Abuse-deterrent formulations (ADFs) of opioids have been in existence since the 1970s,Citation1 with abuse-deterrent mechanisms including physical barriers (eg, barriers to crushing), chemical additives such as opioid antagonists or irritants, and prodrugs that require conversion of the medication into their active forms in the gastrointestinal tract.Citation2 A recent systematic review and meta-analysisCitation3 found no difference between ADFs and non-ADFs in terms of efficacy or adverse events including nausea, vomiting, dizziness, headache, somnolence, constipation, and pruritus. Notably, the efficacy of ADFs in preventing abuse is not yet established, and therefore the authors could only comment on their “potential … to deter or resist some of the common forms of tampering associated with opioid misuse and abuse”. While Turk et alCitation2 have elucidated the complexity of producing high-quality research on the efficacy of ADFs to reduce opioid abuse, recent data are encouraging. For example, since Purdue Pharma’s (Stamford, CT, USA) voluntary reformulation of OxyContin® to an ADF in 2010, abuse of the medication has decreased significantly.Citation4–Citation6 As a specific example, National Poison Data System statistics indicated a 36% reduction in abuse exposure for OxyContin following ADF reformulation. Meanwhile, researchers for Purdue Pharma found an increase in abuse exposure for other single-entity oxycodone products and a 42% increase in abuse exposure for heroin during the same time frame.Citation7 Although OxyContin has been the most investigated abuse deterrent formulation, ADFs of other opioids have demonstrated promise in preliminary investigations.Citation8,Citation9
Data have indicated that despite being home to only 4.6% of the world’s population, the US consumes 80% of the world’s prescription opioid analgesics.Citation10 The overreliance of Americans on prescription opioid analgesics for chronic noncancer pain has brought into question the integrity of the nation’s pain care system, not just in the US,Citation11 but in the eyes of the international pain community.Citation12 After more than a decade of problems related to opioid use and misuse (eg, overprescription, fraudulent marketing,Citation13 diversion, abuse, overdose deathsCitation14), and denial of the iatrogenic complications of opioids,Citation15 various factions of government have initiated measures to control opioids, measures that have been referred to as the “war on opioids”. As is the case in any “war”, casualties abound. For instance, the collateral damage associated with reducing access to opioids in the US has been an increase in the abuse of other drugs, often black tar heroin, in people who previously had access to prescription opioids.Citation16 Although experts have called for the establishment of a “middle ground”,Citation17 such a balance has been elusive, especially in the US.
In the US, drugs are scheduled-based according to the Controlled Substance Act of 1970, which designates drugs into one of five schedules based upon medicinal value, harmfulness, and potential for abuse and addiction.Citation18 Schedule I drugs are those considered to have a high potential for abuse with no medicinal value, Schedule II drugs have a high potential for abuse with medicinal value, Schedule III designates drugs that have a lower potential for abuse than Schedule I and II drugs, Schedule IV drugs have a low potential for abuse, and Schedule V drugs are thought to have an abuse potential even lower than those designated as Schedule IV.Citation18 The vast majority of opioids prescribed orally for analgesia are classified as Schedule II drugs, with the exceptions being certain codeine compounds and hydrocodone compounds.Citation19 Due to a controversial 1971 decision by the US Food and Drug Administration (FDA), hydrocodone was given a “split” Schedule, with pure hydrocodone (which was unavailable in the US until October 2013) designated as a Schedule II and hydrocodone in combination with a nonopioid analgesic (hydrocodone combination drugs) assigned Schedule III status.Citation20 The problem with this designation is that there is no evidence that hydrocodone combination drugs are any less abusable than is pure hydrocodone. Accordingly, the FDA convened early in 2013 to consider upscheduling hydrocodone combination drugs from Schedule III to Schedule II. Critics of the potential upscheduling of hydrocodone combination drugs claim that, should this occur, patients and physicians will suffer great inconvenience (as Schedule II drugs require a hard copy prescription and cannot be automatically refilled), resulting in a deleterious impact on pain management.Citation21
The scheduling of opioid analgesics in the US does not take into account whether the medication is an ADF or a non-ADF. In fact, all ADFs currently available on the US market are classified as Schedule II drugs. We find this schema of scheduling to lack consistency with the purpose of the scheduling classification system. Presumably, the goal of classifying a drug as Schedule II versus Schedule III is to provide appropriate safety structures, thus creating an abuse deterrent system. Accordingly, one would expect that ADFs would be classified as Schedule II and non-ADFs as Schedule III. Despite efforts to improve risk mitigation within medical practices through opioid agreements, pill counts, urine drug testing, and prescription monitoring programs, the lethality of prescription opioid analgesics in the US has continued to increase, based upon the most recent available Centers for Disease Control data.Citation22 Prescription opioid abuse is not likely to simply “go away”, and the 16,000+ prescription opioid-related deaths that occur annually in the USCitation22 are not likely to decrease unless manufacturers and the FDA cooperate in an effort to make all prescription opioids available only as ADFs. Concern regarding the costs of ADFs has been voicedCitation23,Citation24 and indeed, the American health insurance industry has at times refused to provide coverage for these potentially life-preserving medications.Citation25 ADFs have been posited to have specific value in treating patients at high risk for prescription opioid abuse.Citation26,Citation27 However, Stanos et alCitation28 have opined that: “Limiting prescription of tamper-resistant opioid formulations to patients assessed to have an elevated risk of abuse may prove ineffective if these patients can obtain traditional prescription opioid formulations from another source.”
As opioid prescription increases in other developed and less developed nations as well,Citation29 problems with abuse, diversion, and overdoses are increasing in tandem.Citation30 The World Health Organization “ladder” for pain reliefCitation31 also does not take into account abuse-deterrence, and therefore an update to this international classification system should be considered. Indeed, the continued relative ease of access to non-ADFs is a serious international concern that merits examination (and appropriate revision) of existing systems of classification in all nations. This may be accomplished by encouraging a relatively simple and practical scheduling system that appropriately classifies opioids based on each drug’s formulation and its associated risk profile. Such a system would create a logical, inverse relationship between opioid access and risk, and thus would optimize patient safety.
Disclosure
The authors report no conflicts of interest in this work.
References
- KatzNAbuse-deterrent opioid formulations: are they a pipe dream?Curr Rheumatol Rep200810111818457606
- TurkDCO’ConnorABDworkinRHResearch design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendationsPain20121531997200822770841
- MichnaEChengWYCorvesCSystematic literature review and meta-analysis of the efficacy and safety of prescription opioids, including abuse-deterrent formulations, in non-cancer pain managementPain Med9232013 [Epub ahead of print.]
- CiceroTJEllisMSSurrattHLEffect of abuse-deterrent formulation of OxyContinN Engl J Med201236718718922784140
- ButlerSFCassidyTAChilcoatHAbuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatmentJ Pain20131435135823127293
- SevertsonSGBartlesonBBDavisJMReduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010J Pain2013141122113023816949
- CoplanPMKaleHSandstromLLandauCChilcoatHDChanges in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristicsPharmacoepidemiol Drug Saf201322121274128224123484
- VosburgSKJonesJDManubayJMAssessment of a formulation designed to be crush-resistant in prescription opioid abusersDrug Alcohol Depend201212620621522721679
- VosburgSKJonesJDManuabayJMA comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin® (non-TRF) in prescription opioid abusersAddiction20131081095110623316699
- ManchikantiLFellowsBAilinaniHTherapeutic use, abuse, and nonmedical use of opioids: a ten-year perspectivePain Physician20101340143520859312
- DarnallBDSchatmanMEArgoffCEBallantyneJCUnderstanding opioids: part 1Medscape Neurology192013 Available from: http://www.medscape.com/viewarticle/777126Accessed December 2, 2013
- BannwarthBWill abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?Drugs2012721713172322931520
- FredericksonPDCriminal marketing: corporate and managerial liability in the prescription drug industryMidwest Law J200822115147
- OkieSA flood of opioids, a rising tide of deathsN Engl J Med20103631981198521083382
- SchatmanMEThe role of the health insurance industry in perpetuating suboptimal pain management: ethical implicationsPain Med20111241542621332933
- HartrickGTGatchelRJConroySIdentification and management of pain medication abuse and misuse: current state and future directionsExpert Rev Neurother20121260161022550988
- HardenRNChronic pain and opiates: a call for moderationArch Phys Med Rehabil200889Suppl 1S72S7618295654
- US Food and Drug AdministrationControlled Substances Act Available from: http://www.fda.gov/RegulatoryInformation/Legislation/ucm148726.htmAccessed October 31, 2013
- US Department of Justice Drug Enforcement AdministrationDrugs of Abuse, 2011 ed Available from: http://www.justice.gov/dea/docs/drugs_of_abuse_2011.pdfAccessed November 3, 2013
- MehendaleAWGoldmanMPMehendaleRPRanaKOpioids: myth versus reality, calling all physiciansJ Palliat Care Med20133151
- GudinJLeeAJThe downside of upschedulingPain Med2013141628162924238353
- Centers for Disease Control and PreventionOpioids continue to be associated with an increase in drug overdose deaths2202013 Available from: http://www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.htmlAccessed November 3, 2013
- von GuntenCFBrueraEPirrelloRDPortenoyRKNew opioids: expensive distractions or important additions to practice?J Palliat Med20101350551120406105
- MastropietroDJOmidianHCurrent approaches in tamper-resistant and abuse-deterrent formulationsDrug Dev Ind Pharm20133961162422537282
- ArgoffCEStanosSPWiemanMSValidity testing of patient objections to acceptance of tamper-resistant opioid formulationsJ Pain Res2013636737323696714
- BrushwoodDBRichBAColemanJJLegal liability perspectives on abuse-deterrent opioids in the treatment of chronic painJ Pain Palliat Care Pharmacother20102433334821133741
- LourençoLMMatthewsMJamisonRNAbuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-medical use?Expert Opin Drug Deliv20131022924023252692
- StanosSPBruckenthalPBarkinRLStrategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic deterrents to tamperingMayo Clin Proc20128768369422766088
- United NationsReport of the International Narcotics Control Board for 2012 Available from: https://www.incb.org/incb/en/publications/annual-reports/annual-report-2012.htmlAccessed November 3, 2013
- TobinCLDobbinMMcAvoyBRegulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United KingdomAust N Z J Public Health20132548348824090333
- World Health OrganizationWHO’s pain ladder for adults Available from: http://www.who.int/cancer/palliative/painladder/en/Accessed November 15, 2013