Journal of Otology & Rhinology Review of Opioid-Associated Review Article

Transcription

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].
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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-
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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
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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
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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].
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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.
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UCLA School of Medicine, Los Angeles, California, USA
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