Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: evidence from two parallel in vitro mouse models.
OBJECTIVE
Acetaminophen/hydrocodone, a commonly used analgesic preparation, has been linked to rapidly progressing sensorineural hearing loss in human patients. The cellular and molecular mechanisms underlying the ototoxic effects of this drug combination are currently unknown, but are usually associated with high doses of hydrocodone. This study was aimed at identifying the specific agent responsible for hearing loss from toxic killing of cochlear sensory cells.


METHODS
Dose-response study.


METHODS
University laboratory and private research facility.


METHODS
Math1 green fluorescent protein neonatal mouse cochlear cultures as well as a mouse auditory cell line (HEI-OC1) were exposed in vitro to different concentrations of acetaminophen, hydromorphone (the active metabolite of hydrocodone), and the micronutrient L-carnitine, either alone or combined. Using fluorescent and light microscopy, we quantified the sensory hair cells from a 600-microm basal segment before and after treatment. Acetaminophen/hydrocodone-induced apoptosis of HEI-OC1 was evaluated by caspase 3-activation studies. Statistically significant cell survival was determined with Student t test and analysis of variance.


RESULTS
Cell death was associated mainly with exposure to acetaminophen, was slightly potentiated when combined with hydromorphone, and was partially prevented by L-carnitine. Exposure to hydrocodone or hydromorphone alone failed to kill either cochlear hair cells or HEI-OC1 cells.


CONCLUSIONS
Our findings point to acetaminophen, rather than hydrocodone, as the primary cytotoxic agent. Hydrocodone, however, may work synergistically with acetaminophen, increasing the damage to auditory cells. These findings are an important first step toward understanding the mechanism of acetaminophen/hydrocodone ototoxicity and may lead to future treatment strategies for hearing loss from ototoxic medications.
Yorgason
Joshua G
JG
Division of Otolaryngology, University of Utah, Salt Lake City, UT, USA. joshyorgason@gmail.com
Kalinec
Gilda M
GM
Luxford
William M
WM
Warren
Frank M
FM
Kalinec
Federico
F
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004338:Drug Combinations; D006853:Hydrocodone / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004338:Drug Combinations; D000082:Acetaminophen; D006853:Hydrocodone