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Nguyen et al., J Otol Rhinol 2014, 3:2 http://dx.doi.org/10.4172/2324-8785.1000145 Review Article Review of Opioid-Associated Hearing Loss and Possible Mechanism of Opioid-Mediated Endothelin-1-Dependent Cochlear Vasoconstriction Kimanh D Nguyen1*, Ivan Lopez1, Gail Ishiyama1, and Akira Ishiyama1 Abstract Within the past several decades, there have been multiple reports of profound sensorineural hearing loss attributed to opioid use. Among the implicated opioids are both prescription analgesics used within their recommended dosages such as codeine, hydrocodone/ acetaminophen, and oxycodone/acetaminophen, as well as illicit substances such as heroin. Opioid-associated hearing loss has lead to both reversible and irreversible profound bilateral hearing loss, and the mechanism by which this occurs is currently unknown. Audiometry, otoacoustic emission, and auditory brainstem responses suggest that the lesion is cochlear in origin, as does the finding that patients with irreversible loss respond well to cochlear implantation. A plausible mechanism for this loss is opioid-induced vasoconstriction causing cochlear ischemia and subsequent hearing loss. Opioid receptors have been found in the inner ear in various animal models, and opioids are well-known to promote diminished blood flow, ischemia, and infarction. Opioids are also known to increase the production of and stimulate the release of endothelin-1, which is a potent endogenous vasoconstrictor that is found throughout the body as well as in the inner ear. In this review, we summarize the reports of opioid-associated hearing loss and propose that this hearing loss is mediated by vasoconstriction and cochlear ischemia via opioid-mediated stimulation of the vasoconstrictor endothelin-1. Keywords Opioid; Hearing loss; Endothelin-1; Mu opioid receptor Introduction Opioids have been utilized for their remarkable analgesic and euphoric properties since 4000 B.C. Today, approximately 90% of patients with chronic pain rely on opioid medications for analgesia [1], and within a given week, 5% of adults in the United States will take a prescription opioid [2]. 4.3 million individuals nationwide use opioids on a regular basis, and additionally, 1.8 million people abused or depended on pain relievers in 2011, an increase of 400,000 compared to 2004 [2,3]. In 2011, 0.5% of the population, or 1.4 million individuals, used cocaine, while 620,000 used heroin [3]. Opioid use *Corresponding author: Kimanh D Nguyen, UCLA School of Medicine, Los Angeles, USA, Tel: 310-825-4949; Fax: 310-206-5106; E-mail: kimanhnguyen@ mednet.ucla.edu Received: November 15, 2013 Accepted: January 12, 2014 Published: January 25, 2014 International Publisher of Science, Technology and Medicine Journal of Otology & Rhinology a SciTechnol journal is surprisingly common in the general population, and the sales of both prescription and illicit opioids have increased dramatically over the past few years [3,4]. Within the past several decades, there have also been increasing numbers of reports of profound or rapidly-progressive sensorineural hearing loss associated with opioid use. The opioids implicated in this phenomenon have included commonly-prescribed analgesics such as hydrocodone/acetaminophen, oxycodone/acetaminophen, codeine, and propoxyphene, as well as illegal compounds such as heroin, and other opioids such as methadone, amphetamine, paracetamol/ dextropropoxyphene, and bupivacaine. In some cases, poly-substance narcotic abuse has also been implicated in association with deafness. The opioid dosages have varied widely, and have included both short-term prescription opioid use within the recommended dosage guidelines, as well as longstanding opioid use and abuse. Reports of Opioid-Induced Hearing Loss The first case of opioid-induced hearing loss was reported in 1978, when a patient suffered profound hearing loss after chronic propoxyphene use [5]. Currently, hydrocodone/acetaminophen is the narcotic most commonly associated with opioid-induced hearing loss. There have been 19 cases of profound bilateral hearing loss attributed to hydrocodone/acetaminophen use [6-8]. These patients had ranged in age from 28 to 57 years, and had consumed 8-60 tablets daily for duration of one month to over ten years. Eleven patients had associated tinnitus and two had dizziness, although it is uncertain whether the dizziness was vestibular in origin. Seven patients initially complained of unilateral hearing loss, which eventually progressed to bilateral involvement; the other twelve had bilateral involvement on presentation. Unfortunately, none of the patients were responsive to steroids, and all but one patient eventually underwent cochlear implantation to successfully restore functional hearing. A review of the literature showed eight cases of sensorineural hearing loss induced by heroin consumption [9-16]. Patients were young (ages 20-47) and mostly healthy other than having a history of substance abuse. All patients had bilateral hearing loss except for one individual with right-sided hearing loss after injection of heroin into his right carotid artery. Sudden hearing loss occurred either after an overdose or after re-consumption of heroin following a long period of abstinence. Often, patients reported sudden hearing loss upon awakening from a period of unconsciousness preceded by a heroin overdose. Routes of administration included intravenous injection, intracarotid injection, and inhalation. Hearing loss resolved in only half of the patients, some occurring spontaneously, and others occurring after treatment with steroids and/or pentoxifylline. There are three reports of patients with cocaine-induced, profound hearing loss (ages 26-43) [17-19]. Two of these patients had a history of substance abuse, while one patient suffered hearing loss after his first lifetime episode of consumption. Two patients administered cocaine intravenously, and one patient consumed it intra-nasally. Interestingly, this latter patient was found to have a unilateral intralabyrinthine hemorrhage on MRI, correlating with his permanent, unilateral hearing loss and tinnitus. Hearing was restored in the other two patients after medical management with steroids and mannitol All articles published in Journal of Otology & Rhinology are the property of SciTechnol, and is protected by copyright laws. Copyright © 2014, SciTechnol, All Rights Reserved. Citation: Nguyen KD, Lopez I, Ishiyama G, Ishiyama A (2014) Review of Opioid-Associated Hearing Loss and Possible Mechanism of Opioid-Mediated Endothelin-1-Dependent Cochlear Vasoconstriction. J Otol Rhinol 3:2. doi:http://dx.doi.org/10.4172/2324-8785.1000145 or pentoxifylline. Sudden or rapidly-progressive hearing loss has also been reported in association with other opioids. Methadone-induced hearing loss has been reported in four patients [20-22]. All patients were in their twenties and thirties, and suffered bilateral hearing loss which resolved spontaneously within ten days. Amphetamine, propoxyphene, and paracetamol/dextropropoxyphene have also been implicated in cases of deafness, as has poly-substance narcotic abuse of cocaine and heroin. Prior investigators have questioned whether the hearing loss induced by hydrocodone/acetaminophen, oxycodone/ acetaminophen, or codeine/acetaminophen combination pills should be attributed to the opioid or the acetaminophen component. However, a literature search revealed no reports of hearing loss linked solely to acetaminophen use or abuse. Interestingly, a mouse model investigating hydrocodone/acetaminophen toxicity showed that high doses of acetaminophen led to death of inner and outer hair cells, but hydrocodone or hydromorphone alone did not kill cochlear hair cells [23]. The authors postulated that this differential killing may be due to different isoforms of cytochrome enzymes that are found in murine livers. For example, rodents possess the cytochrome CYP2E1 which metabolizes acetaminophen, but have a different isoform of CYP2D, which metabolizes hydrocodone and codeine to hydromorphone. It is also possible that hydrocodone/acetaminophen may be more ototoxic in patients with underlying liver disease, who may consequently lack or possess altered cytochrome enzymes that are involved in metabolizing opioids. Indeed, among those patients who had hydrocodone/acetaminophen-induced hearing loss, two patients had elevated liver function tests (although this could be secondary to underlying liver disease or conversely be due to hepatic toxicity from acetaminophen overuse), three had Hepatitis C, and one had cirrhosis [8]. Of note, 7% of the Caucasian population lacks a functional CYP2D6 phenotype, and those who do have the functional phenotype have great variation in enzymatic activity [8]. Co-administration of high doses of acetaminophen has been found to degrade cytochrome CYP3A4, causing decreased metabolism of hydrocodone to norhydrocodone with simultaneously increased metabolism of hydrocodone to hydromorphone, which has a higher affinity for the mu opioid receptor. This certainly hints at a plausible explanation for increased susceptibility to hydrocodone/ acetaminophen-associated hearing loss in certain individuals, although research on this topic is still inconclusive. At this time, it remains unclear whether liver disease or acetaminophen use predisposes patients to opioid-induced hearing loss. Effects of Intrauterine Opioid Exposure on Neonatal Hearing Several studies have examined the effects of intrauterine narcotic exposure on the neonatal auditory system. Although these infants were not found to have newborn hearing loss, they were 4-5 times more likely to have abnormal auditory brainstem responses (ABR) than control infants [24,25]. Another study, by Trammer et al., reported that prenatal narcotic exposure was associated with prolonged ABR wave V latencies and increased wave I-V intervals [26], while Shih et al. demonstrated both prolonged inter-peak latencies and prolonged absolute latencies [27]. A fourth investigation examined 70 children with perinatal cocaine exposure, but found a hearing deficit in only one child [28]. Volume 3 • Issue 2 • 1000145 There have been several animal studies investigating this topic. An investigation of young rats with prenatal cocaine exposure also documented abnormal ABR results, which were consistent with the human findings. However, this study also found that some animals continued to have abnormal ABR responses and permanent sensorineural hearing loss as adults [29]. In adult baboons, intramuscular cocaine administration was associated with impaired tone identification and speech discrimination, as well as decreased inner ear cochlear blood flow [30,31]. Location of Insult to the Auditory Pathway It is likely that the mechanism of opioid-induced hearing loss is cochlear in origin, given that audiometry, otoacoustic emission testing, and auditory brainstem responses overwhelmingly indicate a cochlear deficit. Transient evoked otoacoustic emissions, when tested, were absent, indicating outer hair cell pathology. ABRs were abnormal, with no identifiable waves, indicating a deficit peripheral to the vestibule cochlear nerve [15]. Additionally, the majority of patients had no vestibular signs or symptoms and negative caloric testing, while neurological exam and imaging of the brain were negative. One patient, who developed a unilateral intra-labyrinthine hemorrhage and corresponding unilateral hearing loss after intranasal cocaine consumption, was found to have unilateral are flexia on caloric testing and contralateral spontaneous horizontal nystagmus, the latter of which resolved after one week [17]. However, his vestibular findings were likely attributed to the hemorrhage, which was an unusual mechanism for opioid-induced hearing loss. Patients also attained restoration of functional hearing status with cochlear implants, further supporting the claim that the hearing loss arises within the cochlea. All documented reports of cochlear implantation following opioid-induced hearing loss showed that patients were satisfied with post-implantation results [6-8,32]. Possible Etiologies of Opioid-Induced Hearing Loss Common etiologies of sudden or rapidly-progressive sensorineural hearing loss include autoimmune disorders, vascular pathology, and viral infection, although cases are most often idiopathic. Autoimmune panels and standard laboratory testing performed at presentation were routinely negative in cases of opioid-induced hearing loss, as were computed tomography of the head and temporal bones, and magnetic resonance imaging of the brain. Several mechanisms for opioid-induced hearing loss have been proposed previously, including narcotic adulterants or contaminants mechanically impeding perfusion or causing direct ototoxicity, opioid-induced vasospasm leading to ischemia, allergic reactions, inhibition of basal adenylate cyclase activity via cochlear opioid receptors, genetic polymorphisms of drug-metabolizing enzymes, mitochondrial mutations causing increased susceptibility, and traumatic rupture of the intra-labyrinthine membrane [7,8,13,16,18,21,33]. Schrock et al. [13], Antonopolous et al. [15], and Christenson et al. [21] postulated that quinine contamination could be responsible for heroin-associated sudden sensorineural hearing loss, but conceded that this was unlikely due to the low amounts of quinine that are found in heroin samples. Furthermore, sensorineural hearing loss has been associated with many other opioids in addition to heroin, and it is unlikely that methadone or any of the other commercially-available narcotic analgesics would contain contaminants. Similarly, it has also been proposed that additives in intravenously- • Page 2 of 7 • Citation: Nguyen KD, Lopez I, Ishiyama G, Ishiyama A (2014) Review of Opioid-Associated Hearing Loss and Possible Mechanism of Opioid-Mediated Endothelin-1-Dependent Cochlear Vasoconstriction. J Otol Rhinol 3:2. doi:http://dx.doi.org/10.4172/2324-8785.1000145 administered cocaine and heroin may mechanically impede vascular perfusion or irritate vessel walls and cause subsequent vasculitis, vasospasm, or hypoperfusion. Although it is well-documented that heroin and cocaine procured from the street is often contaminated with a variety of fillers such as talcum powder, sugar, cornstarch, caffeine, procaine, baking soda, boric acid, and powdered milk [34], one would need to use intravascular administration to introduce these materials into the bloodstream. Many cases of opioid-induced hearing loss, however, involved oral or inhalational routes of administration which would preclude direct deposition into the bloodstream. Vasoconstriction and Cochlear Ischemia as a Possible Cause of Opioid-Induced Hearing Loss A more plausible mechanism for opioid-induced deafness involves vasoconstriction causing cochlear ischemia leading to hearing loss. The dominant vascular supply to the cochlea is derived from the spiral modiolar artery (SMA), which arises from the common cochlear artery, which is derived from the labyrinthine artery. The SMA has three branches. The first branch supplies the microvascular networks in the lateral wall of the cochlea, namely the capillaries of the spiral ligament, stria vascularis, and spiral prominence. The second branch feeds the limbus, tympanic lip, and basilar basement membrane. The third branch supplies the modiolar tissue, namely the cochlear plexus, spiral ganglion, and auditory nerve [35]. Located further upstream of the labyrinthine artery are the anterior inferior cerebellar artery, the basilar artery, and the vertebral arteries, in that order. Cochlear blood flow relies on systemic blood pressure and cardiac output, and is further regulated both by the SMA within the cochlea, and by upstream vasculature [35-37]. The cochlea is very sensitive to its oxygen supply, and guinea pig histological findings have shown that cochlear structures are more vulnerable that vestibular structures to hypoxia [38]. Alterations in cochlear blood flow have been associated with a variety of otologic conditions, such as noiseinduced hearing loss, endolymphatic hydrops, and presbycusis, among others [39]. Vasoconstriction is also the mechanism by which some ototoxins cause hearing loss [40-44]. Additionally, slower blood flow in the vertebrobasilar system has been directly linked to sudden sensorineural hearing loss [45]. The mechanism by which cochlear ischemia leads to hearing loss involves the disruption of inner ear fluid homeostasis. Impairment of the blood supply to the capillaries of the stria vascularis prevents the stria vascularis from adequately secreting high concentrations of potassium into the endolymph. The endolymphatic potential subsequently drops, which restricts the outer hair cell potassium current, and thus impairs the cochlear function. This occurs in a matter of seconds, and is accompanied by a reduction in otoacoustic emissions due to hair cell dysfunction [38,46,47]. Studies have shown that ischemia-associated hearing loss can be prevented or reversed with agents that improve cochlear blood flow. Etanercept, a TNF-α inhibitor that antagonizes TNF-α-dependent vasoconstriction can prevent noise-induced hearing loss by increasing blood flow [48,49]. Several patients who presented with opioidinduced hearing loss recovered their hearing after treatment with pentoxifylline, which is known to promote blood flow in capillary beds and to maintain cochlear microcirculation [50]. Heroin and Cocaine Cause Cerebral Ischemia Heroin has been found to be responsible for a variety of changes Volume 3 • Issue 2 • 1000145 in blood flow patterns. Opioids are known to have receptors within the inner ear [51-54], as well as on red blood cells and vascular smooth muscle. Zeiger et al. [55] reported that 47% of opioid users have mµ opioid receptors (MOR) on their erythrocytes, compared to only 23% of controls. Additionally, there were found to be two distinct subgroups among opioid users – those with very high MOR levels, and those with low MOR levels. Erythrocytes with high concentrations of receptors were found to have higher deformability characteristics, and additionally chronic opioid users were found to have a higher prevalence of anemia than the general population. Antonoma et al. [56] examined hemorrheological changes in chronic heroin users, and found that whole blood viscosity and red blood cell and platelet aggregation were elevated compared to controls. Geibprasert et al. [57] reported that stimulation of MOR found on vascular smooth muscle causes a reversible vasospasm. It is therefore possible that exogenous opioids may activate MOR located on SMA vascular smooth muscle, stimulating vasoconstriction and decreased cochlear microcirculation, and this effect may be further potentiated by the higher degree of erythrocyte deformability. Supporting these microscopic findings, imaging has also demonstrated diminished blood flow patterns in the brains of heroin users. Indeed, ischemia is the most frequent acute neurovascular complication associated with heroin use [57]. Botelho et al. [58] used SPET imaging to show that heroin abusers have decreased levels of brain perfusion, most commonly in the orbito-frontal regions of the frontal cortex, and the occipital and temporal lobes. Guyer et al. [59] used perfusion-weighted MRI imaging to show significantly decreased levels of perfusion in the amygdala following IV heroin administration. These findings are consistent with multiple reports of ischemic stroke or infarction resulting from heroin abuse. Methods of heroin administration linked to hypoperfusion have ranged from injection to inhalational routes, and territories of the brain supplied by the posterior cerebral artery, anterior choroid artery, and basal cerebral artery, along with the globus pallidus, have been affected [60-66]. It has been found that ischemia is more common after injection than after oral or inhalational intake [57]. Cocaine is another substance that is widely known to stimulate cerebral vasoconstriction and infarction. Magnetic resonance angiography has shown that intravenous cocaine use causes dose-dependent vasoconstriction of the posterior cerebral artery, middle cerebral artery, vertebral artery, anterior and posterior communicating artery and their individual branches, and that greater lifetime cocaine use increases the likelihood of vasoconstriction [67]. Crack cocaine causes cerebral infarction, as does a combination of intravenous cocaine and heroin commonly referred to as “speedballing” [68]. Cocaine augments the platelet response to arachidonic acid, leading to enhanced platelet aggregation, and increasing the risk of thrombosis and infarction. It also has direct pro-coagulant effects due to decreased levels of protein C and antithrombin III [57]. In the rat basilar artery, cocaine was shown to cause endothelin-1dependent vasospasm [69]. Endothelin-1 Mediates Vasoconstriction of the Spiral Modiolar Artery Endothelin-1 (ET-1) is a member of the endothelin family of peptides that is produced by endothelial cells and vascular smooth muscle cells [70]. Endothelins bind to two types of receptors, Endothelin-A (ET-A) and Endothelin-B (ET-B) receptor, which • Page 3 of 7 • Citation: Nguyen KD, Lopez I, Ishiyama G, Ishiyama A (2014) Review of Opioid-Associated Hearing Loss and Possible Mechanism of Opioid-Mediated Endothelin-1-Dependent Cochlear Vasoconstriction. J Otol Rhinol 3:2. doi:http://dx.doi.org/10.4172/2324-8785.1000145 are expressed on endothelial cells and vascular smooth muscle cells. Endothelin-1 is one of the most potent endogenous vasoconstrictors [70], and binding to ET-A and/or ET-B causes increased intracellular calcium concentrations and increased calcium sensitivity of the contractile apparatus [71], leading to vasoconstriction. Many factors activate synthesis of ET-1, including hypoxia, shear stress, and thrombin, and furthermore ET-1 has often been implicated in the pathogenesis of ischemia and cerebral vasospasm [70,72-75]. Other factors that may affect opioid metabolism include underlying medical conditions, such as hepatic and renal impairment, which are known to affect metabolism of opioids other than methadone and fentanyl [89]. Since opioids are so extensively metabolized in the liver, medications that interact with the cytochrome enzymes, of which there are many, may also hinder or augment opioid metabolism. Even common foods such as grapefruit juice and cafestol, which is found in unfiltered coffee, can inhibit or induce CYP3A4, respectively [89]. Multiple animal studies have demonstrated that ET-1 mediates vasoconstriction of the SMA via ET-A receptors [71,76-78]. This occurs in a dose-dependent fashion in vitro, and reversal can be achieved with pharmacological agents. In the gerbil inner ear, reversal of ET-1 with rho-kinase inhibition and dbc AMP modulation leads to reversal of the effects of ET-1 on the spiral modiolar artery [77], as does application of the ETA receptor antagonist BQ123 [78]. Additionally, ET-1 and its receptors have also been localized to the mouse and guinea pig spiral ganglion cells [79,80], indicating its strong presence in the inner ear. Blood-Labyrinth Barrier Opioids Stimulate Increased Production and Release of Endothelin-1 Opioids are known to be involved in the endothelin-1/endothelin receptor pathway. Cocaine stimulates ET1 release in a dosedependent manner in endothelial cells [81,82], and also increases ET-1 production and enhances ET-A expression in endothelial cells [83]. In the rat basilar artery, cocaine was shown to induce ET1-dependent vasospasm; co-infusion of an endothelin receptor antagonist prevented this vasoconstriction [69,84]. Morphine causes significant elevation of plasma ET-1 levels in the systemic arterial and sagittal sinus venous system, and also upregulates ET-1 and ET-A mRNA in the brainstem [85]. Naltrexone injection causes elevated serum ET-1 concentration [86]. In the rat pituitary gland, the muopioid system appears to control ET-1 release [86]. ET-A is also involved in neonatal morphine tolerance in the rat [87]. Multiple Factors May Increase Individual Susceptibility to Opioids Since reports of opioid-induced hearing loss do not seem to be dependent on drug dosage or duration of use, it is possible that genetic factors may play a role in individual susceptibility. For example, it has been shown that mutations in a mitochondrially-encoded ribosomal RNA gene are associated with aminoglycoside-induced hearing loss [88]. Most opioids are metabolized in the liver by cytochrome P450 (CYP) enzymes prior to entering the systemic circulation. Hydrocodone, oxycodone, codeine, methadone, and fentanyl are metabolized by CYP2D6 and CYP3A4, of which there are multiple allelic variants in the general population [89]. 5-10% of Caucasians carry an allelic variant of the CYP2D6 gene associated with poor metabolism, while 1-7% possess a variant associated with rapid metabolism [90-94]. Less than 1% of Asians are poor metabolizers, compared with 0-34% of Africans; conversely, 9-30% of Africans are rapid metabolizers [95-100]. Cocaine and heroin hydrolysis is catalyzed by liver carboxylesterases (hCE-1 and hCE-2), which may also have allelic variants [101]. Additionally, mutations of the OPRM1 gene, which encodes a MOR, has been linked to decreased opioid activity [102], and inter-individual differences in responses to opioids are likely due to polymorphisms in the MOR regulatory region [103]. Volume 3 • Issue 2 • 1000145 Differences in transport rates across the blood-labyrinth barrier may also contribute to inter-individual variations in the differential ototoxicity of opioids. It is widely known that the tight junctions of the spiral ligament capillary bed form a barrier of limited permeability called the blood-labyrinth barrier (BLB). The BLB restricts the movement of many ions and molecules from the vasculature into the perilymph and endolymph, functioning in a manner similar to that of the blood-brain barrier [104]. The BLB is an important homeostatic mechanism for maintaining the composition of inner ear fluid, and it generally facilitates the passage of molecules according to their molecular weight [105]. Differences in the sizes of various opioid compounds and their metabolites could explain why some are more frequently associated with hearing loss than others. Genetic variations in the transport channels could lead to differences in opioid concentrations in the cochlea, perhaps contributing to variations in susceptibility to opioid-induced hearing loss. Additionally, genetic variations in these transport mechanisms could also lead to disturbances in inner ear fluid composition and homeostasis, and thus contribute to hearing loss [106]. It has also been shown that disruption of the BLB with epinephrine-induced hypertension, or insults such as diuretics or noise exposure, increases the uptake of ototoxins into inner ear fluids [107,108]. Conclusion Opioids are commonly used in the general population for both medical and recreational purposes. Recently, there have been increasing reports documenting opioid-induced, sudden or rapidlyprogressive sensorineural hearing loss. These have been attributed to a variety of opioids, including hydrocodone/acetaminophen, heroin, and methadone. Although the mechanism of opioid-induced hearing loss remains unknown, it is likely due to cochlear hypoxia from endothelin-1-mediated vasoconstriction of the spiral modiolar artery. Genetic variations in liver cytochrome P450 genes and the MOR regulatory region may explain why some users experience hearing loss while others do not. References 1. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, et al. 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