The safety of painkillers

Perhaps as many as one in every 5 American adults will get a prescription for a painkiller this year, and many more will buy over-the-counter medicines without a prescription. These drugs can do wonders—getting rid of pain can seem like a miracle—but sometimes there’s a high price to be paid.

Remember the heavily marketed COX-2 inhibitors? Rofecoxib, sold as Vioxx, and valdecoxib, sold as Bextra, were taken off the market in 2004 and 2005, respectively, after studies linked them to an increased risk of heart attack and stroke.

The nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, ibuprofen (sold as Advil and Motrin), and naproxen (sold as Aleve) seem like safe bets. But taken over long periods, they have potentially dangerous gastrointestinal side effects, including ulcers and bleeding. Kidney and liver damage are possible, too. More recently, some of the NSAIDs have been linked to an increased risk of cardiovascular disease. Low doses of aspirin (usually defined as 81 mg) is an exception and is often prescribed to lower the risk of heart and stroke.

Even acetaminophen, which is often viewed as the safest pain drug and a low-risk alternative to the NSAIDs because it doesn’t have their gastrointestinal side effects, comes with a caution about high doses possibly causing liver failure.

Then there are powerful opioid painkillers, which include codeine, morphine, methadone, and other drugs that are much better known by their brand names. These include Oxycontin, a sustained-release form of oxycodone; Percocet, a combination of oxycodone and acetaminophen (acetaminophen is the active ingredient in Tylenol); and Vicodin, a combination of hydrocodone and acetaminophen.

The number of prescriptions being written for the opioid drugs has skyrocketed in the last 10 years or so, partly because doctors are encouraged to treat chronic pain these days and partly because the problems with the non-opioid  painkillers have become more evident.

Of course, the opioid painkillers are not without their problems. People misuse them to get high. The risk of addiction is real. And even when used as prescribed for pain, larger and larger doses may be needed to achieve the same effect. Deaths from overdoses of opioids have been  increasing at an alarming rate.

And in November, an opioid called propoxyphene (sold as Darvocet and, when combined with acetaminophen, as Darvon) was taken off the market after the FDA advised doctors to stop prescribing the drug because it can cause fatal heart arrhythmias.

Making side-by-side comparisons

Two studies published in the Archives of Internal Medicine last week help put the safety problems of many of the  painkillers in perspective by making some side-by-side comparisons. One of the studies compared the safety of NSAIDs with the safety of COX-2 inhibitors and the opioid painkillers when they are prescribed for osteoarthritis and rheumatoid arthritis. The other study compared the safety profiles of five opioids (codeine, hydrocodone, oxycodone, propoxyphene, tramadol) when they were prescribed for pain not related to cancer.

Researchers at Harvard-affiliated Brigham and Women’s Hospital conducted both studies. The raw data for their analysis came from pharmaceutical assistance programs for low-income adults in New Jersey and Pennsylvania in the late 1990s and early 2000s. The researchers used an interesting statistical technique called propensity scoring, which tries to make the comparison groups developed from observational data the same,  just as the comparison groups would be in a randomized clinical trial, the gold standard for medical research. Both studies were paid for by a grant from the Developing Evidence to Inform Decisions about Effectiveness program run by the Agency for Healthcare Research and Quality, a federal government agency.

In many ways, the results from the study comparing NSAIDs, COX-2 inhibitors, and opioids aren’t all that surprising. They show that in most respects, the NSAIDs are as safe, and probably safer, than the COX-2 inhibitors. The notable exception is gastrointestinal bleeds, and that’s not going to turn many heads because “sparing the gut” had been the chief selling point for the COX-2 inhibitors.

Also to be expected: the opioids are riskier in almost all categories than the NSAIDs and COX-2 inhibitors.

Still, it was a surprise that the opioids are associated with a higher risk for cardiovascular events (heart attacks, strokes, out-of-hospital cardiac death) than the NSAIDs and COX-2 inhibitors, according to Dr. Daniel H. Solomon, the lead author. Reviewers and some senior colleagues were skeptical, he says (keep in mind the paper was under review before Darvocet and Darvon were taken off the market).

Dr. Solomon says the next step is to re-analyze the data to see whether specific opioids might be related to specific kinds of arrhythmias or other sorts of heart problems.

Another novel finding was that opioid users were much more likely to break a bone than people taking NSAIDs or COX-2 inhibitors. An opioid–fracture link has been reported before. Opioids increase the risk of falling and may also weaken bones by altering hormone levels. But the fracture risk among opioid users was much higher than the risk seen in prior studies.

Codeine not-so safe

As for the second study comparing the five opioid drugs, the biggest surprise there was that codeine emerged looking much riskier than the other four drugs with respect to cardiovascular events and all-cause mortality.

That’s unexpected because doctors tend to view codeine as a milder, safer opioid. An editorial in the Archives about the study talks about codeine being a “middle-ground treatment” between all the various non-opioid painkillers and the more powerful opioids. It continues:

The untested but widespread assumption that codeine is safer from an addiction standpoint because of its lower potency may need to give way to these data demonstrating increased risk of cardiovascular events and all-cause mortality. If codeine is of middling efficacy for pain and is more risky than other opioids, there would be little reason to use it.

Of course, as the editorial points out, it will take more research to figure out whether that is really the case.

A more complete conversation needed

So where does this leave us?

Certainly that much more wary of opioid painkillers, and perhaps of codeine in particular. The FDA has been moving toward requiring special training for doctors who prescibe extended-release and long-acting opioids because of abuse and overdose problems. These results add side effects and safety considerations to the argument that it’s time to rein in the runaway use of opioid painkillers.

Dr. Solomon said the broader theme of the research is to re-evalate painkillers as a group and across various safety problems. Often, he says, researchers and doctors have been a bit myopic, focusing on one drug and one side effect or safety problem at a time. “The conversation about the side effects from painkillers needs to be more complete,” he says.