extended release oxycodone.
Table 2. Opioid Antagonist ADFs (14,15) (view PDF)
Medications formulated with opioid antagonists such as naloxone or naltrexone (Table 2) have been found to be relatively effective in preventing abuse, particularly by non-oral routes such as intravenous injection and insufflation. These formulations have similar safety effects as current FDA-approved opioid analgesics.  However, adverse effects are common when they are crushed or chewed. This limits the use of these medications in patients who have trouble swallowing or require the use of a feeding tube for medication administration.   

Table 3. Aversive Excipient-Based ADFs (16) (view PDF)
Aversive excipient formulations such as the use of niacin (Table 3) are effective in preventing opioid abuse.  However, they have a high incidence of adverse effects in all patients. Studies showed that 98-100% of patients experienced treatment emergent adverse effects.  

Authors’ Conclusions, Discussion and Future Research 
In summary, technology-based formulations of oxycodone were shown to be effective in preventing opioid abuse and they have a much lower incidence of adverse effects compared to aversive excipient formulations of oxycodone. Opioid antagonists are effective in preventing abuse.  However, these formulations are more successful in preventing abuse via non-oral routes, such as intravenous or insufflation. Formulation technology prevents opioid abuse by oral route and non-oral routes of administration and offer a safety profile similar to currently approved opioid analgesics. These medications can also be given to patients who have difficulty swallowing or require medication administration via G-tube routes. 

By reducing the abuse potential from non-medical routes of administration, especially those seen with heroin use, rates of abuse may be reduced. Although educating patients remains the most important step in reducing the epidemic of opioid abuse and overdose, studying additional ways to deter and reduce abuse can be extremely helpful in furthering reducing the abuse potential.4  Figure 2 illustrates the efficacy ranking of the three categories of ADFs.
Figure 2: ADF Category Efficacy Ranking

  1. Technology-based formulations had the highest efficacy, safety, and overall ability to be used by patients. It can prevent opioid abuse by oral route and non-oral routes of administration and has a safety profile similar to currently approved opioid analgesics.
  2. Opioid antagonists are effective in preventing abuse, however, these are more successful in preventing abuse via non-oral routes such as intravenous or insufflation.
  3. Although oxycodone and niacin produced significant reduction in drug liking, the adverse event profile is a barrier to adherence.
At the time the study was conducted, the authors searched several national association websites to identify recommendations on ADFs and found that there was no consensus on the use of abuse deterrent formulations. The Centers for Disease Control and Prevention (CDC) did not currently have recommendations on abuse-deterrent formulations.17 The American Society of Health-System Pharmacists (ASHP) supported formulation development of abuse deterrent narcotics as one of a collection of strategies to address opioid abuse.18 The American Pharmacists Association (APhA) indicated that ADFs are a potential strategy to complement education programs.19  APhA encourages research into ADFs and encourages manufacturers to develop ADFs to combat opioid misuse and abuse.20  Future studies should focus on current recommendations and guidelines offered by national associations on opioid deterrent formulations.

References
  1. Wide-ranging online data for epidemiologic research (WONDER). Centers for Disease Control and Prevention. http://wonder.cdc.gov. Accessed July 2, 2016.
  2. Facts & Comparisons. St. Louis, MO: Wolters Kluwer Health, Inc; 2016. https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5545901. Accessed July 2, 2016.
  3. Kosten TR, Haile CN. Opioid-related disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, eds. Harrison's principles of internal medicine, 19e. New York, NY: McGraw-Hill Education; 2015. accesspharmacy.mhmedical.com/content.aspx?aid=1120820647.
  4. Siegal HA, Carlson RG, Kenne DR, Swora MG. Probable relationship between opioid abuse and heroin use. Am Fam Physician. 2003;67(5):942. 
  5. Gudin J, Levy-Cooperman N, Kopecky EA, Fleming AB. Comparing the effect of tampering on the oral pharmacokinetic profiles of two extended-release oxycodone formulations with abuse-deterrent properties. Pain Med. 2015;16(11):2142-2151. 
  6. Webster LR, Kopecky EA, Smith MD, Fleming AB. A randomized, double-blind, double-dummy study to evaluate the intranasal human abuse potential and pharmacokinetics of a novel extended-release abuse-deterrent formulation of oxycodone. Pain Med. 2016;17(6):1112-1130.
  7. Kopecky EA, Fleming AB, O’Connor M, Varanasi RK. Oral human abuse potential of oxycodone DETERx: An abuse-deterrent, extended-release formulation in recreational opioid users.  J Clin Pharmacol. 2017;57(4):500-12.
  8. Friedmann N, Klutzaritz V, Webster L. Long-term safety of Remoxy®. Pain Med. 2011;12(5):755-760. 
  9. Friedmann N, Klutzaritz V, Webster L. Efficacy and safety of an extended-release oxycodone (remoxy) formulation in patients with moderate to severe osteoarthritic pain. J Opioid Manag. 2011;7(3):193-202.
  10. Roland CL, Setnik B, Cleveland JM, Brown DA. Clinical outcomes during opioid titration following initiation with or conversion to Remoxy®, an extended-release formulation of oxycodone. Postgrad Med. 2011;123(4):148-159. 
  11. Morton TL, Devarakonda K, Kostenbader K, Montgomery J, Barrett T, Webster L. Correlation of subjective effects with systemic opioid exposure from fixed-dose combinations of oxycodone/acetaminophen in recreational users of prescription drugs. Pain Med. 2015;17(3):539-550.
  12. Cicero TJ, Ellis MS, Kasper ZA. A tale of 2 ADFs: Differences in the effectiveness of abuse-deterrent formulations of oxymorphone and oxycodone extended-release drugs. Pain. 2016;157(6):1232-1238.
  13. Katz N, Kopecky EA, O'Connor M, Brown RH, Fleming AB. A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain. Pain. 2015;156(12):2458-2467. 
  14. Colucci SV, Perrino PJ, Shram M, Bartlett C, Wang Y, Harris SC. Abuse potential of intravenous oxycodone/naloxone solution in nondependent recreational drug users. Clin Drug Investig. 2014;34(6):421-429. 
  15. Setnik B, Bramson C, Bass A, et al. Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users. J Clin Pharmacol. 2015;55(12):1351-1361. 
  16. Webster LR, Rolleri RL, Pixton GC, Sommerville KW. Randomized, double-blind, placebo-controlled and active-controlled study to assess the relative abuse potential of oxycodone HCl-niacin tablets compared with oxycodone alone in nondependent, recreational opioid users. Subst Abuse and Rehabil. 2012;3:101-113. 
  17. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315(15):1624-1645. 
  18. Topoleski CJ. RE: FDA-2014-N-1359; Development and regulation of abuse-deterrent formulations of opioid medications; public meeting. American Society of Health-System Pharmacists. 2015. https://www.ashp.org/-/media/assets/advocacy-issues/docs/ashp-comments-on-fda-development-and-regulation-of-abuse-deterrent-formulations-of-opioids.ashx?la=en.  Accessed July 2. 2016.  
  19. FDA issues draft guidelines for generic abuse-deterrent opioids. American Pharmacists Association Web site. https://www.pharmacist.com/fda-issues-draft-guidelines-generic-abuse-deterrent-opioids. Updated 2016. Accessed July 2, 2016.
  20. Prevention and intervention strategies to decrease misuse of prescription pain medication. American Public Health Association Web site. https://www.apha.org/policies-and-advocacy/public-health-policy-statements/policy-database/2015/12/08/15/11/prevention-and-intervention-strategies-to-decrease-misuse-of-prescription-pain-medication. Accessed July 2, 2016.  
  
http://www.ichpnet.org/publications_resources/keeposted/articles/2017/Vol_43-09/43-09-ed_affairs.pdf

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