The safety of painkillers

Peter Wehrwein

Contributor, Harvard Health

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 pharamaceutical 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.



    Drugs abuse is always a bad thing !!!

  2. Jevaughn Brown

    It’s kind of backwards to me that the medical pain relief treatment in our advanced times consists of waffling between different classes of artificial chemicals which all harm, seriously injure, addict, or even kill users if there’s even a small mistake in their usage, never mind outright abuse. Or even if they’re used as prescribed.

    Meanwhile the way to figure out how not to use a painkiller, or which not to use, amounts to watching and waiting to see who turns up in the ER or morgue, then looking at how/what they were using the stuff so we can say, “OK, don’t do THAT.” Maybe that’s an unavoidable reality of testing & observation but the human cost is so terrible.

    And it seems that as the years go by every single painkiller available – after all the assumptions and assurances of them being “less harmful” or “less addictive than” – is eventually shown to have been causing injuries and deaths that were not recognized as being their fault all this time…

    I think if we’re all honest about it these various research studies are just saying that they’re all dangerous toxic compounds to some degree that just happen to have a pain relief (side)effect to them that we can use. I hope the field of Medicine or at least individual doctors and pharmacists start actively shifting towards non-toxic painkillers rather than just distributing whatever strictly-for-profit pharmaceutical companies hand them. It’s *first* do no harm, after all.

    Jevaughn Brown

  3. Ray Foucher, natural pain relief guide mgr

    The first line of defense against pain or the need for pain killers should be a healthy lifestyle to minimize the need for solutions to pain. The second line of defense should be natural means of pain reduction [URL removed by moderator].

    It is also important to realize that prescription drugs that merely shut down pain are actually turning off an important (even if painful) signal by the body that something is wrong. That the pain often reaches an intolerable level is just further evidence that the cause is not being adequately dealt with. And then drugs, which do nothing to address the cause are obviously nor the solution.


    It’s so sad – all the negative side effects from these drugs and the dependency on them that can set in. We can only do our part by informing people of the dangers and offering our help. Remember, this month is National Alcohol and Drug Addiction Recovery month (every Sept).

  5. autoseedsbank..

    Do you have any information on the use of Cannabis as a Pain Killer please.

  6. J Cat

    Many people take these pain killers when they have an injury. People really need to look to alternatives. Cold Therapy is often a treatment that is many times over looked. Also a brace to relieve pressure can be helpful. is a great source of information. Herbal medicines don’t really work and also have side affects. Medicine is not the only answer.

  7. AL

    Well said! While cleaning the apartment of my recently deceased sister-in-law, I filled an entire suitcase with her many, many bottles of the same drugs. She had doctor shopped and pharmacy shopped to acquire these. I know both doctors and pharmacists are extremely busy and I don’t know how they could have discovered her visits to different doctors and pharmacies for the same malady…perhaps a central registry? I know; I can hear the screams of invasion of privacy but could it not be done with just numbers that a computer check would prompt further investigaation b4 the rx was filled?

  8. CM

    My sister died from Percocet addiction. She did search out the drug and it was prescribed by several doctors who didn’t know the others were prescribing it as well. I would like to see a national registry of opiod painkillers established so patients can’t doctor and pharmacy shop and where the pharmacy would have to notify the doctors of multiple prescriptions and the possible abuse by their patient. I also blame pharmacists who know they are filling multiple prescriptions.
    The death rate is soaring. And mixing them with ant alcohol is also deadly.

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