Controversy around FDA approval of an extended-release formulation of the opioid hydrocodone includes well-founded concerns about abuse but also exposes enduring ignorance about opioid analgesics in general.
Over the past several months, one of the hottest debates about the use of opioid analgesics has centered on the FDA’s approval and the release of the first extended-release (ER) form of hydrocodone, Zohydro ER.
The concerns about its use have primarily focused on its abuse potential in light of the relatively high doses in which it is available-the maximum-strength tablet contains 50 mg compared with 10 mg for the maximum amount of hydrocodone in the immediate-release [IR] forms (eg, Vicodin, Lortab). In addition, unlike the currently available ER form of oxycodone (OxyContin), Zohydro is not a tamper-resistant formulation.
Recently the concern has reached such a fever pitch that two governors have taken action to limit its use in their states. Massachusetts Governor Deval Patrick tried to ban the use of Zohydro outright, describing it as “a potentially lethal narcotic painkiller.”1 A federal court judge overturned the ban, ruling that a state could not nullify the action of a federal agency such as the FDA.
Vermont Governor Peter Shumlin, who used his entire State of the State Address this year to discuss the growing problem of drug abuse, issued an emergency order requiring that all patients under consideration for a prescription for Zohydro undergo a full medical evaluation and a risk assessment for substance abuse, and give informed consent. Prescribing physicians must provide a range of specific services-from urine drug testing to follow-up care. Twenty-nine state attorneys general have also requested that the FDA reconsider the drug’s approval.
FDA Commissioner Margaret Hamburg has defended her agency's decision to approve Zohydro, despite the 11-to-2 vote of its advisory committee recommending against approval, citing that unlike the IR forms of hydrocodone, it contains no other drugs (eg, acetaminophen) and therefore is a safer alternative.2
I am certain that both governors believe that they have taken the right actions to protect the residents of their states and that most, if not all, the attorneys general share this belief-meaning, I trust that these politicians have taken these actions not for political reasons but for the good of their constituents. Similarly, I think that Dr Hamburg believes the FDA made the right decision, although I am also sure she understands the concerns about Zohydro.
Based on statements made by each, however, I have questions about whether they truly understand what Zohydro is and what place it has in the management of pain.
I will begin with Governor Patrick’s previously mentioned statement that Zohydro is “. . . potentially lethal . . .” This description applies to any opioid analgesic, primarily because overdose of any opioid can cause respiratory depression and death. The governor’s statement could also be applied to many non-opioid analgesics, including some that are available without a prescription, such as acetaminophen and NSAIDs.
As for Governor Shumlin’s rule, I would hope that before any opioid analgesic is prescribed other than for brief periods of acute pain (which, based on prescribing information, excludes an ER opioid such as Zohydro), that a full medical evaluation and risk assessment would be performed and that the prescribing physician would ensure that proper follow-up is in place. Regarding informed consent, patients who self-administer prescription medication are already giving tacit consent to using it. I’m not sure why an additional rule is needed, but I do agree that the risks and benefits of any medication should be explained to a patient before it is prescribed.
If the actions by Governors Patrick and Shumlin are taken at face value, it would appear that they believe that in the hands of physicians in their respective states, opioids could be prescribed inappropriately, such as for people for whom they aren’t indicated and at unnecessarily high doses, or that there are many unethical physicians who are willing to prescribe anything to turn a buck. I highly doubt that the latter is true, since it would be frightening to think that any governor would have such a low opinion of the doctors in his state.
However, I believe that the governors are inadvertently suggesting that their states’ doctors don’t know how to properly prescribe opioids or assess their patients’ needs for them.
If Zohydro is used as indicated, it probably will be infrequently prescribed. It is generally recommended that an IR form of the drug be started first because all ER opioids take several days to reach maximal effect. (I consider the only exceptions to this rule to be methadone and the fentanyl transdermal patch; the former because of the excellence of the analgesia provided by its unique dual opioid receptor agonist and NMDA receptor antagonist actions and the latter because it offers an alternative to taking the drug by mouth.)
Because there is no single-agent IR hydrocodone product available, dosing would be complicated when switching from the IR to the ER form. We already have multiple opioids available in both IR and ER forms that are not combined with other drugs, including morphine, hydromorphone, oxycodone, and oxymorphone.
Furthermore, I know of no studies that indicate that hydrocodone is any more efficacious than any of these drugs. There may be patients for whom hydrocodone provides better analgesia, although, since it principally exerts its analgesic effect when it is metabolized to hydromorphone, this is probably rare.
I do feel that the governors have some valid fears about the overprescription of Zohydro. IR hydrocodone products are the most commonly prescribed opioid analgesics in the United States, so no doubt there is concern that prescriptions for these will become prescriptions for Zohydro.
I can also understand concerns about the availability of Zohydro in a 50-mg dose. The drug is, however, available in lower doses (beginning at 10 mg). Unfortunately, widespread professional ignorance about proper dosing conversion from IR to ER formulations is a problem that applies to virtually all ER opioids.
Dr Hamburg, in her defense of the FDA approval, noted that Zohydro, because it is a single-agent opioid, may be safer than the combination IR hydrocodone formulations. Acetaminophen, the most common agent used in combination analgesics, itself can cause serious adverse events and even death. From Dr Hamburg’s point of view, therefore, Zohydro, used properly, would be a safer replacement. However, as is true of other ER opioids, Zohydro isn’t exactly a replacement for IR formulations.
What may give some doctors pause about prescribing Zohydro is that unlike the IR hydrocodone formulations, it is a Drug Enforcement Administration (DEA) Schedule II drug. It appears that the primary reason why the IR forms are so frequently prescribed is that they have always been Schedule III drugs.
The DEA and FDA have recommended that the combination IR hydrocodone products be changed to Schedule II drugs; if this goes into effect, it is quite possible that they will lose much of their popularity.
Finally, although the concerns that Governors Patrick and Shumlin and the state attorneys general have about misprescription and overprescription of Zohydro may be a step in the right direction, I would suggest that they spread their nets wider and address the woeful state of US physician education on pain management, and particularly the use of opioids, by mouth or parenterally.
1. Rabin RC. New painkiller rekindles addiction concerns. New York Times. April 22, 2014. Available at: http://well.blogs.nytimes.com/2014/04/21/new-painkiller-rekindles-addiction-concerns
2. FDA Pain - FDA's Hamburg on Zohydro; abuse risk, substituting politics for science [transcript]. BioCentury This Week. April 20, 2014. Available at: http://www.biocentury.com/bctvthisweek/all/2014-04-20/bctv-fda-pain---fdas-hamburg-on-zohydro-abuse-risk-substitutingpolitics-for-science-bctv.