Anesthesiologists who use perioperative clonidine in the hope of reducing acute postoperative pain or opioid consumption need to reconsider their efforts.
According to a randomized controlled trial at the Cleveland Clinic, in Ohio—the largest such trial ever—researchers found that the drug has neither of these perceived benefits, and its use may come at the expense of hypotension.
“Anesthesiologists have been using clonidine for sedation and analgesia for years, even though it’s primarily a blood pressure medication,” said Alparslan Turan, MD, professor of anesthesiology and vice chair of the Department of Outcomes Research at the Cleveland Clinic. “However, the only place where it’s been proven to work is in epidural and caudal analgesia. Oral and transdermal use have not been tested in large trials, and the data in the literature is not that solid.”
To help bridge this research gap, Dr. Turan and his colleagues enrolled 624 patients into the trial, all of whom were undergoing elective, noncardiac surgery under general or spinal anesthesia. The study, he noted, is a substudy of the POISE-2 (PeriOperative ISchemia Evaluation-2) trial.
Patients were excluded if their procedures were performed under local anesthesia, or if they received epidural analgesia or nerve blocks. Participants were randomly assigned to receive either 0.2 mg of oral clonidine (n=303) or placebo (n=321) between two and four hours before surgery, followed by a transdermal patch of either 0.2 mg per day of clonidine or placebo, which was maintained for 72 hours after surgery.
Similar Pain, Similar Opioid Use
As Dr. Turan reported at the 2016 annual Regional Anesthesiology and Acute Pain Medicine meeting (abstract 1312), no significant differences were found between groups with respect to pain scores. Indeed, patients in both groups reported a mean pain score of 3.6±1.8. Pain scores were comparable between groups at more than 24, 24 to 48 and 48 to 72 hours after surgery.
Similarly, the investigators found that patients in the two groups consumed similar amounts of opioids. Those who received clonidine consumed a total of 63 mg morphine equivalents over the 72-hour study period; placebo patients consumed 60 mg (ratio of means, 0.98; superiority P value, 0.92).
These results took Dr. Turan by surprise. “I wasn’t expecting a negative study; I was expecting positive results,” he said in an interview with Anesthesiology News. “Like most anesthesiologists, I believed that clonidine works on pain and reduces opioid consumption. Many ERAS [enhanced recovery after surgery] protocols call for clonidine, too, because it’s inexpensive. But the benefits have not been justified.”
The investigators conducted a meta-analysis of all available data on the subject of intraoperative clonidine’s effect on pain scores in noncardiac surgery patients. Five studies were included and bore a similar conclusion: Clonidine has no effect on pain at 24 or 48 hours after surgery.
“I think if you’re going to use clonidine, it shouldn’t be in the hopes of reducing pain or opioids, because I don’t think there’s any kind of data that supports that type of use,” Dr. Turan said. “This is especially so because clonidine has been shown to cause significant hypotension.
“So bear in mind that by giving clonidine you are not going to decrease pain scores or opioid consumption, but at the same time you may increase the risk of intraoperative hypotension.”
Future research, he added, will examine the effect of clonidine on the development of persistent surgical pain, which affects some patients months after surgery. “However, after the results of this study, we think that study will be negative as well, since the best predictor of persistent surgical pain is increased acute postoperative pain,” Dr. Turan explained.
Nebojsa Nick Knezevic, MD, PhD, clinical assistant professor of anesthesiology at the University of Illinois at Chicago, and director of clinical research at Advocate Illinois Masonic Medical Center, also in Chicago, noted that these results should make clinicians question whether clonidine still has a place as part of a multimodal strategy in noncardiac surgeries. “I was surprised with the results of this study, largely based on some positive effects of the drug on postoperative pain in children and also in studies that showed beneficial effects of clonidine as an adjuvant to local anesthetics,” he said. “I certainly wasn’t expecting the same pain scores in both the clonidine and placebo group.”