Authors

  1. O'Malley, Patricia Anne PhD, RN, CNS

Article Content

I work in a busy academic medical center emergency department. Every week, the number of opioid and other drug overdoses grows. Why is this happening? What is really scary is to see how nervous prescribers are when writing prescriptions for pain. I think there is a lot of undertreatment of pain in the community.

 

How did this happen? Prescribed opioid analgesics now account for more drug overdose deaths in the United States than heroin, cocaine, and illicit drugs.1 A critical examination of events over the past 20 years reveals several possible paths that have merged to create the current "perfect storm" of prescription drug abuse and death. Significant increases in prescriptions for hydrocodone, morphine, and oxycodone and other scheduled drugs based on emerging best practices at rates significantly higher than the rate of population increase are 1 path. The second path to illness and death remains wide open despite increased regulatory monitoring of prescribers, pharmacists, and manufacturers of controlled substances because friends and family continue to share, sell, or steal dangerous prescriptions obtained from multiple prescribers. Everyday, the epidemic of prescription drug abuse brings not only death but also illness, job loss, and overwhelming burdens on the healthcare and judicial systems.1,2

 

The Table presents drug-related deaths for 1999 to 2013.2 The numbers reveal significant increases in deaths associated with prescription drugs and opioids compared with heroin, cocaine, and illicit drugs. While the pharmaceutical industry has not significantly invested in research and development of chemotherapy for drug addiction, the industry has increased the marketing of abuse-deterrent drugs.1 For this article, drug barrier technology will be explored as well as 2 extended-release formulations recently approved by the US Food and Drug Administration (FDA) of single-entity hydrocodone, a drug with extensive history of abuse and misuse since the 1940s.

  
Table. Drug-Related ... - Click to enlarge in new windowTable. Drug-Related Deaths 1999-2013

DRUG BARRIERS

Abuse-resistant drug formulations have emerged over the past 50 years with advances in pharmaceutical sciences. Built-in barriers within drug formulation can stop or inhibit abuse or misuse by blocking access to the active ingredient that provides the desired effect. Barriers can be physical, chemical, aversion, delivery system, prodrug, and combinations and are designed to stop fatal overdoses for the individual intent on consuming the entire extended release dose at 1 time by chewing, inhaling, or injecting.1,3

 

Encasing a tablet within a hard shell is an example of a physical barrier. A chemical barrier or antagonist is designed to become available when the tablet is crushed and blocks drug effects and makes it more difficult to access the drug active ingredient. Aversion barriers act like chemical barriers. However, if the person takes an altered tablet or exceeds the prescribed dose, effects such as nausea, itching, and headache can occur, based on the chemical structure of the aversion barrier. Delivery system barriers are a combination of chemical and physical barriers such as gel formulation in transdermal patches. Prodrug barriers require biotransformation through metabolic activity to make available the therapeutic agent. Hybrid or combination barriers combine physical, chemical, and delivery system barriers.1

 

EXTENDED-RELEASE SINGLE-ENTITY HYDROCODONE

Hydrocodone and acetaminophen are the most widely prescribed and abused medications in the United States.4 Hydrocodone produces analgesia by activating [mu]-opioid receptors and is about 10 times more potent than codeine and equal to morphine with similar risks for adverse effects. Hydrocodone crosses the blood-brain barrier quickly, which enhances abuse potential and tolerance requiring increasing doses to achieve relief of pain.3

 

In the midst of calls to reduce opioid prescribing by multiple regulatory bodies, Zohydro or hydrocodone bitartrate (Zogenix Inc, San Diego, California), an extended-release form of hydrocodone without acetaminophen, was approved in 2013 against the recommendations of the FDA Advisory Panel concerned about the lack of a drug barrier and potential for abuse. Zohydro did offer sustained controlled analgesic effects for the management of chronic pain with consistent 12-hour coverage, which eliminated the peaks and troughs associated with frequent dosing. Zohydro also offered a needed risk reduction in hepatotoxicity for patients with drug tolerance and/or abuse of hydrocodone with adjuvant acetaminophen. With significant liver damage and liver transplants so highly correlated with acetaminophen abuse and toxicity, Zohydro was approved despite objections with subsequent calls for drug bans and resignations from both political and health groups.3,5

 

In November 2014, the FDA approved another extended-release single-entity hydrocodone, Hysingla ER or hydrocodone bitartrate (Purdue Pharma LP, Stamford, Connecticut), which is taken once every 24 hours. While misuse, abuse, or fatal overdose is still possible, the barrier formulation of Hysingla ER provides properties that make the tablet difficult to crush, break, or dissolve. In addition, the formulation creates a viscous hydrogel for those attempting injection. Like Zohydro, Hysingla ER is not a take-as-needed pain relief medication.6 Based on the FDA 2013 Draft Guidance on Abuse-Deterrent Opioids: Evaluation and Labeling, Hysingla ER has tier 1 and tier 3 labeling. A tier 1 label means that Hysingla is formulated with physical-chemical barriers to deter abuse. Tier 3 labeling means that Hysingla ER is expected to result in a meaningful reduction in abuse. The FDA's final Guidance on Abuse-Deterrent Opioids is scheduled to be released in 2015.3 The draft document can be found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida.

 

Hysingla ER should be prescribed for patients where alternative treatments such as nonopioid analgesics or immediate-release opioids are not effective or tolerated.4 Hysingla ER should not be prescribed to patients with respiratory depression, acute or severe bronchial asthma in an unmonitored setting known or suspected paralytic ileus, or bowel obstruction. Hysingla ER has a boxed warning that includes warnings for the risk of addiction, abuse, misuse, and life-threatening respiratory depression. Crushing, chewing, or dissolving the tablet can result in rapid release and absorption of a fatal dose of hydrocodone. Accidental ingestion particularly by children can result in a fatal overdose as well. Neonatal opioid withdrawal syndrome can result if Hysingla ER is used during pregnancy. Finally, concomitant use of Hysingla ER with ALL cytochrome P450 CYP3A4 inhibitors may result in significant increase in hydrocodone plasma concentrations, which may prolong adverse drug effects or cause respiratory depression. Discontinuation of a concomitantly used cytochrome P450 3A4 inducer may also increase hydrocodone plasma concentrations.4 Serious adverse events and death can occur by taking intact tablets in doses greater than prescribed, and by crushing, chewing, or snorting or injecting crushed formulations. If used parenterally, inactive ingredients can cause death, local tissue necrosis, infection, pulmonary granulomas, endocarditis, and heart valve injury. Results are available in prescribing information for clinical abuse potential studies in nondependent opioid users.7,8

 

After protests of consumer groups and medical experts, Zogenix Inc announced a new drug application for Zohydro ER. In October 2014, Zogenix Inc submitted to the FDA a supplemental new drug application for the drug-deterrent formulation of Zohydro ER. The capsule formulation with additional inactive ingredients makes Zohydro ER more difficult to abuse by injection or snorting. In January 2015, the FDA approved the new Zohydro ER formulation. Ongoing human abuse liability studies to further describe the abuse deterrent properties of BeadTek technology will be released later in 2015. These actions will also amend the product label congruent with the FDA's draft Guidance for Industry, Abuse-Deterrent Opioids: Evaluation and Labeling. Transition to the new formulation is expected the second quarter of 2015 without disruptions for patients currently prescribed Zohydro ER.5,9,10

 

THE FUTURE

The treatment of chronic pain will probably always be an ongoing challenge complicated by misuse, abuse, or addiction even with improved barrier technology. Furthermore, it is not possible to foresee all possible methods by which abusers can subvert abuse-deterrent formulations because persons addicted to opioids tend to find a way to circumvent abuse-deterrent formulations.11

 

Beginning in the 1990s, opioids gained increasing acceptance for treatment of chronic nonmalignant pain. However, weak pain assessment skills of prescribers combined with a limited evidence base for drug selection and lack of monitoring for abuse, diversion, and addiction may have set the stage for the overprescribing of opioids.3

 

Two decades later, prescribers walk a very thin line between the ethical demand to treat pain and how not to contribute to the rise in opioid abuse and death.3 The resulting debate rests on 2 polarizing positions; either overprescribed opioids have led to an epidemic of abuse and death, or opioids are underprescribed, which has resulted in epidemic of pain and suffering with patients seeking relief outside the healthcare system. Probably the truth lies in the middle of this debate. Regardless of one's position, opioid therapy should be prescribed based on in-depth patient assessment, which includes a risk assessment for abuse and a monitoring plan with an exit strategy at the beginning of therapy.11

 

While evidence suggests that increased surveillance of prescribers has not resulted in significant regulatory sanctions and actions against prescribers are generally rare, every clinical nurse specialist knows the prescribing environment has changed. There is increasing reluctance and even fear to prescribe appropriate scheduled medications for pain. As a result, abusers and patients seek other providers for prescriptions, and patients are dissatisfied with their treatment for pain.1

 

Furthermore, while drug barriers appear potentially effective, the actual benefits of the technology may be overestimated. Future development of barriers must take into account the ability of the addict to pursue and obtain the "fix" to develop effective barriers. Without economic incentives, research and development of abuse-resistant drugs will probably remain a low priority because barrier technology is expensive. And in a market with increasing pressure to contain costs, drugs with barriers for abuse or misuse use may be restricted to less expensive generic forms that can be easily abused.1

 

For now, with the emergence of more extended-release opioids, prospective research is needed to uncover the potential risks associated with these new formulations. Even more than barrier technology, higher-dose extended-release formulations require careful and detailed patient education regarding the right use, risks, and benefits of extended-release compared with immediate-release agents. The patient must know clearly the risks, limitations, and dangers, especially of death, for failing to adhere to instructions. Well-designed treatment plans, realistic goals for therapy, and monitoring are crucial tools that can help minimize the disastrous effects of opioid therapy for the individual and society.3

 

References

 

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2. National Overdose Deaths From Select Prescription and Illicit Drugs. NIH, National Institute on Drug Abuse. Karithanom M. Multiple cause of death, 1999-2013 query. http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates. Accessed March 6, 2015. [Context Link]

 

3. Gould HJ, Paul D. Hydrocodone extended-release: pharmacodynamics, pharmacokinetics and behavioral pharmacology of a controversy. Pharm Res. 2015; 91: 99-103. [Context Link]

 

4. Hysingla(TM) ER (hydrocodone bitartrate) extended release tablets CII. Purdue Pharma News & Media. http://www.purduepharma.com/news-media/2015/01/hysingla-er-hydrocodone-bitartrat. Accessed March 6, 2015. [Context Link]

 

5. Jeffrey S. FDA okays abuse-deterrent Zohydro ER. Medscape Multispecialty-Medscape Medical News/FDA approvals. February 2, 2015. http://www.medscape.com/viewarticle/839054. Accessed February 14, 2015. [Context Link]

 

6. FDA News Release. FDA approves extended-release, single-entity hydrocodone product with abuse-deterrent properties. Press Announcement. November 20, 2014. http://www.fda.com/NewsEvents/Newsroom/PressAnnouncements/ucm423977.htm. Accessed February 2, 2015. [Context Link]

 

7. Hysingla ER (hydrocodone bitartrate) extended-release capsules, for oral use, prescribing information. November 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm423977.htm. Accessed March 6, 2015. [Context Link]

 

8. Hysingla ER (hydrocodone bitartrate) extended-release capsules, for oral use, prescribing information. November 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf. Accessed March 6, 2015. [Context Link]

 

9. Wasserman E. Zogenix submits modified formulation of Zohydro(R) ER with potential abuse deterrent properties for FDA review. http://fiercepharma.com. Accessed January 2, 2015. [Context Link]

 

10. ZOHYDRO(R) ER (hydrocodone bitartrate) extended-release capsules, for oral use, prescribing information. January 2015. http://www.zogenix.com/pdf/ZOHYDROERFullPrescribingInformation.pdf. Accessed March 6, 2015. [Context Link]

 

11. Schneider JP, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioid formulations. CNS Drugs. 2010; 24 (10): 805-810. [Context Link]