When deciding what medication to prescribe for any specific problem, physicians are faced with the ongoing challenge of balancing the efficacies of the various choices with the relative risk of adverse events. An additional factor to consider is convenience of use, usually reflected in how frequently the medication must be taken and how many pills are involved. For some problems, medication choices are limited and choices are constrained. When it comes to analgesics, however, there are usually many options and various factors must be weighed to make the best choice for each patient.
In January 2011, the FDA announced that over a 3-year period it will phase in an order that limits the amount of acetaminophen that can be included in combination medications with opioids to 325 mg per pill (ie, with codeine [Tylenol with codeine], with hydrocodone [Vicodin], and with oxycodone [Percocet]).1
The lowest-dose Vicodin compounds contain 500 mg of acetaminophen and 5 mg of hydrocodone; Vicodin ES has 750 mg of acetaminophen with 7.5 mg of hydrocodone. There is also a hydrocodone/acetaminophen compound (Zydone) that contains 400 mg of acetaminophen. Percocet contains up to 650 mg of acetaminophen per pill. In the real world, it is very easy for patients taking these medications to exceed the maximum recommended daily dose of 4 g of acetaminophen. Thus, the dose limitation is an improvement.
However, I would have preferred that the FDA follow the recommendation of its advisory panel to ban these combination medications altogether. Acetaminophen is readily available and inexpensive; as such, there does not appear to be any clear reason to continue to have combinations with this agent available, except for dosing convenience. Furthermore, patients who take products such as Vicodin and Percocet may be unaware that these medications contain acetaminophen and they may take additional doses of acetaminophen separately.
The FDA limitation also fails to address the issue of tolerance adequately. Because there is no ceiling on the dosing of µ-opioid receptor agonists that include hydrocodone, oxycodone, and codeine, the dosage can be increased safely when the opioid is taken alone. However, the maximum recommended daily dose of acetaminophen never changes and patients do not become tolerant to its potential hepatotoxicity.
Fortunately, there is no reason to wait for the FDA restriction to be fully implemented to eliminate the risk of acetaminophen toxicity associated with the use of these combination medications. While hydrocodone is only available in compounds with other medications, oxycodone and codeine can be given alone.
Oxymorphone—the analgesic metabolite of oxycodone—is also available in both immediate- and extended-release formulations (Opana). There is no evidence, however, that oxymorphone provides any more analgesia than oxycodone, and because it is not yet available in a generic formulation, it is more expensive than generic oxycodone. Oxymorphone is a useful alternative for patients taking medications that inhibit the cytochrome P-450 2D6 (CYP2D6) isoenzyme system, such as some of the SSRIs: oxycodone is metabolized to oxymorphone through this system.
Furthermore, if patients require around-the-clock opioids for more than a few days, extended-release forms of opioids—none of which contain acetaminophen—would make more sense. These formulations are taken once or twice a day and appear to provide more stable pain relief than do their immediate-release counterparts. Moreover, they eliminate the risk of inadvertent acetaminophen overdose.
In a recent editorial, MacDonald and MacLeod2 noted ongoing concerns about codeine. Although they focused on its use in children, their concerns would also appear to apply to adults. Codeine is metabolized to its analgesic form—morphine—by the CYP2D6 system. Because of variability in this system, some patients metabolize codeine rapidly. The authors report that it might be safer to prescribe morphine for patients instead of codeine, thereby eliminating the risk of morphine toxicity resulting from this faster metabolism.
1. FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm. Accessed March 14, 2011.
2. MacDonald N, MacLeod SM. Has the time come to phase out codeine? Can Med Assoc J. 2010;182:1825.
3. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. doi:10.1136/bmj.c7086.