Best Evidence Analyses and Commentary

Re-scheduling of hydrocodone: deterring abuse or pain control?
Yevgeniy Lyutov; Mitchelle Rodriguez; Minh Trinh; Tam Tran, PharmD Candidates; Marcus W. Campbell PharmD, BC-ADM
04/30/13

Hydrocodone is a semisynthetic opioid agonist which works by binding to opiate receptors in the CNS, altering the perception of and response to pain as well as suppress the cough in the medullary center. Hydrocodone is commonly prescribed for analgesia in combination with non-analgesic pain relievers (eg. acetaminophen or ibuprofen) or as an antitussive in combination with chlorpheniramine.1 In addition to these therapeutic effects, hydrocodone can also cause drowsiness, mental clouding, euphoria and changes in mood as do all centrally-acting opioid agonists.2

The Controlled Substance Act (CSA) was developed to regulate the manufacturing, importation, possession, use, and distribution of certain substances. In the United States, drug formulations that contain only hydrocodone are listed in Schedule II of the CSA. Hydrocodone combination products containing specified amounts of hydrocodone and one or more therapeutically active non-narcotic ingredients are listed in Schedule III of the CSA. More specifically, these combination products cannot contain more than 3 mg per 1 ml or more than 15 mg of hydrocodone base per dosage form in combination with an active non-narcotic ingredient to be listed in Schedule III.3,4

The controversy over the scheduling of hydrocodone combination products is not a new one. The Drug Enforcement Administration (DEA) received a citizen’s petition in 1999 requesting that hydrocodone combination products be moved to Schedule II. This led to a request by the DEA to the Secretary of Health and Human Services (HHS) to investigate the issue in 2004. In March of 2008, the HHS recommended to the DEA that hydrocodone combination products should remain in Schedule III of the CSA.5 This decision was based on the finding that hydrocodone combination products have less potential for abuse than the drugs in schedule II because less hydrocodone will be needed to treat pain in comparison with lower doses of single entity scheduled II opioids. Although acetaminophen does decrease the amount of hydrocodone needed for its therapeutic effect, it is perceived that the toxic effect of high doses of acetaminophen acted as a deterrent for abuse. This was found to be untrue when hydrocodone combination products were compared to oxycodone. They possessed a higher number of toxic exposures and fatalities which demonstrates its misuse and abuse.3

In response to the 2008 recommendation, the DEA collected more data regarding the abuse and diversion of hydrocodone combination products and submitted a request to the FDA’s Center for Drug Evaluation and Research (CDER) to reconsider up-scheduling all hydrocodone containing products. On January 25, 2013, an FDA advisory committee voted 19-10 in favor of rescheduling hydrocodone combination products from Schedule III to Schedule II.3 Now the FDA has to decide whether to follow the committee’s recommendation.

Some of the evidence supporting the committee’s decision includes data on abuse potential and epidemiological data. According to IMS Institute for Healthcare Informatics, hydrocodone and acetaminophen combination products were the most prescribed medication in 2010. The DEA reports that combination products of hydrocodone and other medications have been prescribed to 47 million patients and included in 131 million prescriptions in 2011.3 This volume of prescribing and use far exceeds other opioids and this increased availability has the potential for increased abuse.

In addition, scientific literature review showed that hydrocodone and hydrocodone combination products produced similar effects to those of Schedule II drugs such as morphine, oxycodone and hydromorphone in a dose-related manner. These opioid effects include “high” and “drug-liking” as well as nausea and dizziness and were observed when hydrocodone doses were 15 mg or higher. In terms of epidemiological data analysis, hydrocodone combination products were involved in less emergency room visits. However, there was a higher prevalence of use of hydrocodone containing products by high school students. This is likely due to the fact that hydrocodone combination products are prescribed more often and more readily available which increases the opportunity for experimentation.3,6

Bates et al. performed a study by doing a survey of patients 2-4 weeks post-operation in the University of Utah Urology center. In this study, 63% of the prescriptions were for hydrocodone. Of the 47% of patients that participated in the post-op survey, only 58% of the patients consumed their pain medication, 67% of the respondents had leftovers from the initial prescription. Then 92.2% of patients indicated that no instructions were given on how to properly dispose of unused medications and of those patients 90.8% indicated that they had kept the extra medication at home. The study supports the idea that limiting the oversupply of prescription opioids and properly educating patients on proper drug disposal will minimize the potential source of prescription diversion.7

Leftover medications, including narcotics, become readily accessible to all household members. More specifically, teenagers and young adults have access to prescription medications that can be easily diverted. In 2010 the National Survey on Drug Use and Health data showed that nonmedical use of prescription pain relievers in youths (12-17 years of age) and young adults (18-25 years of age) was the second most prevalent illicit drug use category, with marijuana being first. It demonstrated that 55% of the prescription pain relievers were given free by a friend or relative, 11.4% of prescription pain relievers were bought from a friend or relative and 4.8% of prescription pain relievers were taken from a friend or relative. This was true in regards to all opioids whether schedule II or III.8

Rescheduling hydrocodone from schedule III to schedule II will affect prescribers, pharmacists and patients. One potential benefit of re-scheduling hydrocodone is more restrictive prescribing. The restrictions associated with schedule II medications would allow for a decrease in the quantity, frequency and prescribers of hydrocodone. As pointed out by one of the bill’s sponsors, US Senator Joe Manchin (D-WV) “patients would need an original prescription for refills, pills would be stored and transported more securely, and traffickers would be subject to increased fines and penalties.” Overall, this may lead to potential decrease in diversion, misuse and abuse of hydrocodone.

However, the change from schedule III to schedule II would not come without implications for patients and healthcare professionals. The rescheduling of hydrocodone products will affect its availability to numerous patients currently managing their pain with these products. Patients will not be able to have refills on their prescriptions and the prescriptions will be limited to a three month supply. Only written prescriptions from a physician would be allowed and this would also prohibit nurse practitioners and physician assistants in the majority of states from prescribing the drug. Patients would have to visit their physicians more frequently to get additional prescriptions which would increase cost and make it harder for patients in underserved rural areas to get their medications .4,9

Rescheduling hydrocodone may also result in increased co-pays and higher costs to patients. A potential increase in prescriptions of less effective medications may lead to more patients suffering from inadequate pain management. Prescribing alternative medications at a lower controlled level to avoid regulatory restrictions may increase adverse effects, possibly making treatments unsafe for patients. For example, tramadol may cause seizures and serotonin syndrome when used in higher doses. Codeine has an unpredictable genetic predisposition that can cause a variation in treatment which may result in treatment failure or lead to an overdose. Then non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastrointestinal, renal, and hematological side effects which can be detrimental in some patients. Mortality risk may increase if patients are switched from short-acting hydrocodone to a long-acting opioid product because a majority of deaths related to opioids included long-acting dosage forms. When methadone, a long acting opioid is used as a substitute for hydrocodone as a pain reliever, it resulted in about 33% of opioid related deaths in 13 states.9

The rescheduling of hydrocodone will also impact the administrative procedure in pharmacy service. Additional steps are required when pharmacists process a Schedule II medication compared to a Schedule III medication. Refill requests are no longer faxed to medical offices as, prescribers are unable to call pharmacies to send refill authorization and additional administrative documentation will be mandated. 9 Not to mention, prescribers and pharmacists face an increased risk of penalties when incorrectly prescribing and dispensing schedule II medications.4,9,10


The proposed changes to hydrocodone combination products scheduling intend to curtail the current prescription drug abuse problems present in the United States. New York has already implemented the new policy as of February 23, 2013. The new policy will not allow the pharmacist to dispense hydrocodone that exists in the pharmacy file before the new policy was implemented. The new policy will also mandate that hydrocodone prescriptions written after the new policy was put in effect, will need to be filed with the other Schedule II substances and a physical inventory will be necessary. However, a DEA-222 form will not be required for placing an order for hydrocodone because as of October 10, 2012, it is still listed as a schedule III controlled substance in the Federal Code of Regulations. As current and future health care providers it is imperative we are aware and current on all laws and regulations regarding medications such as hydrocodone due to the impact this has on so many current and future patients.11

1. Lexi-Comp, Inc (electric version). Hudson, Ohio, USA. Available at: http://online.lexi.com

2. Lortab [package insert]. Atlanta, GA: UCB Pharma, INC; 1996

3. FDA Briefing Document October 29-30 Meeting Notes. Drugs Safety and Risk Management Advisory Committee (DSaRM). Last accessed 2/13/2013 <http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM325708.pdf>

4. FDA advisory committee votes in favor of hydrocodone rescheduling. 29 Jan 2013. American Pharmacists Association. Web. Last accessed 2/4/2013http://www.pharmacist.com/fda-advisory-committee-votes-favor-hydrocodone-rescheduling

5. FDA Briefing Document. January 24-25 Meeting Notes. Drug Safety and Risk Management Advisory Committee (DSaRM). Last accessed 2/13/2013 <http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM337148.pdf>

6. Walsh S. Abuse Potential of Hydrocodone in Human Studies. Center on Drug and Alcohol Research. Last accessed 2/13/2013 <http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM337158.pdf>

7. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011 Feb;185(2):551-5.

8. Substance Abuse and Mental Health Services Administration, Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings. Health Services Administration, 2011.

9. American Academy of Pain Medicine Comments on Rescheduling Hydrocodone: Patient and Public Health Considerations. American Academy of Pain Medicine. Web. 29 Jan 2013 http://www.painmed.org/Workarea/DownloadAsset.aspx?id=9003

10. Controlled Substances by CSA Schedule. Control Substance Act. Last accessed 2/13/2013 <http://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf>

11. Department of Health. Frequently Asked Questions Part C Chapter 447 Laws of 2012 (Controlled Substance Schedule Changes) http://www.health.ny.gov/professionals/narcotic/laws_and_regulations/part_c-chapter_447-laws of_2012-faq.htm


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