Analgesic Medications: Balancing Efficacy, Adverse Effects, and Convenience

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.

Opioid/acetaminophen combinations

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.

This is a good recommendation. However, I have not been a supporter of the use of oral formulations of these medications. For moderate pain that requires an oral opioid, I prefer oxycodone instead of codeine or, for that matter, hydrocodone. For more severe pain, I believe hydromorphone (Dilaudid) is much more effective than oral morphine.

An extended-release form of hydromorphone (Exalgo) is now available. My lack of support for hydrocodone stems not only from its unavailability in a non-combination formulation but also from similar concerns regarding toxicity that might be raised about hydrocodone because it, too, is metabolized by the CYP2D6 system to its analgesic form, hydromorphone. As a result, I rarely prescribe hydrocodone.

Cardiovascular toxicity and NSAIDs

When one thinks of adverse events related to NSAIDs, GI problems are usually at the top of the list. However, following the discovery of cardiovascular (CV) problems with rofecoxib (Vioxx) and its subsequent removal from the market, there has been increasing awareness that other selective cyclooxygenase-2 (COX-2) inhibitors and the nonselective NSAIDs may also cause similar problems.

A recent meta-analysis sought to determine whether there is any oth-er difference between the various NSAIDs with regard to CV toxicity.3 Trelle and colleagues3 ex-amined 31 studies that looked at 7 different NSAIDs. Three were nonselective (ibuprofen, diclofenac, and naproxen). Four were selective COX-2 inhibitors (celecoxib, the only one of this class now available in this country; rofecoxib; and 2 agents that have never been approved in this country-etoricoxib and lumiracoxib).

Compared with placebo, all these drugs were associated with an increased risk of stroke. Ibuprofen and diclofenac were most strongly associated; naproxen was least strongly associated. Rofecoxib and lumiracoxib were most strongly associated with myocardial infarction (MI); there was no apparent increased risk of MI with the other medications. Finally, all the drugs except naproxen were associated with an increased risk of CV death relative to placebo.

Trelle and colleagues³ thus concluded that with regard to CV adverse events, naproxen appears to be the safest of the NSAIDs. Celecoxib is an alternative, especially for patients who have difficulty with tolerating naproxen secondary to GI distress.

Obviously, this recommendation is limited by the relatively few NSAIDs for which the CV risks have been studied. Of special interest would be how the nonacetylated salicylates, such as choline magnesium trisalicylate (Trilisate), compare with the others. Medications in this class appear to be associated with less GI toxicity than the other nonselective NSAIDs, and their use avoids the concerns associated with selective COX-2 inhibitors.

References:

References

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.