Nancy A. Melville

October 15, 2009

October 15, 2009 (Phoenix, Arizona) — An intravenous formulation of ibuprofen, Caldolor (Cumberland Pharmaceuticals), can help offset the amount of opioid drugs required to manage postoperative pain and thereby help reduce some of the narcotic's sometimes significant gastrointestinal adverse effects, according to 2 studies presented here at the American Association of Pain Management (AAPM) 20th annual clinical meeting.

Although opioid drugs provide highly effective analgesia, they don't address postoperative inflammation, and with their high potential for gastrointestinal adverse effects, there is motivation to find modalities that lessen the reliance on such drugs, said Stephen R. Southworth, MD, an orthopaedic surgeon based in Tupelo, Mississippi, and lead author of one of the studies evaluating the optimal intravenous ibuprofen dose for postoperative pain management.

"The side effects from opioids, such as nausea, sedation, and constipation, all cost time and dollars to manage," Dr. Southworth said. "So the medical community is increasingly looking toward multimodal treatments to address pain management, with products such as ibuprofen as baseline [analgesia] and opioids added as needed to address pain."

Dr. Southworth and colleagues randomized 406 patients undergoing elective single-site orthopedic or abdominal surgery to 400 mg intravenous (IV) Caldolor, 800 mg IV Caldolor, or placebo. All patients also had access to morphine through patient-controlled analgesia, providing doses of 1 to 2 mg every 5 minutes.

The results showed that patients in the 800 mg group had a 25.6% lower median morphine use (P = .026) over the first 24 hours of treatment than the placebo group. Patients in the 400 mg group did not have a lower use of morphine, but both the 400 and 800 mg groups reported less pain at rest and with movement than with placebo.

Adverse events were similar across the 3 study groups. However, patients receiving Caldolor experienced fewer gastrointestinal disorders than those who received placebo (400 mg, P = .050; 800 mg, placebo, P = .009), and pyrexia was lower in the 400 and 800 mg groups than in the placebo group (400 mg, P = .013; 800 mg, P = .015).

Dizziness was higher among patients in the 800 mg group (9%) than in the 400 mg (6%) and placebo (1%) groups.

Dr. Southworth noted that since Caldolor is indicated for pain and fever, the reduction in fever was not surprising, and the dizziness could have resulted from the combination of drugs.

"While there was dizziness in patients receiving Caldolor in this study, all patients received concomitant morphine, which may have contributed to dizziness in patients."

In addition to Dr. Southworth's phase 3 dose-ranging study, a phase 3 study looking at the effect of IV ibuprofen on abdominal pain after hysterectomy was also presented at the AAPM meeting.

The multicenter randomized double-blind trial, led by Peter Kroll, MD, from Comprehensive Pain Specialists at Hendersonville Medical Center in Tennessee, involved 319 patients who underwent elective abdominal hysterectomy. The patients were randomized to receive 800 mg of Caldolor or placebo every 6 hours, in addition to self-administered morphine at a dose of 1 to 2 mg every 5 minutes.

The results showed that the Caldolor group had a median morphine requirement 21.5% lower over the first 24 hours of treatment than the placebo group (P < .001), and there was a reduction in pain at rest and with movement (P < .001 for both) in the Caldolor group.

In addition, the time to ambulation was faster in the Caldolor group (P = .018) than in the placebo group, and there were no significant differences between the 2 groups.

Dr. Southworth noted that the drug could be beneficial for a broad range of postsurgical patients; however, it is contraindicated in patients undergoing coronary artery bypass graft surgery.

"Caldolor is indicated in adults for the management of mild to moderate pain, the management of moderate to severe pain as an adjunct to opioid analgesics, and the reduction of fever," he said. "As such, the potential patient population for this product is broad, and not limited to any particular surgical population."

Some clinicians have concerns about bringing a drug like Caldolor into the mix during recovery, said Jane C. Ballantyne, MD, professor of anesthesiology and critical care at the Hospital of the University of Pennsylvania in Philadelphia. The nonopioid injectable analgesic ketorolac offers an adjunct option for postoperative pain relief, but there are concerns with that agent as well.

"The injectable NSAID [nonsteroidal anti-inflammatory drug] ketorolac is very useful for postoperative pain management, and is undoubtedly opioid-sparing, as are oral NSAIDs, and I would expect IV ibuprofen to be the same," she said.

However, "the reason surgeons do not like using NSAIDs postoperatively is 2-fold. First, renal dysfunction is expected after major surgery, so there is concern about their effect on renal function," she said. Second, "since bone healing is a significant factor after orthopedic surgery, there is also a worry about that."

Dr. Southworth said no adverse events related to kidney function were observed in his study or in subsequent abdominal and orthopedic studies with Caldolor.

"Side effects such as renal dysfunction sometimes seen with oral NSAIDs are often attributed to long-term use, whereas Caldolor will be used in a monitored hospital setting," he said.

Both ibuprofen studies received funding from Cumberland Pharmaceuticals. Dr. Southworth reports receiving investigational support through the study phase (ending in 2006), but has no ongoing connections to Cumberland Pharmaceuticals other than collaboration for the study publication. Dr. Ballantyne has disclosed no relevant financial relationships.

American Association of Pain Management (AAPM) 20th annual clinical meeting: Abstracts 49 and 50. Presented October 10, 2009.

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