Morphine/Oxycodone Combination Superior to Separate Components
Montreal—MoxDuo, a fixed-dose combination of morphine sulfate and oxycodone hydrochloride, helped relieve patients’ acute moderate to severe pain following bunionectomy surgery and led to fewer side effects compared with equivalent analgesic doses of morphine and oxycodone alone, according to a Phase II clinical trial presented at the International Association for the Study of Pain meeting in Montreal (posters PH326 and PH328).
“To obtain market approval for combination analgesics, the FDA requires the combination be better than its individual components,” explained lead author Warren Stern, PhD, executive vice president of drug development at QRxPharma, the study’s sponsor. “This two-part study shows that treatment with the combination regimen is more effective than with its components.”
The study, presented in two poster sessions, compared the analgesic effects and side effects of MoxDuo with its individual components administered at equianalgesic doses to patients who experienced moderate to severe pain following a unilateral bunionectomy. Patients were included if they had baseline pain intensity of at least 2 on a Likert scale and at least 4 on the 10-point Numerical Pain Rating Scale (NPRS) within six hours after the surgery. Patients were excluded if they were receiving nonopioid analgesics at doses high enough to interfere with the study medications.
Dr. Stern and his colleagues randomized 196 patients, from six sites across the United States, to receive oral treatments of MoxDuo morphine 12 mg/oxycodone 8 mg (12/8 mg), morphine 12 mg, oxycodone 8 mg, MoxDuo 6/4 mg, morphine 6 mg or oxycodone 4 mg every six hours over a 48-hour period (PH326). Of the patients in the study, 83.8% were women. Study participants had a mean age of 46 years and a mean baseline PI score of 6.6 on the NPRS. The primary measure was time-weighted sum of pain intensity differences zero to 24 hours postsurgery (SPID24).
The investigators found that, compared with its individual milligram components, the dual-opioid MoxDuo produced better pain relief with the 12/8-mg and 6/4-mg doses. The higher-dose combination regimen (MoxDuo 12/8 mg) was significantly more effective than either component administered separately (P<0.05). The 12/8-mg combination also had the highest number of responders at 24 (76.5%) and 48 hours (94.1%), and was superior at reducing pain compared with the morphine 12-mg and oxycodone 8-mg groups. Results were comparable for the MoxDuo 6/4-mg group compared with its components.
Despite having twice the analgesic power, the higher-dose combination showed similar treatment-emergent adverse events compared with the other doses. The number of patients who had at least one adverse event was similar in the 12/8-mg group (91.2%) compared with the morphine 12-mg group (96.6%) and the oxycodone 8-mg group (70.6%). The incidence of opioid-related events in the MoxDuo 6/4-mg group also was lower than that in the morphine- or oxycodone-alone group.
The most common moderate to severe adverse events in the 12/8-mg group compared with the morphine and oxycodone groups, respectively, were nausea, 35% vs. 28% and 26%; vomiting, 35% vs. 21% and 21%; and dizziness, 12% vs. 7% and 12%. Overall, both dose levels provided substantial pain control and were well tolerated by patients.
In the second part of the study (PH328), the investigators found that three morphine-equivalent dose treatments (MoxDuo 6/4 mg, morphine 12 mg and oxycodone 8 mg) had comparable analgesic effects as measured by SPID24 (least squares mean, 30, 28.5 and 35.7, respectively).
The percentage of patients reporting common opioid adverse events, however, was markedly reduced in the 6/4 mg group compared with the morphine 12-mg or oxycodone 8-mg groups. The patients indicated lower rates of moderate to severe nausea (9.4% vs. 27.6% and 26.4%, respectively), emesis (6.3% vs. 20.7% and 20.5%), dizziness (3.1% vs. 6.9% and 11.7%) and treatment-emergent constipation (3.1% vs. 10.3% and 5.9%). The percentage of dropouts also was lowest in the 6/4-mg group (3.1% vs. 6.9% and 11.8%).
The investigators suggested that the tolerability and low rate of discontinuation of patients in the dose-combination regimens might lead to greater acceptance for using combination doses of opioids.
“Anesthesiologists discovered years ago that it was easier to control pain intraoperatively and postoperatively by using a combination of analgesics,” said Lynn Webster, MD, medical director of Lifetree Clinical Research and Pain Clinic in Salt Lake City.
Dr. Webster added that this concept is now used to combine opioids because each opioid has a different chemical and unique effect and some patients have more relief with one type of opioid than another.
Based on the study results, Dr. Stern said that QRxPharma, which has locations in Bedminster, N.J., and Sydney, Australia, will seek approval for four fixed-dose combinations of MoxDuo: 12/8, 9/6, 6/4 and 3/2 mg.
“The concept is sound, but we will have to see how it pans out when the drug is approved,” said Dr. Webster. “I believe it will be more effective at lower opioid doses than using one opioid at higher doses.”http://www.anesthesiologynews.com/ViewArticle.aspx?d=Pain%2BMedicine&d_id=2&i=January%2B2011&i_id=693&a_id=16453
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