Safety and pharmacokinetics of inhaled morphine delivered using the AERx system in patients with moderate-to-severe asthma.
OBJECTIVE
The safety and pharmacokinetics of inhaled morphine in asthmatic subjects were investigated using the AERx System, a novel aerosol system.


METHODS
Twenty subjects with asthma received inhaled placebo and inhaled morphine sulfate, 2.2 mg, 4.4 mg and 8.8 mg, on separate days in a single-blind crossover study. Six of the subjects received an additional open-label dose of 17.6 mg on a separate day. Plasma morphine concentrations and safety evaluations including pulmonary function testing were performed.


RESULTS
Mean tmax values were similar following all dose groups at approximately 1-2 minutes. Mean AUC(0-->1) values showed dose proportionality for the first 3 dose groups (6.3, 12.3 and 24.3 ng x h x ml(-1)), the mean AUC(0-->1) for the 17.6 mg dose group was 1.6x that of the 8.8 mg dose group. No statistically significant differences in forced expiratory volume in 1 sec (FEV1) were found for the 2.2 mg, 4.4 mg, or 8.8 mg dose groups; at 17.6 mg, a statistically significant but not clinically meaningful reduction in mean FEV1 (-8.18%) from baseline occurred at 10 minutes compared to placebo, spontaneously returning to baseline by 60 min. Four subjects experienced significant but reversible decreases in FEV1 of > or = 20% compared to baseline and across all dose levels including after placebo, but with no associated increase in dyspnea, wheezing or other adverse events.


CONCLUSIONS
Inhaled morphine using the AERx System was absorbed rapidly and demonstrated dose-dependent plasma concentrations. It was well-tolerated and did not cause clinically significant bronchoconstriction in most subjects with moderate-to-severe asthma.
Otulana
B
B
Aradigm Corporation, Hayward, CA 94545, USA. totulana@aradigm.com
Okikawa
J
J
Linn
L
L
Morishige
R
R
Thipphawong
J
J
D000280:Administration, Inhalation; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012720:Severity of Illness Index; D016037:Single-Blind Method
D018927:Anti-Asthmatic Agents; D009020:Morphine