In trials testing steroid injections and other active treatments, saline is typically used as the placebo. But Brown researchers found that saline can actually benefit individuals with spinal injuries, calling into question whether saline is the best placebo for these trials.
The team of researchers began looking at saline after patients who received saline injections around the spine “still seemed to improve” in a number of studies, according to Principal Investigator and Assistant Professor of Orthopaedics Bryce Basques.
If patients receiving saline are also improving, “comparing an active drug to saline might be underestimating the drug’s real benefit, since the ‘control’ itself is producing an effect,” co-author Maxwell Dassow ’27 explained.
Puru Sadh, first author and researcher for the department of orthopaedics, explained that this led the researchers to wonder if it was the tested injected fluid within the joints or the saline causing effects.
“That was really the turning point,” Sadh said.
The researchers conducted a systematic review and meta-analysis where they reviewed 18 randomized controlled trials including 759 patients who had received saline injections.
Within the study, the researchers focused on two different kinds of injuries: lumbar radiculopathy — pain from a pinched nerve in the spine — and discogenic pain, which is caused by damage to intervertebral discs.
Dassow explained that his work for the study included extracting data such as pain scores and disability information at various follow-up points within one year of injection.
According to Dassow, patients with lumbar radiculopathy who were given saline injections had statistically significant reductions in leg pain and disability, “exceeding clinically meaningful thresholds.” These improvements often lasted over time, Basques added.
The study also found improvements in patients with disc-related low back pain, but the effect size was less, Basques wrote. The injection point of the saline mattered as well with epidural saline providing “more consistent benefits” than intramuscular injections, Dassow added.
The saline injections might be producing these effects for a few possible reasons.
The fluid may reduce inflammation around an irritated nerve or wash out inflammatory chemicals around an irritated nerve, according to Basques.
Dassow also noted the “positive-feedback mechanism” that comes with the effects of saline where early relief and anti-inflammation from saline injections could help patients participate in rehabilitation and normal activity sooner.
“You can almost think of that early saline injection as an investment in the recovery process that allows for even more healing over time,” Dassow wrote.
For Alan Daniels, a professor of orthopaedics and spine division chief who was not involved in the study, the most important implication of this study is understanding “what component of an injection procedure is actually responsible for improvement,” he wrote in an email to The Herald.
“Researchers may need to think twice about using saline as the only placebo group,” Basques wrote, noting that the effect of the medication could be further explored by testing its effects against control groups that receive an active medication, saline and a true no-injection control group.
According to Sadh, future research into this topic is important to determine the “actual benefit” of the drugs being tested.
“Saline may not be as neutral as we once assumed, and we need to account for that when we compare treatments,” Basques wrote.
Alice Xie is a section editor for Science and Research from Los Angeles, California. She studies Applied Mathematics and Biology, and enjoys reading gut wrenching literature in her free time.
