Opioid and cannabinoid combination showed no added pain relief in knee osteoarthritis, according to a new study

Opioid and cannabinoid medications did not provide strong pain relief or added benefit when used together in patients with knee osteoarthritis, according to a new study published in Anesthesiology.

Knee osteoarthritis is the most common form of arthritis and a progressive joint disease caused by the breakdown of cartilage, often leading to chronic pain, stiffness and reduced mobility, especially in older adults. Symptoms can worsen over time and limit daily activities, and while treatments such as medications and joint injections may help manage pain, there are no therapies proven to stop or reverse the disease. As rates rise with aging populations and increasing obesity, many patients continue to look for better pain relief options, including cannabinoids, which are natural or synthetic compounds that act on the body’s endocannabinoid system and help regulate pain, mood and inflammation.

Researchers from Johns Hopkins University School of Medicine, Ohio University, Heritage College of Osteopathic Medicine, Arizona State University and University of Maryland School of Medicine conducted a randomized, double-blind, placebo-controlled study to test whether the synthetic cannabinoid dronabinol and the opioid hydromorphone could improve pain control in patients with knee osteoarthritis. Interest in this approach has grown as clinicians look for alternatives to opioids, though past research on combining these drugs has shown mixed results.

In this study, researchers tested a lower dose of the opioid Dilaudid (hydromorphone) with the cannabinoid Marinol or Syndros (dronabinol) to measure pain relief, side effects, physical and cognitive function, drug effects and the risk for misuse.

The study enrolled adults with knee osteoarthritis between January 2021 and November 2023, with participants recruited through local advertisements, online postings and media outreach. All participants completed screening that included medical history, physical exams, drug testing and imaging to confirm disease severity.

Each participant also received multiple treatments across separate visits where they attended four study sessions spaced at least one week apart. During each session, they received one of four scenarios: hydromorphone alone, dronabinol alone, the combination of both drugs or a placebo. The first session always included hydromorphone alone to ensure safety, while the order of the remaining sessions was randomized.

According to the study, trial medications were given as oral capsules at doses commonly used in clinical care. Before and after dosing, researchers measured pain using both patient-reported scales and laboratory-based testing. These included heat, pressure and cold pain tests, as well as a capsaicin — the active component of chili peppers — model to simulate longer-lasting pain.

Additionally, participants completed physical function exams, such as walking and stair climbing, and cognitive tests that measured memory and reaction time. Researchers tracked drug effects, side effects and signs of potential misuse, including whether participants liked the drug or would take it again. Statistical analyses were conducted to compare outcomes across treatment conditions while accounting for factors such as sex and body mass index.

Out of the 21 participants, who on average were about 63 years old and were 57% female, researchers found no evidence that dronabinol improved the pain-relieving effects of hydromorphone across multiple experimental pain tests. Hydromorphone alone showed the least benefit in certain acute pain measures. For example, it increased pressure pain threshold compared with dronabinol and reduced mechanical temporal summation compared with placebo.

However, these effects were limited and were not seen across other pain measures, including heat, cold or overall pain sensitivity. In models designed to reflect longer-lasting pain, hydromorphone reduced mechanical temporal summation compared with placebo, but the addition of dronabinol did not improve outcomes, and no differences were seen in other chronic pain measures.

It was also revealed that no significant differences were observed across treatment groups for clinical pain severity or physical function, including walking distance, mobility or stair climbing. Patients did report noticeable drug effects, which differed across groups. Ratings of feeling “high” were significantly greater with dronabinol alone and in combination with hydromorphone compared with placebo. The combination also increased nausea compared with hydromorphone alone. Measures of misuse risk did not differ between groups.

Cognitive testing showed mixed effects. Hydromorphone alone impaired working memory compared with placebo, while the combination treatment slowed reaction time. Adverse events occurred in 28.6% of study sessions, with no serious events reported and no significant differences between treatment groups.

Overall, the findings resulted in limited pain relief and no clear added benefit from combining these medications in this patient group.

Based on study methods and data, its strengths include its randomized, double-blind, placebo-controlled design and use of clinically common doses, offering a careful look at how these drugs affect pain, function and safety in patients with knee osteoarthritis. However, a number of limitations could have influenced the results. For example, the study used an oral synthetic cannabinoid rather than natural cannabis, which may work differently in the body, and only tested one dose, limiting insight into dose response. The small sample size and short study period also limit how broadly the findings can be applied.

Researchers suggest future studies examine different cannabis forms, dosing strategies and longer-term use.