FDA Proposes Extended-Release Hydrocodone as Schedule II Drug

This article reviews the current role of hydrocodone and puts the potential advantages and disadvantages of the recentlyapprovedlong-acting hydrocodone preparation into perspective.The authors note that hydrocodone, a semi-synthetic opioid, has been used for decades as a short-acting analgesic, and it’s combined with acetaminophen or ibuprofen. The advantages of any hydrocodone product is that it is familiar to many physicians, but adding acetaminophen and ibuprofen limits the safe use of high doses of currently available formulations.The obvious potential problem with high-dose hydrocodone is its potential to cause addiction and overdose.

Hydrocodone-acetaminophen is currently the most commonly prescribed opioid in the United States, marketed under a variety of names such as Vicodin and Lortab.The short-acting hydrocodone was previously mixed with 325 to 750 mg acetaminophen per tablet. Current products have a dosing schedule of every four to six hours, with the number of tablets per day limited primarily by the acetaminophen dose. The new maximum recommended dose for chronic acetaminophen use is only 3000 mg a day, which corresponds to aboutfour to nine tablets per day of the mixed hydrocodone-acetaminophen products. High-dose acetaminophencan cause liver failure, of course, and the FDA mandated in 2011 that combination products contain no more than 325 mg of acetaminophen per tablet.

The DEA had previously classified hydrocodone combined with acetaminophen or ibuprofen as a Schedule III drug, meaning it can be phoned into a pharmacy with up to six refills. Schedule II oxycodone preparations cannot be phoned in and cannot be written for more than a one-month supply, and anappropriate prescription must be presented at the pharmacy to obtain the medication. Rescheduling the current hydrocodone products is currently in the works.

The use of opioids by even middle school or high school students has risen in the United States, but hydrocodone has one of the lowest rates of abuse given its volume of prescribing.It is also available in cough medicine, and changing it to a schedule II drug has been opposed by some medical personnel and pharmacies.

The most commonly used high-dose, extended-release opioidsare morphine (MS-Contin-Purdue Pharma) and oxycodone (Oxycontin-Purdue Pharma). These medicationsare available in a variety of dosage forms without any acetaminophen, and these analgesics are a godsend to those in chronic pain. Both are frequently diverted, stolen, and highly abused. Long-acting transdermal fentanyl is another example of a sustained-release opioid that must be used by only the most sagacious clinician. (Read Dr. Roberts’ column about fentanyl abuse at http://bit.ly/18XH1bv.)

It is common practice among pain specialists to advance patients with chronic pain to daily long-acting opioids supplemented by short-acting opioids for breakthrough pain. Current information is insufficient to draw any firm conclusions about the relative role of long-acting versus short-acting opioid analgesics. It is generally thought that long-acting opioids have a higher incidence of abuse, and they certainly can cause addiction. Many chronic pain patients become addicted through genuine and honest attempts to treat them adequately.

The positive side of a long-acting hydrocodone is obvious. This drug has been used for acute and chronic pain for decades. The availability of the long-acting higher dose formulation might provide additional options for patients who cannot tolerate morphine or oxycodone, but that’s an unusual scenario. The lack of acetaminophen inhigher dose hydrocodone decreases the risk for liver damage in those who require long-term maintenance.

The potential for abuse among morphine, oxycodone, and hydrocodoneis similar. The longer acting drugs, such as MS Contin and Oxycontin, had solid abuse monikers when the abuser crushed and dissolved the tablets to release all the opioid at once, and thenthey snort or inject the easily madeliquid.Long-acting opioids were chemically reformulated in 2010 to resist this type of tampering. One side effect of hydrocodone is a sensorineural hearing loss that has been reported in patients taking highdoses of the drug. Hearing loss did not respond well to discontinuing the drug or to corticosteroid therapy, and higher doses of hydrocodone could pose a more significant risk of hearing loss.

These authors call for prudence and adherence to best practices in opioid prescribing designed to reapthe benefits of these medications without producing harm. Conscientious prescribing likely helps to reduce diversion and misuse. It’s best to prescribe any long-acting opioid only for suitablepatients. Emergency physicians should be rarely prescribing them. Appropriate indications and patient instructions will certainly be necessary. The authors suggest a number of parameters that would negate giving long-acting hydrocodone to patients, including an unstable or abusive living situation, inadequate social support, patients with poorly defined pain complaints, and those with limited response to moderate opioid dosages.

Comment: Zohydro ER has not met with great enthusiasm by all. In fact, a recent letter submitted to the Department of Health and Human Services seeks to overturn its FDA approval.That approval was granted last October despite an 11–2 vote against it in committee, an unusual outcome. The concern wasthat introducing long-acting hydrocodone essentially rolls out the welcome mat to a new, more powerful, and more easily abused super drug while policymakers and law enforcement officials are waging war on the growing prescription drug crisis. The abuse-deterrent mechanism that prevents users from crushing, chewing, injecting, or snortingother long-acting opioids is not present in this hydrocodone preparation, and may not be seen for years.

The abuse of prescription opioids is not a minor issue.It was reported in 2010 that seven million individuals 12 and older had abused prescription pain medication in the previous month.About eight percent of 12th graders reported in 2011 that they had abused Vicodin the previous year.

This new pure hydrocodone medication is classified as schedule II. Zogenix, the company making Zohydro ER, has made the drug available in 10, 15, 20, 30, 40, and 50 mg tablets, which they said are not for PRN use. The cost of 100 of the 10mg tablets is about $700. The starting dose of hydrocodone ER is 10 mg. That’s equivalent to 10 mg of oxycodone, 10 mg of methadone, 15 mg of morphine, or 100 mg of codeine. The manufacturer provided a full black box warning about addictionand abuse in the safety information, and italso highlights misuse, respiratory depression, accidental exposure, and adverse interaction with alcohol.

The approval of Zohydro ER was a surprise to many lawmakers. An FDA advisory panel overwhelmingly voted against the recommendation for approval in December 2012. The FDA is not required to follow the panel’s recommendation, but it usually does.Given the well-known problems with opioid prescriptions, it was thought that the FDA would probably go along with the panel’s decision. Zohydro ER will be available sometime later in 2014.

EPs will likely see overdoses of this new opiate. It should respond to naloxone, but larger doses and repeated reversals will likely be required. Anyone presenting with an overdose of this product will have to be carefully observed for 18–24 hours, and one cannot release a patient who does not have immediate symptoms or seems totally reversed with 1 dose of Naloxone.

Purdue Pharma, which makes tamper-proof extended-release oxycodone (Oxycontin), has stated that it plans to apply for regulatory approval for a tamper-resistant form of high-dose hydrocodone, a safety feature not found inZohydro ER. Some U.S. senators have also lobbied the FDA requesting that Zohydro be removed from the market because the medication is not tamper-proof and can have substantial abuse potential when crushed, snorted, or injected. Find out more information here: http://practicemax.com/challenges-we-solve/maximizing-reimbursements/