**4. Paracetamol (acetaminophen) and hydrocodone**

Paracetamol, also known as acetaminophen (in the USA and Canada) or APAP, is the most commonly used pain killer in North America and Europe. It inhibits selectively cyclooxygenase-2 (COX-2) and may also exert other pain-relieving functions. Recent studies on selfreported professionally diagnosed hearing loss and use of analgesics indicated that regular use of paracetamol significantly increases the risk of hearing loss in men [45] and women [46]. The large size of samples with which the studies were performed (26,917 men and 62,261 women) makes both studies particularly credible.

The main conclusion from this study was that the long-term use of paracetamol (acetaminophen) increases the risk of developing hearing loss in men and women.

The mechanism of paracetamol-induced hearing loss was experimentally addressed in vitro [47]. The authors demonstrated that in the mouse auditory epithelium cell line, paracetamol and its metabolite NAPQI (*N*-acetyl-p-benzoquinoneimine) induce ototoxicity by causing oxidative stress as well as endoplasmic reticulum (ER) stress. These basic research results possibly explain the ototoxicity seen in people who regularly consume paracetamol. The question about usage of paracetamol and its frequency should be included in the surveys/questionnaires of patients with otologic and audiologic considerations.

Hydrocodone is a semi-synthetic opioid used for pain therapy and in common anti-cough medications. Hydrocodone is often prescribed in combination with paracetamol. In a report describing 12 patients with a history of hydrocodone overuse and progressive irreversible sensorineural hearing loss, the authors implicated nonresponsiveness of this type of hearing loss to corticosteroid therapy [48]. The authors reported that seven of eight patients who underwent consecutive cochlear implantation benefited from this type of auditory rehabilitation. Similar recent case report described a patient with unilateral hearing loss attributed to abuse of hydrocodone and paracetamol [49]. Also this patient was treated with cochlear implant.

The information delivered from the in vitro model with auditory epithelial cell line suggested that the combination of hydrocodone and paracetamol results in ototoxicity not due to hydrocodone but rather due to paracetamol [50]. The authors suggested that the contribution of hydrocodone to clinically seen ototoxicity may lay in hydrocodone assisting the addiction to the drug combination.
