MoxDuo's respiratory safety profile vs. morphine or oxycodone alone
Strong opioids can adversely impact respiratory function, as reflected by dose-dependent increases in oxygen desaturation (SpO2 <90%), low respiratory rates (<10/min), and the need for rescue by an opioid receptor blocker. Typically, such events are infrequent (<2%) when morphine equivalent doses (MED) of <15mg are used in healthy postsurgical subjects.
Patricia Richards, MD, PhD, and colleagues from QRxPharma Inc., Bedminster, NJ, reported results of a meta-analysis of respiratory data from three double-blind, 48-hour, bunionectomy trials of 975 subjects who were randomized to various doses of MoxDuo, morphine, or oxycodone.
In the first trial, patients (n=256) were randomized to treatment with MoxDuo 3/2, 6/4, 12/8, 18/12mg (MED 12-36mg), or placebo. In the second trial, patients (n=522) received MoxDuo 12/8mg, morphine 12mg, or oxycodone 8mg (MED 12-24mg) and, in the third trial (n=197), MoxDuo 6/4mg, 12/8mg, morphine 6mg, 12mg, or oxycodone 4mg, 8 mg (MED 12-24mg). Oxygen saturation was measured continuously during baseline and the 48-hour treatment periods with pulse oximetry.
The analysis included 60 patients receiving placebo, 433 receiving MoxDuo, and 482 receiving morphine or oxycodone. A total of 71.5% of those receiving MoxDuo received an MED that was at least twice that of the morphine or oxycodone groups, which provided a conservative bias (against MoxDuo) in the analyses.
The investigators found higher doses of MoxDuo (24mg MED) had almost twice the rate of desaturation as a lower dose (12mg MED), 4.6% vs 2.5%. Among patients experiencing desaturation at an MED of 12-24mg with MoxDuo or 6-12mg with morphine or oxycodone, the median cumulative dose to the time of the first desaturation was 72mg with MoxDuo and 24mg with morphine or oxycodone; therefore, three times more MoxDuo than morphine or oxycodone was required to achieve the first desaturation. Median number of episodes of SpO2 <90% was 1.5 with MoxDuo and 2.0 with morphine or oxycodone, indicating fewer desaturations occurred following MoxDuo in subjects who later experienced at least one desaturation.
Mean desaturation values were 86.9% with MoxDuo and 86.7% with morphine or oxycodone. The investigators noted that while the magnitude of desaturation appeared to be comparable between treatments, this could have resulted from administration of supplemental oxygen or arousal of patients by the medical staff as soon as a desaturation was detected.
Incidence of SpO2 <90% was similar when comparing treatment groups at an MED of 12mg: proportion of patients with SpO2 <90% by treatment group was 2.5% in the MoxDuo 6/4 (n=80), 2.4% in the morphine 12mg (n=209), 2.9% in the oxycodone 8mg (n=209), and 4.6% in the MoxDuo 12/8mg group (n=304). Incidence ranged from 2.4% to 2.9% with MoxDuo 6/4mg, morphine 12mg, and oxycodone 8mg; however, when high altitude sites were omitted from the data, differences between opioid treatments emerged. Data from two study sites located at a high elevation (4000+ feet) had a desaturation rate of 9.5-19.6% in the 57 subjects tested.
In contrast, the SpO2 <90% rate for the lower-altitude study sites was 1.6% for the 12mg MED doses of morphine or oxycodone, but was 0% for the 12mg MED dose of MoxDuo. The 24mg MED dose of MoxDuo had the same 1.6% desaturation rate as the 12mg MED doses of morphine or oxycodone. These results suggest that MoxDuo treatment at non-elevated sites was associated with a decreased risk of a desaturation when compared to morphine equivalent doses of morphine or of oxycodone.
“The lower partial pressure of oxygen in the inspired air at higher altitude is likely to have contributed to the markedly higher desaturation rate at the high altitude sites,” Dr. Richards noted.
No patients experienced a respiratory rate <10/min with MoxDuo at MED doses of 12-24mg, which was twice the MED of morphine or oxycodone. An infrequent, but detectable, effect of MoxDuo on respiratory rates was found at MED doses ≥30mg.
Dr. Richards et al found that the combination of morphine + oxycodone may have a superior respiratory safety profile to that of equianalgesic MED of morphine or oxycodone alone, with no patients demonstrating signs or symptoms of respiratory distress during treatment at the maximal doses evaluated up to 144mg MED over one or more 6-hour periods..
“MoxDuo represents a new approach for treating acute postoperative pain that offers enhanced efficacy with an improved safety tolerability profile, including a reduced risk of respiratory effects compared to equianalgesic MED of morphine or of oxycodone,” she concluded.