Injectable COX-2 Inhibitor Effective in Postsurgery Pain

ATLANTA—Parecoxib, the first injectable COX-2 inhibitor, demonstrated impressive analgesic efficacy in postsurgical patients, according to a study presented at the 19th Annual Scientific Meeting of the American Pain Society (APS).

Additional studies at the APS showed that postsurgical pain and analgesic side effects negatively affect hospital length of stay and return to normal activity. The new injectable cyclooxygenase (COX)-2 inhibitor may provide a new postoperative pain management option.

The NSAID ketorolac (Toradol), currently the only nonnarcotic injectable analgesic available in the United States, is routinely used in pain management because it lacks the adverse side effects of opioids, while achieving comparable analgesia in some settings. Narcotic analgesics have the potential for causing respiratory depression, shock, and cardiac arrest.

Ketorolac’s side-effect profile, however, makes postsurgical use difficult because it lengthens clotting time, can reduce blood flow to the kidneys, and can cause gastrointestinal ulceration and potentially severe GI bleeding.

COX-2 specific inhibitors are thought to relieve pain and inflammation by targeting the COX-2 enzyme. At therapeutic doses, they do not affect COX-1, which helps regulate normal cell function in the stomach and blood.

Unlike ketorolac, which affects both COX-1 and COX-2, COX-2-specific inhibitors like parecoxib are less likely to cause GI ulceration or promote bleeding, while still effectively reducing pain and inflammation.

A comparative analgesic efficacy study presented by Fred Langeland, MD, a clinical researcher at LDS Hospital, Salt Lake City, followed 202 women after abdominal hysterectomy. The multicenter, double-blind, controlled study evaluated parecoxib, ketorolac, and morphine vs placebo.

The study showed that single-dose parecoxib 20 mg and 40 mg were similar in their efficacy and side-effect profile, both providing analgesic efficacy superior in onset to that of morphine or placebo (parecoxib 40 mg, 14 min; parecoxib 20 mg, 23 min; ketorolac 30 mg, 10 min; morphine 4 mg, 23 min; placebo more than 24 hours).

Duration of analgesia was also significantly superior with ketorolac and parecoxib, compared with morphine or placebo (parecoxib 40 mg, 6 h 30 min; parecoxib 20 mg, 6 h 10 min; ketorolac 30 mg, 6 h; morphine 4 mg, 2 h 36 min; placebo, 1 h 50 min).

Additionally, the percentage of patients with a good or excellent pain self-evaluation was lowest in the placebo (16%) and morphine (44%) groups, intermediate in the parecoxib 40 mg (61%) group, and highest in the parecoxib 20 mg (73%) and ketorolac (78%) groups.

Among patients receiving active treatment, adverse events were lowest in the parecoxib 40 mg group at 84%, compared with parecoxib 20 mg at 87%, morphine at 88%, and ketorolac at 93% (placebo was 74%).

In the first of two related studies, postsurgical management methods and outcomes in 175 patients were assessed. Endpoints included postsurgical length of stay, pain severity, and side effects.

Twenty percent of women and 12.5% of men reported severe pain in the postoperative setting, which correlated with increased fentanyl dosing, increased recovery time, and greater incidence of fentanyl-related side effects (ie, nausea, vomiting, drowsiness).

D.J. Pavlin, MD, University of Washington, stated, "We found that pain was the leading medical cause of delayed discharge, followed by drowsiness, nausea, and vomiting."

In the second study, data were collected after discharge on pain scores, analgesic use and perceived satisfaction, incidence of side effects, percent functional recovery, and overall symptom distress scores.

A significant proportion of patients (24% of females and 32% of males) reported severe pain after returning home from outpatient surgery, and fewer than half were able to return to normal activity within 48 hours of discharge.

"A fairly significant predictor of activity level was the amount of CNS symptomatology (ie, drowsiness, difficulty concentrating, dizziness, and light-headedness), presumably related to opioids," Dr. Pavlin said. As expected, the severity of pain was also inversely correlated with activity level, second only to the CNS side effects. The side effect most strongly correlated with patient-perceived dissatisfaction was nausea, a key side effect of opioid analgesia.

Injectable parecoxib is under FDA review. Its role, after approval, Dr. Pavlin said, might be to help lower opioid dosing, minimize side effects, and thereby shorten length of stay and hasten return to normal activity in the postsurgical patient.

Dr. Langeland commented, "Part of the challenge has been to find an injectable analgesic that effectively relieves pain without causing the kinds of side effects we see with narcotics or ketorolac." He added, "It’s been more than a decade since we’ve seen a new injectable analgesic for the control of surgical pain. Our results suggest that parecoxib may be an efficacious and safe option."