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The FDA and Hydrocodone


The hydrocodone/acetaminophen combination is moved to Schedule II from III while single-agent extended-release hydrodocone is approved without a tamper-resistant mechanism.

The FDA recently made two decisions regarding medications containing the opioid analgesic hydrocodone. I believe the first of these made perfect sense. The second is much more confusing and doesn't appear to make much sense at all.

The FDA decision I support is the one that moves hydrocodone combination products from a Schedule III to a Schedule II controlled substance. This move does not in any way prevent physicians from prescribing these products if they feel they are indicated. It means that prescription refills will no longer be allowed and there will be limitations on the amount of medication that can be prescribed at one time.

Since the decision was made I have read and heard a great deal of criticism of it. The major criticism appears to be that it will result in many patients not receiving these analgesics and so cause unnecessary suffering. There also is a widespread belief that the FDA’s decision was based on a desire to limit opioid abuse and not on the needs of patients who benefit from the use of these drugs.

I adamantly disagree with this view. Although I can't peer into the minds of the people at the FDA who made this decision, I believe that they did it in the best interest of patients with pain who require opioid analgesics.

First, I have long believed that medications that combine an opioid with another medication are a very poor and a very risky choice for anything other than brief use for acute pain.

The most common medication in combination with hydrocodone in these products is acetaminophen, as in Vicodin and Lortab. There are many problems with tying the doses of these two disparate drugs together, especially for patients who require them for extended periods. Over time, patients can develop tolerance to the analgesic effects of the opioid and require higher doses to attain the same pain relief. However, this can result in ingestion of potentially toxic doses of acetaminophen.

Similarly, patients taking opioids for more than a few weeks can develop hyperalgesia in which the individual’s pain threshold is lowered. This, too, can result in patients believing they require more of the opioid, which doesn't relieve the problem but can also result in patients taking too much acetaminophen.

Patients are often unaware that either tolerance or hyperalgesia is developing. Thus it is important for physicians to frequently monitor patients taking opioids.

There is the additional issue of how beneficial opioids actually are for chronic pain. Unfortunately, virtually all of the studies done on these drugs have been for a few months or less.

Patient hardship or protection?
I have read that the FDA's decision will be a special hardship on patients who have terminal illnesses or are elderly and frail because it will require them to see their physicians more frequently if a hydrocodone product is prescribed for them. This argument makes absolutely no sense to me and appears to be contradictory to the best interests of patients. It is unlikely that terminally ill patients would go months without seeing a physician so the argument that the scheduling change will burden them with visits to their physician more frequently than every 6 months doesn’t hold water. 

Furthermore, by definition, a terminal illness is one that can't be cured or its progression halted. As the disease progresses, the pain associated with it may worsen, as commonly happens with terminal cancer, requiring patients to take more medication for pain relief. 

Also, patients who are terminally ill and the frail elderly often have impairment in multiple organ systems and are taking many medications. It is important to consider both of these in patients taking opioids, and combination opioids in particular.

Hydrocodone is metabolized to its analgesic form, hydromorphone, through the hepatic cytochrome P-450 2D6 isoenzyme system. If hepatic function is impaired, the analgesia received with hydrocodone will be limited. Kidney function can also be affected, which can reduce excretion of opioids and their metabolites and require adjustments in dosing. Because both terminally ill patients and the frail elderly often experience changes in cognition, it is important to also observe whether opioids may be contributing to this. 

All these factors indicate that opioid use by these patients should be monitored the most carefully and frequently-not the least.

To simply give a prescription for a hydrocodone product and tell the patient to come back in 6 months unless there are problems requires patients to watch not only for the development of tolerance and hyperalgesia but also for evaluation of whether they are suffering a reduction in hepatic or renal function or cognitive changes. I believe these are responsibilities of physicians, not patients.

Finally, the FDA decision makes logical sense. Hydrocodone alone has long been a Schedule II drug. The only reason the combination drug was classified in a lower schedule is that apparently it was once believed that the acetaminophen component would limit patient intake. There is no evidence that this has ever been true and we've just ended up with more cases of acetaminophen toxicity. Oxycodone combination products (eg, Percocet) are on Schedule II as is oxycodone alone.

The only difference between hydrocodone and oxycodone is that until now there has never been a single-agent hydrocodone drug. 

Which leads us to the second decision the FDA made and the one I don't understand.

Extended-release hydrocodone
In this one, the FDA approved an extended-release (ER) form of hydrocodone (Zohydro) that does not contain another drug. Why it chose to do this is somewhat confusing, especially in light of the fact that last year an FDA advisory panel voted 11 to 2 against approving this drug.

What makes this decision even more of a head scratcher is that Zohydro is not tamper-resistant. This seems to be going in the opposite direction of previous FDA policy, although to some degree this policy has already been enforced inconsistently.

In the wake of the much reported "epidemic" of misuse of the ER form of oxycodone, OxyContin, there was a great deal of focus on limiting this misuse. In order to address this, its manufacturer stopped producing the original formulation and changed to a tamper-resistant one. The intention was to prevent patients from subverting the time release mechanism, thereby taking a 12-hour dose all at once. The FDA even prevented introduction of a generic form of OxyContin because it didn't have this tamper-resistant system.

However, in contrast, the FDA approved a generic form of ER oxymorphone, Opana ER, without its tamper-resistant mechanism, giving as its reason that the group had come to believe that the mechanism in this drug could be subverted and therefore was of questionable benefit in reducing its abuse. 

Whether or not tamper-resistant mechanisms actually reduce to any significant degree the abuse of the ER opioids formulated with them is still an unanswered question. However, inclusion of these mechanisms has appeared to be the overall direction the FDA has preferred.

So why was Zohydro approved? Again, I can't be certain, but it appears that the FDA decided that having an additional extended-release/long-acting (ER/LA) opioid available will be beneficial for patients.

I have to admit that this doesn't make much sense to me. We already have multiple ER/LA opioids available. In addition to the oxycodone and oxymorphone drugs, there are also ER/LA forms of morphine (MS-Contin, Kadian), hydromorphone (Exalgo), transdermal fentanyl (Duragesic) and buprenorphine (Butrans), tapentadol (Nucynta ER), and the pharmacologically long-acting drugs, methadone and levorphanol (Levo-dromoran).

One possible explanation is that the FDA decided to approve Zohydro in hopes that physicians will prescribe it instead of a hydrocodone combination product, still the only immediate-release forms of hydrocodone available, when it is felt that patients will benefit from taking hydrocodone for an extended period. If patients don't attempt to tamper with the Zohydro, it would appear to be a safer medication than the combination ones.

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