In 2001, radio talk show host Rush Limbaugh announced to his listeners that he woke up one morning deaf in his right ear and that deafness had progressed to complete hearing loss over 4 months. A tentative diagnosis of autoimmune hearing loss was made, and he received cochlear implants, restoring his hearing. Two years later, on his October 10th, 2003 broadcast, he described his long-term addiction to prescription painkillers after a failed back surgery. While a definitive diagnosis of opioid-induced hearing loss was not established (and is not possible), the clinical course is precisely what is described in many cases of opioid-associated hearing loss.
What’s going on here? Is this a thing? Is this anything?
An unusual effect of opioids, hearing loss is well-described in acute overdose, short-term use, and chronic abuse. Patients with opioid-associated hearing loss usually describe a precipitous onset of unilateral or bilateral hearing loss, which can become profound. Descriptions of the changes in hearing include a feeling of being underwater, or in a tunnel. Tinnitus occurs variably, and vestibular functions are spared. About 50% of cases resolve, and patients on whom audiometric testing is performed demonstrate flat, profound hearing loss (Figure 1) with absent otoacoustic emissions (more on that later) and normal vestibular evaluation.1 In cases which don’t improve, cochlear implants are curative. But how does this happen?
Fig 1. Audiogram demonstrating the bilateral severe hearing loss in a patient after heroin use1
Theories abound, from hypoxia and focal cochlear ischemia to a direct drug effect. How might this fit into what we know about drug ototoxicity? Let’s take a look at how hearing actually works.
Sound waves begin their journey in the external auditory canal, encountering first the tympanic membrane, the three middle ear ossicles, and then the inner ear (cochlea). From there, hair cells in the Organ of Corti convert mechanical waves into neurologic signals. The otic hair cell is a delicate genius and requires the support of the nearby stria vascularis to maintain needed substrates like endolymph, perilymph, and electrochemical gradients to effectively depolarize. Hair cells work their magic transforming shear forces into potassium influx and neurotransmitter release at the vestibulocochlear nerve. Then neural signals propagate throughout the brain, terminating in the auditory cortex in the temporal lobes and . . . Voila! Sound.
This can go wrong in two broad categories, conductive or sensorineural hearing loss. Conductive hearing loss results when something prevents the sound from reaching the cochlea: external or middle ear damage, obstruction, impaction, foreign bodies, and even ear wax. Sensorineural hearing loss is the category into which all drug-induced ototoxicity falls.
Most ototoxic drugs exert their effect on the cochlea itself. This includes the well-known Big Bad Wolves of ototoxicity – aminoglycosides, platinum chemotherapeutics, quinine, loop diuretics, salicylates, and NSAIDs – as well as others like bromates, styrene, metals, carbon monoxide, and cocaine. Drilling down further into the site of cochlear injury, this can occur either directly to the hair cells or at the stria vascularis. Hair cells are vulnerable to hypoxia/ischemia, hemorrhage, vasoconstriction, and alterations in membrane fluidity and blood flow. The stria vascularis’ complex metabolic functions are often the target of drug-induced ototoxicity and are disrupted through interference with sodium/potassium pumps, adenyl cyclase, carbonic anhydrase, and free radical-induced damage. For example, salicylates are thought to cause reversible hearing loss due to alterations in hair cell turgor as well as inhibition of prostaglandin synthesis and sodium/potassium pump function.2 Drugs with both oto- and nephrotoxic properties most likely share ion channel-disrupting properties.
Where do opioids fit in here?
The literature is mostly a salad of case reports and case series, and the overall numbers are small. There are more questions than answers, but here’s what we do know:
1) This is not unique to oxycodone, or heroin, or any other opioid. Although a recent review of our deafness data in NJ demonstrates a preponderance of heroin exposures, opioid-associated ototoxicity has been reported with oxycodone, hydrocodone, propoxyphene, dextropropoxyphene, methadone, heroin, codeine, and morphine.3 This variety dispels the notion that hearing loss is a result of individual pharmacogenomic variation (like a CYP3A4 polymorphism) because each drug is metabolized by different enzymes. There may be some agent-specific nuances in terms of which drug achieves the highest cochlear concentrations, but there is no data on this front.
2) The route does not seem to matter. Neither does age, gender, or chronicity. Inhalation, oral, injection – all 3 are reported in acute overdose but also long-term high-dose use. What probably does contribute itoacute exposure cases is the presence of adulterants or other drugs. For example, heroin adulterated with quinine (a known ototoxin) could pack a one-two punch. Cocaine has been linked to cochlear hemorrhage and vasoconstriction, so a patient after speedballing has (at least) 2 reasons to wake up deaf.4
3) We can’t blame hypoxia, at least not entirely. Deafness occurs in the absence of apparent hypoxic insult. The initial impression in these cases is often that, because the patient was “found down”, they had a hypoxic insult which causes all manner of end-organ dysfunction, including to the hair cells. But some patients have no such episode. Interestingly, many cases present with deafness as the chief complaint. This is very different from waking up deaf after a period of unresponsiveness and a smidge of resuscitation, although this happens as well.
4) Prognosis may depend on chronicity. No statistical association has been demonstrated, but the cases in the literature which resolve completely are mostly acute exposures.5,6
5) The cochlea most likely takes the hit. Unlike some toxins which cause sensorineural deafness by a direct effect on the cochleovestibular nerve or other neural pathways, the injury pattern here all points to the cochlea. This is most evident in the fact that cochlear implantation completely restores hearing in these cases, and the absence of otoacoustic emissions (OAEs). What’s that, what’s that you say? OAEs measure the tiny sounds the inner ear reflects back into the external canal when sound waves are conducted. If there are no OAEs, the cochlea is not working. So in this instance, the tympanogram is normal (because the tympanic membrane is ok), but the audiogram is bad (because the patient can’t hear) and the OAEs are absent (because the cochlea has checked out).7
But how? ¯\_(ツ)_/¯
The answer may lie with cochlear opioid receptors, located on the inner and outer hair cells, and the stria vascularis, which maybe inhibit adenyl cyclase and throw off a delicate balance.2 The opioid itself may act as a neurotransmitter with a direct effect on hearing – a theory which is supported in part by cases in which opioid use after a period of abstinence is followed by sudden onset of hearing loss; this suggests an up-regulation or sensitization of receptors.5,6 There are many variables which could contribute, and the pathway may be somewhat different for acute overdoses compared to chronic exposures.
The bottom line: We don’t know how opioids cause hearing loss. We just know they do. Treatment involves removal of the offending opioid, avoidance of other ototoxins, and hoping for the best (or a new cochlea). And remember, the next patient you see with unexplained hearing loss, don’t Rush to judgement . . . ask about opioid use.