The Ability Of Fentanyls And Other Opioids To Increase Emg Amplitude In Respiratory Musrespiratory Muscles Correlates With Their Agonist Efficacy

Acute overdose deaths involving fentanyls have been dramatically increasing in the USA since 2013. These potent opioids depress respiratory drive and produce rigidity in the intercostal muscles and diaphragm (resulting in what is referred to as Wooden Chest Syndrome) as well as in glottic and supraglottic muscles which further reduces the ability to breathe. In this study we have sought to characterise the ability of various opioid agonists to induce respiratory muscle rigidity using electromyographic (EMG) recording. EMG amplitude was recorded simultaneously from diaphragm, external and internal intercostal muscles of P21 male Wistar rats, using an in situ decerebrated and arterially perfused preparation. First, the effects of fentanyl and morphine on respiratory muscle EMG were studied using a dose of each agonist that depressed respiratory rate by approximately 40%. Fentanyl produced a marked increase in EMG amplitude during expiration in all three respiratory muscles whereas the effect of morphine was very slight. In order to understand whether the difference between fentanyl and morphine related to differences in chemical structure, lipid solubility or agonist intrinsic efficacy we studied the effects of a range of opioids that differed in these characteristics – carfentanil and fentanyl (piperidine derivatives, high lipid solubility, high efficacy), alfentanil (piperidine derivative, moderate lipid solubility, high efficacy) norbuprenorphine (thebaine derivative, high lipid solubility, high efficacy), levorphanol (morphinan, high lipid solubility, low efficacy), morphine and hydromorphone (morphine derivatives, low lipid solubility, low efficacy). With doses of each that produced around 40% depression of respiratory rate we observed that the rank order of ability to increase internal and external intercostal muscle EMG amplitude was carfentanil = fentanyl = norbuprenorphine > alfentanil = hydromorphone > morphine = levorphanol but for the diaphragm the rank order was fentanyl > alfentanil = norbuprenorphine ≥ hydromorphone > carfentanil ≥ morphine = levorphanol. These results suggest that the ability of opioid agonists to increase respiratory muscle EMG amplitude and therefore respiratory muscle rigidity does not depend solely on either chemical structure or lipid solubility of the agonist. For the intercostal muscles there is a better correlation with agonist efficacy. Why the effect of carfentanil on the diaphragm is weak remains to be elucidated.