A study of medication for knee osteoarthritis points the way to new methods for ranking drugs' effectiveness

February 24, 2015 by Jacqueline Mitchell, Tufts University
“Using high-quality, large studies helped us to come up with very precise estimates, which allowed us to make conclusions with a lot of confidence,” says Raveendhara Bannuru. Credit: Depositphotos

Maybe you "trust Tylenol" or (like this writer) you're "all Advil." Research proves that both painkillers work, but many of us, including our doctors, can't help but have a preference shaped by experience and perhaps even advertising. Which really does work better? That's what Raveendhara Bannuru, director of the Center for Treatment Comparison and Integrative Analysis at Tufts Medical Center and a research assistant professor of medicine, wanted to find out.

Bannuru and his colleagues compared the effectiveness of various treatments for pain caused by knee osteoarthritis, one of the most common complaints among older people. Using data from 137 studies, the researchers compared the relative efficacy of five oral pain pills, including acetaminophen and ibuprofen (the generic versions of Tylenol and Advil), and two injectable drugs, and oral and injectable placebos.

Their results, published in last month's Annals of Internal Medicine, were somewhat surprising. Every treatment worked better than acetaminophen (Tylenol) with one exception: celecoxib, an expensive, newer drug once hailed as a miracle treatment for joint pain. Overall, the injectable therapies outperformed the oral pain medications, a finding that runs contrary to the conventional wisdom. What's more, the placebo injectables—that is, a simple shot of saline solution—provided patients pain relief comparable to any oral pain medicine tested.

Tufts Now asked Bannuru, who just completed his Ph.D. in clinical and translational sciences at the Sackler School of Graduate Biomedical Sciences, to tell us more about his .

Tufts Now: How is comparative effectiveness research different from other scientific research?

Ravi Bannuru: In , you randomize people for one treatment—say Tylenol—versus no treatment or placebo. Then you go and find an effect. Those are called efficacy studies. From efficacy studies we know, for example, that Tylenol is better than taking nothing or a placebo/dummy pill. And we also know that taking Aleve is better than taking nothing. But we don't know which of those two works better. With osteoarthritis alone, there are 20 to 30 treatments, and we don't always know which one to choose.

To answer that question, you need to do comparative effectiveness studies—that means you need to compare active treatments against each other.

How exactly do you compare treatments?

We look at existing research, including randomized clinical trials and observational studies, and we're able to estimate the differences between two drugs or therapies that were never compared before in a direct trial. We usually do meta-analyses and new kinds of analytical techniques like mixed treatment or network meta-analysis—when drug A is compared to drug B, and drug A is compared to drug C, we can estimate the difference between drugs B and C, even though they were never compared directly to one another. With this type of analysis, we can compare many treatments, and we can even come up with a ranking—for example, drug A is better than drug B, which is better than drug C.

Publication bias—the problem of some researchers submitting only positive results to publications—is an increasing concern among scientists. Since your work depends on others' research, does impact your results, too?

We try to address it, but we can't completely adjust for it. In this project, we went after and found many studies that were never published. I think that's the best way to address publication bias. We tried lots of tricks. We searched the FDA database for clinical trials that were submitted as part of the drug approval process, but were never published in scientific journals. In recent years, the website clinicaltrials.gov is encouraging authors to publish their study results. Our recent study has a very high number of unpublished studies—at least 15 studies.

How many studies do you need to compare to get good results?

Some people will do a meta-analysis with two studies—which is ridiculous. I could just read both studies. Usually, people say you need at least five for a simple meta-analysis. For a good analysis, 10 would be ideal. But there is no strict rule. Also, fewer large, high-quality studies are better than many small, low-quality studies. The more, the merrier—we used 137. Using high-quality, large studies helped us to come up with very precise estimates, which allowed us to make conclusions with a lot of confidence.

Is it sometimes hard to convince practitioners about your results, say if they fly in the face of conventional wisdom?

I would say it depends. I led a project to develop clinical practice guidelines [PDF] for the Osteoarthritis Research Society International that were released last March. Those guidelines are well accepted. They conditionally recommended the injection therapies.

In the new study that just got published, we are saying that injection therapy is better than pain pills. That's really a surprising finding. Other studies compare oral pills with dummy pills and injection therapies with dummy injections. Comparing these two kinds of studies, people used to say oral treatments are better than injections.

Now we are saying that's not right. To assess two different treatments, they need to be compared against a common treatment. For example, if A is better than B and C is better than D, we can in no way say that A is better than C. Instead, if A is better than B and B is better than C, then we can say that A is better than C by way of comparing both to B.

The study found that hyaluronic acid injections, used to replace natural fluids, ease pain more than many physicians thought. Were there other surprising results?

We found the placebo effects are not quite equal. We found injection placebos have more effect than oral placebos. We really want to explore that. As physicians, we can't separate the placebo effect from the treatment effect. As a patient, if I get that injection and my knee feels better, I don't really care whether it has active drug or placebo. So now we want to look into other placebos, like topical placebos and sham surgeries and sham acupuncture.

In sham surgeries and sham acupunctures, patients are put through experiences very much like surgery or acupuncture, but receive no treatment. In acupuncture, for example, the patient would have acupuncture needles inserted, but not in the specific ways prescribed by trained practitioners. Surprisingly, due to the , these sham procedures sometimes produce pain relief. We want to measure that placebo response as well.

If placebo effects are such powerful painkillers, could they be used to treat knee pain?

That's a philosophical question. As a physician, to make it ethical, I'd have to disclose it. I'd have to tell my patient that it's a placebo, that it doesn't contain any active drugs. But then if I disclose that, I don't know if it will still have the same painkilling effect. I'd like to study that. If it makes your knee feel OK for four weeks, why not just get a saline shot? That would be awesome. How we would pay—or get someone to pay—for the placebo treatment will also play a vital role in this decision-making process.

Explore further: Knee arthritis drugs beat placebos, but study finds no clear winner

Related Stories

Knee arthritis drugs beat placebos, but study finds no clear winner

January 6, 2015
(HealthDay)—Pain-relieving treatments for knee arthritis all work better than doing nothing—but it's hard to point to a clear winner, a new research review concluded.

'Placebo therapy' ineffective for long-term chronic pain relief

December 11, 2014
Scientists at the University of Liverpool have shown that 'placebo therapy' could be effective for short-term pain relief in patients with Complex Regional Pain Syndrome (CRPS), but does not have a lasting impact.

Placebo effects of different therapies not identical

July 31, 2013
Not all placebos are equal, and patients who respond to one placebo don't always respond to others, according to research published July 31 in the open access journal PLOS ONE by Jian Kong from Massachusetts General Hospital, ...

Study finds acupuncture does not improve chronic knee pain

September 30, 2014
Among patients older than 50 years with moderate to severe chronic knee pain, neither laser nor needle acupuncture provided greater benefit on pain or function compared to sham laser acupuncture, according to a study in the ...

Psychological factors play a part in acupuncture for back pain

February 12, 2015
People with back pain who have low expectations of acupuncture before they start a course of treatment will gain less benefit than those people who believe it will work, according to new Arthritis Research UK-funded research.

Why placebos for chemotherapy side effects are hard to swallow

November 10, 2014
It's unthinkable to give a placebo to someone to treat their cancer, but could we use one to treat chemotherapy's well-known side effects? Unfortunately, we may never be able to answer this question because the biggest obstacle ...

Recommended for you

Bug guts shed light on Central America Chagas disease

October 18, 2018
In Central America, Chagas disease, or American trypanosomiasis, is spread by the "kissing bug" Triatoma dimidiata. By collecting DNA from the guts of these bugs, researchers reporting in PLOS Neglected Tropical Diseases ...

Rapid genomic sequencing of Lassa virus in Nigeria enabled real-time response to 2018 outbreak

October 18, 2018
Mounting a collaborative, real-time response to a Lassa fever outbreak in early 2018, doctors and scientists in Nigeria teamed up with researchers at Broad Institute of MIT and Harvard and colleagues to rapidly sequence the ...

Researchers cure drug-resistant infections without antibiotics

October 17, 2018
Biochemists, microbiologists, drug discovery experts and infectious disease doctors have teamed up in a new study that shows antibiotics are not always necessary to cure sepsis in mice. Instead of killing causative bacteria ...

How drug resistant TB evolved and spread globally

October 17, 2018
The most common form of Mycobacterium tuberculosis (TB) originated in Europe and spread to Asia, Africa and the Americas with European explorers and colonialists, reveals a new study led by UCL and the Norwegian Institute ...

Infectious disease consultation significantly reduces mortality of patients with bloodstream yeast infections

October 17, 2018
In a retrospective cohort study conducted at the University of Alabama at Birmingham Division of Infectious Diseases, patients with candidemia—a yeast infection in the bloodstream—had more positive outcomes as they relate ...

Marker may help target treatments for Crohn's patients

October 16, 2018
Crohn's disease (CD), a chronic inflammatory condition of the intestinal tract, has emerged as a global disease, with rates steadily increasing over the last 50 years. Experts have long suspected that CD likely represents ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.