The objective of our study was to establish in sedated rats the consequences of high-dose fentanyl-induced acute muscle rigidity on the mechanical properties of the respiratory system and on the metabolic rate. Doses of fentanyl that we have previously shown to produce persistent rigidity of the muscles of the limbs and trunk in the rat (150-300 μg/kg iv), were administered in 23 volume-controlled mechanically ventilated and sedated rats. The effects of a low dose of the FDA-approved central α-2 agonist, dexmedetomidine (3 μg/kg iv), which has been suggested to oppose fentanyl-induced muscle rigidity, were determined after fentanyl administration. Fentanyl produced a significant decrease in compliance of the respiratory system (Crs) in all the rats that were studied. In 13 rats, an abrupt response occurred within 90 s, consisting of rapid rhythmic contractions of most skeletal muscles that were replaced by persistent tonic/tetanic contractions leading to a significant decrease of Crs (from 0.51 ± 0.11 mL/cmHO to 0.36 ± 0.08 mL/cmHO, 3 min after fentanyl injection). In the other 10 animals, Crs progressively decreased to 0.26 ± 0.06 mL/cmHO at 30 min. There was a significant rise in oxygen consumption (V̇o) during these muscle contractions (from 8.48 ± 4.31 to 11.29 ± 2.57 mL/min), which led to a significant hypoxemia, despite ventilation being held constant. Dexmedetomidine provoked a significant and rapid increase in Crs toward baseline levels, whereas decreasing the metabolic rate and restoring normoxemia. We propose that the changes in respiratory mechanics and metabolism produced by opioid-induced muscle rigidity contribute to fentanyl lethality. The decrease in respiratory compliance and increased metabolism-induced hypoxemia produced by an overdose of fentanyl, in and of themselves, contribute to fentanyl toxicity.