Three-Drug Combo Wins for Opioid-Sparing Pain Relief After Hip Replacement

Pain control during the first 24 hours after total hip arthroplasty was maximized in a randomized trial with a combination of acetaminophen (A), ibuprofen (I), and dexamethasone (D), as opposed to various combinations of two of these agents, researchers said.

With patients’ 24-hour use of “rescue” morphine as the primary outcome, median self-administered doses were 15 mg with the A-I-D regimen, versus 24 mg with A-I, 20 mg with A-D, and 16 mg with I-D, according to Joakim Steiness, MD, of Zealand University Hospital in Køge, Denmark, and colleagues.

Adverse events, particularly gastrointestinal distress and dizziness, were less common with A-I-D than the other regimens, the group reported in The Lancet Rheumatology.

But the results were disappointing in one respect. Steiness and colleagues had set a difference of 8 mg in morphine usage as the “minimal important threshold” for superiority, which A-I-D did not meet for any comparison after statistical adjustments. On the other hand, the differences were statistically significant for A-I and A-D when compared with A-I-D.

In recent years, the authors observed, postoperative pain control following joint arthroplasty has shifted away from opioids to other agents such as acetaminophen, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs), leaving morphine as an add-on for breakthrough pain. But no consensus exists on the optimal combination of non-opioid drugs in this setting.

That was the rationale for the new trial, dubbed RECIPE, conducted in nine Danish hospitals from 2020 to 2022. A total of 1,043 patients undergoing total hip replacement were assigned in nearly equal numbers to the four regimens. After surgery, patients were given a self-managed morphine pump, which could deliver 2-mg doses in intervals of no less than 10 minutes. (If patients had been on low-dose opioids or gabapentin prior to surgery, these were allowed to continue.)

Median patient age was 69 and just over half were women. Most patients were overweight; only a minority were obese. Preoperative use of acetaminophen and NSAIDs was common, but only about 10% were taking opioids, and just a few had used gabapentin or related agents.

Besides postoperative morphine use, pain levels at hour 24 were included as secondary outcomes. Patients rated their pain on a 100-point scale at rest, during mobilization of the replaced joint, and during a 5-minute walk test. These trended in favor of the A-I-D regimen. For example, the median for 24-hour pain at rest stood at 10 with the three-drug combination, versus 12-13 for the different two-drug regimens. For maximum pain during the 5-minute walk, medians were 27 with A-I-D compared with 30-35 for the others. But interquartile ranges were very broad (e.g., 1-20 for pain at rest with A-I-D), such that these differences were of questionable importance.

Some 35% of patients assigned to A-I-D experienced adverse events during the primary 24-hour observation, compared with 38% with I-D, 39% with A-D, and 63% with A-I. Patients in the latter group suffered many more instances of dizziness during the walk test and more bouts of nausea and vomiting — these were about twice as common with A-I than with the other regimens.

Perhaps most important, there was no outcome tracked in the study for which A-I-D appeared at all inferior to the other treatments. Besides those mentioned above, Steiness and colleagues checked patients’ sleep quality, serious adverse events within 90 days, Oxford hip scores, and self-rated health status.

Steiness and colleagues stopped short of recommending A-I-D as the best opioid-sparing regimen after hip replacement, acknowledging that the results failed to meet the prespecified threshold for morphine usage. But they also stopped short of recommending that another trial be conducted.

A somewhat peevish accompanying editorial accentuated this uncertainty. “Does this study help clinicians answer the question about the optimal multimodal analgesic opioid-sparing regimen for hip arthroplasty? Yes and no,” wrote Paul S. Myles, MD, DSc, and Susan M. Liew, MBBS, both of Monash University in Melbourne, Australia.

Mainly, the editorialists disagreed that morphine use was a good surrogate for postoperative pain. Steiness and colleagues did report patients’ direct pain evaluations both at hour 6 and hour 24, which also generally favored the A-I-D regimen, but as these were exploratory outcomes, apparently Myles and Liew felt they were unreliable. They also complained that the morphine pumps would interfere with “fast-track” recovery, during which patients are encouraged to move around almost immediately, although Steiness and colleagues didn’t indicate that the pumps would be indispensable to the protocol in routine practice.

In any event, Myles and Liew were unpersuaded by the RECIPE results. “The complete analgesic effectiveness of the triple combination of [acetaminophen] plus ibuprofen plus dexamethasone and any benefits for rehabilitation and longer-term prosthetic hip function remain in doubt,” they wrote.

Please enable JavaScript to view the comments powered by Disqus.