**6. Immunosuppressant calcineurin inhibitors (cyclosporine A and tacrolimus)**

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

phen) increases the risk of developing hearing loss in men and women.

naires of patients with otologic and audiologic considerations.

women) makes both studies particularly credible.

240 Advances in Clinical Audiology

the drug combination.

**5. Methadone**

addicted to opioids.

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

The main conclusion from this study was that the long-term use of paracetamol (acetamino-

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/question-

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

Methadone is an opioid drug for treating pain. In addition, it is used for therapy of people

In the year 2014, about 7 million US citizens were abusing prescription drugs (source: National Center for Health Statistics). One of these drugs is methadone. Six recent case reports exposed an unknown before side effect of methadone abuse–the hearing loss [51–55]. The patients described in reports were young (age range 20–37) and were admitted to the hospitals because Since the beginning of transplantology in the sixties, several people with incurable diseases of liver, kidney and other organs received the donor tissues as therapeutic procedure. This type of therapy is combined with an inevitable immune reaction against the *non-self* tissue. To prevent these reactions, immunosuppressants are used. Among them, cyclosporine A and tacrolimus (FK506) are commonly used to prevent graft rejection reaction. Both drugs decrease in various ways the activation of lymphocytes T and thus inhibit the graft rejection process. The immunosuppressants must be taken continuously.

Rifai et al. [56] performed a large study involving 521 liver transplant patients. The study was based on self-reported hearing loss and showed that of 521 individuals, 141 (27%) developed hearing loss following transplantation, particularly in those patients who were receiving tacrolimus as principal immunosuppression. This study was followed by recent trial, where instead of self-reported hearing loss, audiometric measurements were performed [57]. Of 70 liver transplant patients included in that study, 32 reported hearing loss and tinnitus following the transplantation. The types of hearing loss included sudden hearing loss and progressive hearing loss, which developed more than 3 years after transplantation. Audiometry confirmed the patients' reports and identified 12 patients with mild, 28 with moderate and 25 with severe hearing loss following the transplantation. The association between tacrolimus and hearing loss was seen again in this study.

Another group of transplant patients is the renal transplant group. Kidney transplantation is a surgical procedure performed since the mid-fifties last century; however, postsurgical survival was very low, because of the graft rejection [58]. The introduction of cyclosporine A in the eighties significantly improved the post-transplant survival rate but brought another type of problems, namely adverse reactions such as hearing loss. Renal patients are known to often have hearing impairments [59], and it was shown that the renal transplantation restores the hearing abilities, when measured 1 year after surgery. However, some renal transplant patients who are on a long-term immunosuppressant therapy such as cyclosporine A or tacrolimus develop hearing disabilities including sudden sensorineural hearing loss [60–62] or a progressive hearing loss [63].

Particularly, worrying tendency is seen among the pediatric renal transplant patients. A prospective study of 27 children (mean age 14) with normal hearing prior to kidney transplantation determined after a mean follow-up of 30 months that 17 children developed sensorineural hearing loss [60]. Two of 17 children were diagnosed with sudden hearing loss and the rest of the group with a progressive bilateral hearing loss.

It is likely that the ototoxic effect of immunosuppressants depends on the length of time of intake. Groups studying noise-induced hearing loss have successfully used cyclosporine A and tacrolimus to protect the auditory epithelium in mice from the noise-induced injury [64]. However, the dosage was single and not–like in the case of transplant patients–years long.

The treatment of hearing impairment occurring in organ transplant recipients includes hearing aids and cochlear implantation [65]. However, one should not ignore the fact that these patients are immunocompromised, and therefore, the risk of wound infection after CI should be taken under consideration during postsurgical management.
