Marilyn Bulloch, PharmD, BCPS, FCCM
Marilyn Novell Bulloch, PharmD BCPS, is an Associate Clinical Professor of Pharmacy Practice at the Auburn University School of Pharmacy and an Adjunct Associate Professor at the University of Alabama-Birmingham School of Medicine and the University of Alabama College of Community Health Sciences . She completed a post-graduate pharmacy practice residency at the University of Alabama-Birmingham Hospital and a post-graduate specialty residency in critical care pharmacy at Charleston Area Medical Center in Charleston, West Virginia. Dr. Bulloch also completed a Faculty Scholars Program in geriatrics through the University of Alabama-Birmingham Geriatric Education Center in 2011. She serves on multiple committees and in leadership positions for many local, state, and national pharmacy and interdisciplinary medical organizations.
With the opioid epidemic still raging, it leaves many wondering what events could have contributed to the magnitude of this problem and how can it be fixed.
There were 63,632 drug overdoses in 2016, with 42,249 (66%) of those involving opioid drugs, according to the CDC.1
This number continues to rise each year across all ethnicities, races, and regions, and it actually increased by 30% between July 2016 and September 2017.2 In 2016, the highest incidences of opioid overdose occurred in West Virginia, Maine, Maryland, and Utah.3 The drug OxyContin (oxycodone) is among the top 3 opioids that lead to overdose and death in the United States.3 As the opioid crisis continues to worsen, many individuals and states are placing the blame on pharmaceutical companies, claiming that certain opioid manufacturers knew the abuse potential of the drugs and failed to disclose such information.
In 1995, OxyContin was developed and approved as an extended-release reformulation of oxycodone with the intention that this would decrease the abuse of and dependence on the drug. The manufacturer is reported to have focused its marketing efforts on a statement that was written on the original label stating, “Delayed absorption as provided by OxyContin tablets, is believed to reduce the abuse liability of a drug.”4 This claim was used to convince physicians to prescribe OxyContin for many years.4 The marketing strategy was to encourage physicians to prescribe OxyContin 70% of the time, in hopes of reducing the abuse and dependency rates of the drug. Ultimately, the marketing efforts were successful, and the agent became one of the most prescribed opioids in the United States.4
Shortly after allegations of its poor efficacy and lack of evidence supporting its effectiveness began to surface, a trial was initiated to support the 12-hour dosing regimen. The 1996 study, which was funded by the manufacturer, Reder et al, compared steady-state bioavailabilities of controlled-release (CR) oxycodone versus instant-release (IR) oxycodone in normal patients.5 The study included 24 healthy patients who received either 10 mg of CR oxycodone every 12 hours for 4 days or 5 mg of IR oxycodone every 6 hours for 4 days. After reaching steady state, the study compared the serum levels of the drug at 0, 6, and 12 hours. The authors concluded that exposure to the drug was similar all around for both formulation types. The main difference in the formulations was seen in whether it kept the patient within the “therapeutic dosing range” for the entire 12-hour interval.
According to the study results, 10mg of CR oxycodone kept the subjects within the set therapeutic range for the entire 12-hour interval, whereas, 5 mg of IR oxycodone did not.
Overall, the findings of the study supported the manufacturer’s rollout claim of 12-hour dosing intervals for CR oxycodone, and the statement in the drug’s original label that delayed absorption was thought to reduce the drug’s abuse potential.6 When analyzing the study, there seems to be quite a few limitations that put the study’s external validity into serious question. However, the study results helped to show that the marketing claims made by the manufacturer were otherwise legitimate.
Unfortunately, by the early 2000s, there was an obvious spike in opioid overdoses and deaths, especially related to OxyContin.
In 2003, the FDA issued a warning letter to the manufacturer about misleading advertising, lack of warning statements regarding the addictive nature of the drug, and overstated efficacy of the drug without any warning of the risks associated with the drug. The FDA added several black box warnings to the package insert, stating that OxyContin 80 mg and 160 mg should only be used in opioid-tolerant patients and that OxyContin should not be broken, chewed, or crushed, along with many other warnings. The FDA stepped in about 5 years after the original label came out, removed the misleading statement from the label all together and issued another black box warning, stating that OxyContin exposes patients to the risk of addiction, overdose, and death. In 2017, the FDA placed its most recent warning on the drug saying “abuse-deterrent properties [of OxyContin] do not prevent or reduce the risk of addiction. Abuse of OxyContin by the intravenous (IV), intranasal, and oral routes is still possible.”7
The drug’s manufacturer began to face legal allegations after years of marketing the product. In 2007, it pleaded guilty to misbranding OxyContin, a felony under the Food, Drug, and Cosmetic Act, and agreed to pay more than $600 million in fines.8 It was found that Purdue Frederick Co had conducted a study that demonstrated that 68% of oxycodone could be extracted from a 10-mg OxyContin tablet and drawn into a syringe.8 Despite this knowledge, employees and supervisors still endorsed OxyContin to health care providers and sales representatives as more difficult to be abused intravenously, because of the increased difficulty associated with extraction of oxycodone from the tablet. Additional misleading marketing strategies confirmed by the manufacturer included supporting the notion that OxyContin demonstrated less variability in blood levels than immediate-release products, which would convey less euphoria and less likelihood of abuse. Purdue Frederick also noted that OxyContin lacked symptoms of withdrawal upon abrupt discontinuation and that tolerance could not be developed to OxyContin.8
Although already faced with fines of more than $600 million, the company continues to face lawsuits from individual states that claim that false marketing largely contributed to the opioid crisis. Officials in Kentucky, who claimed that the company contributed to opioid-related addiction and deaths, as well as additional statewide medical costs, have already settled a lawsuit with the company.4 Other states and local municipalities are making similar claims, and some are also taking legal action.9
In 2010, a new formulation of Oxycontin was developed, and manufacturing of the original ceased.5 Unlike the original, the 2010 formulation uses an abuse-deterrent formulation (ABF) to be harder to crush and abuse. Nasal discomfort occurs when the excipients are inhaled intranasally, and attempted chemical extraction will form a viscous mixture. ABFs that are approved as such by the FDA are shown to be bioequivalent and have the same pharmacodynamics as the same drug that is not an ABF. The results of many studies have shown that ABF-opioids have less addictive potential.10
Although this formulation did reduce the abuse of OxyContin, a study by Cicero TJ et al showed that the ABF pushed people toward other opioid drugs, including heroin.11 Some patients continued to abuse the new formulation simply by taking the tablets by mouth, while others were still able to circumvent the ABF by using readily available items, such as acidic beverages, microwaves, or spice grinders to enable intravenous (IV) or nasal use.9 There are not a lot of data on physically altered ABF opioids, but because alteration can lead to immediately high blood concentrations they may cause more addiction potential and euphoria.
Unfortunately, oxycodone has now grown to be a highly likeable analgesic by drug abusers, possibly more so than hydrocodone and morphine.
The results of a study published by Wightman R., et al. analyzed the likeability and abuse liability of the 3 opioid drugs.12 The investigators conducted a search of EMBASE and MEDLINE databases, and found 9 studies that met their inclusion criteria. Analysis of the studies found hydrocodone and morphine to have no clinically significant differences in abuse liability. Conversely, oxycodone was found to have a high abuse liability compared with the other opioids, which can be attributed to its high likability scores and relatively low negative subjective effects.12
Both federal and state governments continue to make efforts to help reduce the number of patients on and who are abusing prescription opioids. Due to continuing significant residual abuse with abuse-deterrent formulations of opioids, other options to solve the opioid epidemic must be explored and implemented. A commonly discussed option would be to decrease the supply of opioid medications given and subsequently decrease the amount of prescriptions written for opioid drugs. By limiting the amount of prescriptions to opioid painkillers, it would hopefully prevent more patients from becoming addicted to or dependent on these medications.
As health care providers, pharmacists and physicians must work together to help reduce the number of patients taking prescription opioids. Limiting the number of opioids prescribed, prescribing alternative options for acute and minor pain, and carefully monitoring patients taking opioid analgesics, meaning making certain these patients are not going to multiple prescribers for opioid medications and are taking them according to how they are prescribed, are a few ways pharmacists and physicians can help control the opioid epidemic. These methods alone will not solve the opioid crisis but will at least help steer the nation in the right direction for future generations.
This article was co-written with Rachel Allgood, Allison Bachtle, and Kaci Shuman, PharmD candidates at Auburn University's Harrison School of Pharmacy in Alabama.
1. National Safety Council. Prescription nation 2018: facing America’s opioid epidemic. nsc.org/home-safety/safety-topics/opioids/prescription-nation?gclid=CjwKCAjwopTYBRAzEiwAnU4kb-h6R6rx-XhERYDXLoZC7aEeSYLFoPK-XK4JZh_K5ZZm_amAqP5VshoC7rUQAvD_Bw. Accessed August 2, 2018.
2. FDA. Remarks delivered before FDA's scientific meeting on opioids. Updated March 28, 2018. Accessed August 2, 2018.
3. CDC. Prescription opioid overdose data. cdc.gov/drugoverdose/data/overdose.html. Updated August 1, 2018. Accessed August 2, 2018.
4. FindLaw. Purdue Pharma v. Kentucky. caselaw.findlaw.com/us-2nd-circuit/1619840.html. Accessed August 2, 2018.
5. Reder RF, Oshlack B, Miotto J, Benziger DD, Kaiko RF. Steady-state bioavailability of controlled-release oxycodone in normal subjects. Clin Ther. 1996;18(1):95-105.
6. Esch C. How one sentence helped set off the opioid crisis. Marketplace. marketplace.org/2017/12/13/health-care/uncertain-hour/opioid. Published December 13, 2017. Accessed August 2, 2018.
7. National Institute on Drug Abuse. Opioid overdose crisis. drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis. Updated March 2018. Accessed August 2, 2018.
8. United States vs. The Purdue Frederick Company, Inc., et al. Opinion and Order. vawd.uscourts.gov/OPINIONS/JONES/107CR00029.PDF. July 23, 2007. Accessed August 2, 2018.
9. Moritz, JC. 6 states sue maker of OxyContin as they battle expenses, human costs of opioid crisis. USA Today. usatoday.com/story/news/nation-now/2018/05/15/six-attorney-generals-opioid-lawsuits/612721002/. Published May 15, 2018. Accessed August 2, 2018.
10. Harris SC, Perrino PJ, Smith L, et al. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol. 2014;54(4): 468-77. doi: 10.1002/jcph.235.
11. Cicero TJ, Ellis MS. Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: lessons learned from OxyContin. JAMA Psychiatry. 2015;72(5):424–30. doi: 10.1001/jamapsychiatry.2014.3043.
12. Wightman R, Perrone J, Portelli I, Nelson L. Likeability and abuse liability of commonly prescribed opioids. J Med Toxicol. 2012;8(4):335-40. doi: 10.1007/s13181-012-0263-x.