By Barbara Greenwood Dufour

Osteoarthritis is the most common joint disease in older adults. It’s estimated that by 2035, one in four Canadians will have been diagnosed with it. Osteoarthritis causes chronic pain and stiffness, and it’s a progressive illness for which there is no cure. Therefore, the goal of treatment is to control the associated joint pain and improve function and mobility.

Nonpharmacological options can be tried early in the disease (e.g., exercise, massage therapy, and heating pads or ice packs). But over time, as the severity of the osteoarthritis pain and functional impairment changes, pharmacological treatments are usually added — commonly acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. When the pain increases to the point that it can’t be adequately relieved by NSAIDs or acetaminophen, a weak opioid like codeine is sometimes prescribed. Codeine, available in tablet and liquid formulations, can be administered alone or as a single combination product (e.g., codeine with acetaminophen and caffeine).

Though codeine is weaker than some other opioids, there’s concern over its potential to cause a range of adverse events in some patients — including drowsiness, nausea, constipation, respiratory depression, as well as addiction. You may be aware that, after reports of codeine leading to serious adverse events in children (including death), various health organizations around the world warned against its use in pediatric patients. Codeine relieves pain when the body metabolizes it into morphine, and children who are ultra-rapid metabolizers tend to metabolize codeine too quickly, putting them at a high risk of adverse events.

Although codeine appears to be well tolerated in some adults, there can be variation in the ability of adults to metabolize it as well. Some adults might metabolize codeine too quickly, resulting in an adverse event; while others might metabolize codeine poorly and find that, as a result, it doesn’t control pain well. Adverse events are a concern for this latter group too, as they may accidentally experience one as they take increasing amounts of codeine to try and manage their pain.

To find out what the research says about the effectiveness of, and the risks associated with, codeine for osteoarthritis pain, CADTH reviewed the available research evidence on this topic. CADTH is an independent agency that finds, assesses, and summarizes the research on drugs, medical devices, tests, and procedures.

CADTH looked for studies specifically on codeine for managing pain from osteoarthritis of the knee or hip (though osteoarthritis can also affect other joints such as the hands, big toes, and spine). Three randomized controlled trials and one systematic review with meta-analyses (reporting on the same three randomized controlled trials) were found. One trial looked at codeine alone (as a controlled-release tablet), the second at codeine plus ibuprofen, and the third at codeine plus acetaminophen.

In the randomized controlled trials, one of the effectiveness outcomes was measured by whether patients needed to receive a “rescue” treatment to get their pain under control. The rescue treatment was acetaminophen in the codeine-only and codeine-plus-ibuprofen studies, and ibuprofen in the codeine-plus-acetaminophen study. The codeine-only study found codeine to be effective (reduced the need for a rescue medication), but the other two studies didn’t find that codeine plus acetaminophen or ibuprofen was effective in reducing the need for a rescue medication. However, the systematic review that assessed the pooled results from all three studies concluded that codeine might provide a moderate benefit in terms of osteoarthritis knee or hip pain and function.

Despite the mixed results in terms of the effectiveness of codeine for managing osteoarthritis pain, all three studies found that patients taking it were at a higher risk of adverse events — typically nausea and constipation. Pooled findings from the systematic review suggest that research study participants were more likely to withdraw from a study because of adverse events if they were in the group receiving treatment with codeine. Interestingly, although health organizations have warned against codeine use in certain populations because of the risk of respiratory depression, none of these studies reported on this safety outcome. So, we don’t know how many participants, if any, experienced respiratory depression.

It’s not clear how we can apply this research to clinical decision-making for treating osteoarthritis pain. None of the studies lasted beyond four weeks, so they don’t tell us how effective codeine is over time or about its long-term implications in terms of substance dependence, inappropriate prescribing, opioid misuse, and associated harms. In addition, all three studies were conducted more than 20 years ago. No relevant research has been produced recently — this could be because our understanding of how variable codeine’s effect can be from patient to patient makes the medication less attractive for research study, and the unpredictability of the medication might have already made both prescribers and patients more cautious about using it.

You can access the full report — Codeine for Pain Related to Osteoarthritis of the Knee and Hip — at cadth.ca. CADTH  has also produced reports on a variety of other pain-related topics, which you’ll find at cadth.ca/pain. Follow CADTH on Twitter: @CADTH_ACMTS or talk to our Liaison Officer in your region: cadth.ca/contact-us/liaison-officers.

Barbara Greenwood Dufour is a knowledge mobilization officer at CADTH.