The Effects of Substance Misuse on Auditory and Vestibular Function: A Systematic Review

Abstract

Background:

Chronic substance misuse is an ongoing and significant public health concern. Among a myriad of health complications that can occur, substance misuse potentially causes ototoxic effects. Case reports, retrospective chart data, and a few cohort studies suggest that certain prescription opioids and illicit drugs can have either temporary or permanent effects on auditory and/or vestibular function. Given the steady rise of people with a substance use disorder (SUD), it is of growing importance that audiologists and otolaryngologists have an insight into the potential ototoxic effects of substance misuse.

Objectives:

A systematic review was conducted to (1) synthesize the literature on the illicit drugs, prescription opioids, and alcohol misuse on the auditory and vestibular systems, (2) highlight common hearing and vestibular impairments for each substance class, and (3) discuss the limitations of the literature, the potential mechanisms, and clinical implications for clinicians who may encounter patients with hearing or vestibular loss related to substance misuse, and describe opportunities for further study.

Methods:

Systematic searches were performed via PubMed, Scopus, and Google Scholar, and the final updated search was conducted through March 30, 2022. Inclusion criteria included peer-reviewed articles, regardless of study design, from inception until the present that included adults with chronic substance misuse and hearing and/or vestibular complaints. Articles that focused on the acute effects of substances in healthy people, ototoxicity from already known ototoxic medications, the relationship between hearing loss and development of a SUD, articles not available in English, animal work, and duplicates were excluded. Information on the Population (adults), Outcomes (hearing and/or vestibular data results) and Study design (e.g., case report, cohort) were extracted. A meta-analysis could not be performed because more than 60% of the studies were single-case reports or small-cohort.

Results:

The full text of 67 studies that met the eligibility criteria were selected for the review. Overall, 21 studies reported associations between HL/VL related to illicit drug misuse, 28 studies reported HL/VL from prescription opioids, and 20 studies reported HL/VL related to chronic alcohol misuse (two studies spanned more than one category). Synthesis of the findings suggested that the misuse and/or overdose of amphetamines and cocaine was associated with sudden, bilateral, and temporary HL, whereas HL from the combination of a stimulant and an opioid often presented with greater HL in the mid-frequency range. Reports of temporary vertigo or imbalance were mainly associated with illicit drugs. HL associated with misuse of prescription opioids was typically sudden or rapidly progressive, bilateral, moderately severe to profound, and in almost all cases permanent. The misuse of prescription opioids occasionally resulted in peripheral VL, especially when the opioid misuse was long-term. Chronic alcohol misuse tended to associate with high-frequency sudden or progressive SNHL, or retrocochlear dysfunction, and a high occurrence of central vestibular dysfunction and imbalance.

Conclusions:

Overall, chronic substance misuse associates with potential ototoxic effects, resulting in temporary or permanent hearing and/or vestibular dysfunction. However, there are notable limitations to the evidence from the extant literature including a lack of objective test measures used to describe hearing or vestibular effects associated with substance misuse, small study sample sizes, reliance on case studies, lack of controlling for confounders related to health, age, sex, and other substance-use factors. Future large-scale studies with prospective study designs are needed to further ascertain the role and risk factors of substance misuse on auditory and vestibular function and to further clinical management practices.

INTRODUCTION

Substance misuse is on the rise, with more than 19 million Americans self-reporting that they have a diagnosed substance use disorder (SUD) involving illicit drugs, prescription opioids, and/or alcohol (National Institute on Drug Abuse 2019). Among those with a SUD in 2019, 14 million reportedly misused alcohol, 7.4 million misused illicit drugs, 9.7 million misused opioids, and 2.2 million misused multi-substances (Center for Behavioral Health Statistics and Quality 2020). Substance misuse and SUDs are significant public health concerns, resulting in increased physical and mental health comorbidity, homelessness, and lack of quality medical care (Mitchell et al. 2009; Schulte & Hser 2014). Among a myriad of cascading health complications that can come with SUDs, several case reports and a few small-cohort studies suggest that substance misuse may have ototoxic effects resulting in sudden or progressive hearing loss (HL) or vestibular loss (VL). However, the literature is sporadic and published across numerous fields of study not specific to audiology or otolaryngology. Therefore, it is unclear how familiar audiologists and otolaryngologists are with identifying HL or VL that may be associated with substance misuse. Given that there has been a steady rise in SUDs in the United States, which has increased by 20% since the start of the coronavirus-19 (COVID-19) pandemic (Addiction Policy Forum, National Institute on Drug Abuse, 2020), a comprehensive investigation into the effects of substance misuse on the auditory and vestibular systems is timely.

It is unknown whether ototoxicity stemming from substance misuse results from similar mechanisms known to be involved with ototoxic medications, including aminoglycoside antibiotics, loop diuretics, and platinum-based chemotherapeutics. It is well established that in the initial stages of cochleotoxicity, high-frequency hearing is most affected due to the vulnerability of basal-end cochlear outer hair cells to oxidative stress (Lanvers-Kaminsky et al. 2017). Significant vestibulotoxicity is associated with apoptosis or neurosis of the labyrinthine inner hair cells and oxidative stress to the labyrinths (Sedo-Cabezon et al. 2014; Sánchez-Sellero & Soto-Varela 2016), resulting in functional impairments of imbalance and dizziness (Prayuenyong et al. 2018). The misuse of illicit drugs, prescription opioids and/or alcohol may induce similar patterns of hearing and vestibular dysfunction as ototoxic medications, but as this review will highlight, there is a substantial lack of knowledge of the potential mechanisms and in-depth rigorous studies that account for individual patient factors (e.g., exposure time, concentrations or dosage, the influence of polypharmacy, or medical comorbidities).

Despite the existing knowledge gaps on this topic, having a comprehensive understanding of the HL/VL risks in SUDs and factors that contribute to the heterogeneity of this population could improve audiologists’ and otolaryngologists' decision-making and management practices. Specifically, clinicians may advocate for earlier hearing or vestibular testing in patients with SUDs, which could facilitate faster identification and treatment for these individuals. The implications of having an unidentified and untreated HL create significant barriers for communication, social isolation, and associations with depression (e.g., Li et al. 2014). Similarly, unmediated VL may lead to falls, injury, and anxiety (Yuan et al. 2015). In people with SUDs, their HL or VL impact could be compounded, negatively affecting their ability to remain physically independent or have sufficient functional communication. Given the link between SUDs and high mental health co-morbidity (Grant et al. 2016), people with SUDs may be at an even higher risk for depression and anxiety when they have unmediated HL or VL.

With the emerging literature on substance use-related HL or VL and the high clinical relevance for this topic, the rationale for this review was to provide a comprehensive synthesis of the literature for audiologists and otolaryngologists, and to identify the gaps in the literature that would inform future study designs. The objectives of this systematic review were to (1) synthesize the associations between illicit drugs, prescription opioids, and/or alcohol (henceforth termed “substances”) misuse on the auditory and vestibular systems, (2) highlight where possible, the differential hearing and vestibular manifestations by substance type or use patterns, and (3) discuss the limitations of the evidence, potential underlying mechanisms per substance type, clinical implications for clinicians who may encounter patients with HL or VL related to substance misuse, and identify opportunities for future research in this area.

MATERIALS AND METHODS

The “preferred reporting items for systematic reviews and meta-analyses” (PRISMA) guidelines were utilized in this review (refer to Figure 1 in Page et al., 2021). An internal protocol was developed by the authors that specified the search strategy, eligibility criteria and selection process (inclusion/exclusion), and data collection procedures. The protocol was not registered with the International Prospective Register of Systematic Reviews. No meta-analysis could be performed because a large majority of the studies were single-case reports (60%), and many lacked objective test results; however, the study findings, risk of bias, and general evidence quality were considered to give an informed interpretation of the studies.

Figure 1.

The PRISMA flowchart of the process undertaken to select the relevant studies for this review is depicted. SUD= substance use disorder

Search Strategy

A literature search was conducted using the following electronic databases: PubMed, Scopus, and Google Scholar via their public-facing websites. The search results were initiated in November 2019 and last updated on March 30, 2022. The search was conducted with no restrictions on publication date or study design; however, book chapters [non-studies], animal studies, studies not available in English, and duplicates were initially filtered out prior to further screening using the database’s automatic filtering options. The search terms included combinations of the following: “hearing loss,” “hearing,” “vestibular loss, “vestibulopathy” “vestibular hypofunction,” “ear,” “vestibular,” “substance misuse,” “drug use,” “opioids [methadone, morphine, oxymorphone, oxycodone, hydrocodone],” “cocaine,” “amphetamine,” “heroin,” “alcohol,” “ototoxicity,” and/or “vestibulotoxicity.”

Eligibility Criteria and Selection Process

Where applicable, the Population, Intervention/Exposure, Comparator, Outcome (PICO) framework (Schardt et al. 2007) was used to determine which studies to include in the review. Due to the limited amount of cohort studies available on this topic, a comparator outcome was not used in our criteria. Additionally, the authors selected a broad inclusion criterion because of the literature base available and the widespread nature of the topic area itself. The eligibility criteria used to decide whether a study was included in the full text review were articles that: (a) discussed the auditory and/or vestibular effects of substance use in adults who chronically misused substances, overdosed, and/or had a pre-existing SUD (i.e., population), (b) focused on the misuse of illicit substances, prescription opioids, or alcohol (i.e., intervention/exposure of interest), and (c) discussed a reported decrease in hearing or vestibular function and/or balance complaints suspected from substance ingestion, which could be measured using objective measures or by self-report (i.e. outcomes). The authors chose to not exclude studies based on the lack of objective data presented because the current body of evidence is comprised largely of case reports of single patients who were often identified and treated in the emergency department, so objective audiological and/or vestibular results were limited. However, these reports still provide valuable clinical information regarding the potential ototoxicity from substances, particularly when synthesizing all case reports in the literature to observe similar HL/VL trends. Individuals with substance misuse also represent a vulnerable patient population that can be difficult to prospectively control for study design and individual subject characteristics. For the purposes of this review paper, the authors also wanted to highlight the existing evidence and discuss the limitations to justify the need for future objective outcomes.

Therefore, the authors made no exclusions on study design, sample size, specific audiological or vestibular outcomes, self-reported or objective data, no requirement for baseline audiometric or vestibular data, and/or year of publication. Exclusion criteria included articles that focused on showing the acute effects of substance use in healthy people, effects of ototoxicity from already known ototoxic medications (e.g., aminoglycosides), or reviewing the relations between HL and development of a SUD. The authors’ rationale for limiting the scope of studies to adults in the search was because the literature addressing the effects of substance misuse on children and adolescent hearing (aside from maternal – fetal exposure) are limited and almost non-existent for vestibular function, and substance misuse and its subsequent health effects might differ compared to adults, which could also confound ototoxicity and other findings for this initial review.

Searches using the vestibular search terms were performed by the first author, whereas searches for the hearing or auditory search terms were performed by the second author, independently. The selection process for the studies included the following sequential steps. First, records yielded were screened for potential relevance through their titles. Second, abstracts and full texts were screened using the eligibility criteria above. In some instances, the abstract did not contain enough information, so the full text was screened for eligibility (e.g., the full text not available in English or substance use was ingested only in healthy volunteers).

The reviewers also reviewed the bibliographies of the papers meeting the review criteria to ensure no other relevant articles were missed. A final comprehensive search was performed by the third author, to reduce the chance of missing any articles or eligibility bias. Lastly, all articles identified via the database searches were then cross-checked by the first author, creating an updated and final list of studies. Together, the authors discussed any issues regarding whether a study may or may not have met eligibility.

Data Collection Process

Once an article was selected for full review, the first author extracted outcomes from the vestibular and balance articles and the second author extracted data outcomes from the hearing or auditory articles, independently. Outcomes extracted from each study included: author and year of publication, journal title and type (i.e., otolaryngology, audiology, non-otolaryngology), substance type(s) (e.g., amphetamine, cocaine, heroin, alcohol, prescription opioids, methadone) use pattern (i.e., current use, past use, overdose), route of ingestion and dose if provided (i.e., oral, intravenous, intranasal, unknown), number of patients/sample size, study design (i.e., case report, case series, cohort), HL result (i.e., permanent, temporary, partially recovered), HL onset (i.e., sudden, progressive), HL degree/configuration, inclusion of an audiogram (yes/no), report of tinnitus (yes/no), report of vestibular symptoms (yes/no), inclusion of vestibular testing (yes/no), and result of vestibular testing (i.e., central, peripheral, mixed, non-localizing, normal). If an outcome was not reported, this was denoted as well. Each respective author entered the data outcome results in an Excel file, where each column was a different outcome, and each row was the article. To tabulate and visually synthesize results, articles were grouped by substance type and presented in that manner. The first and second authors collectively reviewed and discussed the findings. The first, second, and third authors cross-checked the auditory and vestibular article data entry during preparation of this paper. When uncertain about a substance type or substance-related outcome, the last author was consulted. No other automation tools were used in the process.

Risk of Result Bias

The Downs and Black Scale (Downs & Black, 1998), a formal tool to assess study quality appraisal and result bias, was reviewed by the study team. It consists of domain specific questions relating to quality of reporting, external validity, internal validity, and statistical power. After reviewing this tool, it was determined that results from the scale would not yield entirely meaningful results, because more than 60% (42/67) of the studies identified were single study case reports or case series with no study design. Additionally, the team evaluated the Joanna Briggs Institute (JBI; Joanna Briggs Institute, 2017) checklists as a formal tool to assess result bias for case reports and case series, but the recommended scoring of the study quality is vague and does not yield a more objective indicator of low, moderate, or high study quality similar to tools used for randomized control trials (Munn et al. 2020). Thus, it was the authors’ opinion that quantifying the risk of bias for these articles would not provide additional objective information about the study quality or risk of bias that is already known about relying on single-subject case reports and limited case series for evidence including high result bias and low external/internal validity (Viswanathan et al. 2012; Nissen & Wynn, 2014). Therefore, the authors did not use a formal measurement of result bias but chose to focus on making an overall judgment about methodological quality of these reports in the discussion of this review.

RESULTS

The PRISMA flowchart in Figure 1 depicts the overall results from the search and the process involved in removing and selecting the final relevant studies. The initial searches yielded a total of 57,854 records. Of the initial search, 25,304 records were removed prior to title screening because they were animal studies, not available in English (e.g., Mulch & Handrock 1979; Lindeman et al. 2014; Pingarrón et al. 2014), and/or book chapters (non-studies). Additionally, 32,192 were duplicated records and were also removed prior to title screening for eligibility. This resulted in 358 unique records that were screened based on the title. A total of 67 articles were then removed because the title suggested ototoxicity from known ototoxic medications or the substance identified was not an illicit or opioid drug or alcohol. This resulted in a total of 291 reports that were then retrieved and underwent an abstract/full text screen, with 224 reports being excluded for not meeting the eligibility criteria as mentioned in the Methods. This resulted in a total of 67 unique articles from 1964 (Nordahl 1964) to 2021 (Mokhtarinejad et al. 2021; Patell et al. 2021; Reich et al. 2021; Repple et al. 2021) that underwent full review (listed in Tables 1–3 by substance type). It should be noted that two papers fell into two different substance categories. Iqbal (2002a) reported on two separate patients who overdosed on either alcohol or illicit drugs, and Jozefowicz-Korczynska et al. (1994) reported on two separate patient groups who chronically misused alcohol or opioids.

Table 1A.

Literature summary of hearing and vestibular outcomes from illicit drug misuse by case reports/case series.

Substance Class & Type	Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Illicit
Amphetamine	Iqbal (2002a)	Case Series n = 20/120	Prior chronic use, in tx	–	Yes*†	–	–	–
Amphetamine	Iqbal (2002b)	Case Series n = 7/7	Prior chronic use, in tx	PO/ 5 – 5 tab	Yes*†	Sudden	–	–
Cocaine	Ciorba et al. (2009)	Case Report	Chronic or acute use w/overdose	IV/–	Yes†	Sudden Severe, Bilateral	No*	–
Cocaine	Stenner et al. (2009)	Case Report	Acute use w/o overdose	IV/0.10 g	Yes†	Sudden Mod-Severe, Bilateral	No	Normal
Cocaine	Patell et al. (2021)	Case Report	Chronic or acute use w/ overdose	IN/4 g	Yes*†	Sudden	–	–
Heroin	Aulet et al. (2014)	Case Report	Chronic or acute use w/overdose	–	Yes†	Sudden Mod-Severe, Bilateral	–	–
Heroin	Iqbal# (2002a)	Case Series n = 2/2	Prior chronic use, in tx	–	Yes*†	Sudden Bilateral	–	–
Heroin	Ishiyama et al. (2001)	Case Report	Prior chronic use, recovery, then relapse w/overdose	IV/0.25 g	Yes*†	Sudden Profound, Bilateral	Yes*†	Bilateral VL
Heroin	Kortequee et al. (2005)	Case Report	Chronic or acute use w/overdose	IV/–	Yes	Sudden Profound, Unilateral (permanent)	Yes*	–
Heroin	Polpathapee et al. (1984)	Case Report	Prior chronic use, recovery, then relapse w/overdose	IV/–	Yes	Sudden Mod-Profound, Bilateral (permanent)	–	–
Heroin	Schrock et al. (2008)	Case Report	Prior chronic use, recovery, then relapse w/overdose	IV/0.20 g	Yes†	Sudden Sev-Profound, Bilateral	No	Normal
Poly-Illicit
Cocaine + Heroin	Fowler & King (2008)	Case Report	Chronic or acute use w/overdose	–	Yes	Sudden, Mild-moderate, Bilateral	–	–
Cocaine + Heroin	Nair et al. (2010)	Case Report	Chronic or acute use w/overdose	–	Yes	Sudden, Severe, Bilateral (permanent)	–	–
Cocaine + Alcohol + Methadone	Nicoucar et al. (2005)	Case Report	Prior chronic use, in tx	IN/-	Yes	Sudden, Profound, Unilateral (permanent)	Yes	Peripheral VL
Heroin + Alcohol	Antonopoulous et al. (2012)	Case Report	Prior chronic use, followed by recovery, then relapse w/overdose	IN/-	Yes†	Sudden Mild – Severe, Bilateral	–	–
Heroin, Crack, Benzodiazepine + Alcohol	Schweitzer et al. (2011)	Case Report	Prior chronic use, recovery, then relapse w/overdose	–	Yes	Sudden, Mod-Severe, Bilateral (permanent)	No*	–
Ecstasy + Methadone	Sharma (2001)	Case Report	Chronic or acute use w/overdose	–	Yes	Sudden, Mod-Severe, Bilateral (permanent)	Yes*†	–
Methamphetamine + Fentanyl	Reich et al. (2021)	Case Report	Chronic or acute use w/overdose	–	Yes	Sudden, Mod-Severe Bilateral (permanent)	–	–

PO=oral

IV= intravenous

IN= intranasal

tab=tablets

tx= treatment

^– Test results not addressed/provided

^*Self-reported only

^†Full or partial recovery

^#Duplicate study

Table 3A.

Literature summary of hearing and vestibular outcomes from alcohol misuse by case study/case series.

Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Iqbal (June 2002a)#	Case Study	Prior chronic use, in tx or recovered	Long-term Ingestion	Yes*†	Sudden Bilateral	–	–
Shen (1993)	Case Series n = 2	Prior chronic use, in tx or recovered	Long-term Ingestion	Yes*† (n = 2/2)	Sudden	Yes* (n = 2/2)	–

PO= oral

IV= intravenous

IN= intranasal

qd= once a day

qid= four times a day

tab= tablets

tx= treatment

^{– =}Author(s) did not address or provide evidence of test results

^*self-reported only

^†full or partial recovery

ENG/VNG= electro/ videonystagmography

VL= vestibular loss

^#duplicate study from Table 1

Overall, the existing literature mostly consisted of case reports as compared to cohort studies. However, a benefit of including the case reports in this review is that it raises justification that future prospective work is needed because the existing literature is weak. For clarity, the following results were organized by substance class type (i.e., illicit, prescription opioids, and alcohol) and by case studies (in aggregate) versus cohort studies to show how certain types of substances show trends or patterns of hearing or vestibular loci damage.

Illicit Drugs

Tables 1A and 1B summarize the resulting 21 unique studies that reported HL and/or VL stemming from illicit drug misuse. Of the 21 total studies, 19 discussed HL associated with illicit drugs. Vestibular status was discussed in 11 of the total 21 case reports/series/cohort studies.

Table 1B.

Literature summary of hearing and vestibular outcomes from illicit drug misuse by cohort study.

Substance Class & Type	Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Illicit
Cocaine	Demer et al. (1989)	Cohort n = 9	Prior chronic use, in tx	–	–	–	No	Normal
Poly-Illicit
^ Simulants, Opioids, or both	Mokhtarinejad et al. (2021)	Cohort n = 15/95 (+44 controls)	Chronic or acute use w/overdose	–	Yes*	–	–	–
Cocaine/Crack or Marijuana + Alcohol	Moreira et al. (2012)	Cohort n = 47 (+47 controls)	Chronic use w/o overdose	–	–	–	Yes n = 4	Peripheral VL and Imbalance
Marijuana or Crack/Cocaine	Weich et al. (2012)	Cohort n = 10 marijuana n = 7 crack/cocaine	Prior chronic use, in tx	–	Yes (n=5) No but abnormal ABR (n=12)	Bilateral (permanent)	Yes n = 6	–

PO=oral

IV= intravenous

IN= intranasal

tab=tablets

tx= treatment

^–Test results not addressed/provided

^*Self-reported only

^†Full or partial recovery

^#Duplicate study

^{^}terminology used by the author

Auditory Findings

Case Reports/Series

As shown in Table 1A, 17 of the 21 total studies were either single or case-series reports describing HL from illicit drug misuse, specifically amphetamines (Iqbal 2002a, b), cocaine (Ciorba et al. 2009; Stenner et al. 2009; Patell et al. 2021), heroin (Polpathapee et al. 1984; Ishiyama et al. 2001; Iqbal 2002a; Kortequee et al. 2005; Schrock et al. 2008; Aulet et al. 2014), and combinations of illicit drugs and other substances (alcohol, benzodiazepines, fentanyl, methadone; Sharma 2001; Nicoucar et al. 2005; Fowler & King 2008; Nair et al. 2010; Schweitzer et al. 2011; Antonopoulous et al. 2012; Reich et al. 2021). Across case reports/series, 30.5% (44/144 total patients) reported HL or otherwise had abnormal auditory function from using illicit drugs or combinations of illicit drugs with other substances: 27 cases from amphetamine, three cases from cocaine, seven cases from heroin, and seven cases involving poly-substances including an illicit drug. Of the 44 patients, 41 were identified as men or males and 3 were women or females.

Hearing function in many of these reports was evaluated through pure-tone audiometry, and for some, coupled with otoacoustic emissions and/or auditory brainstem response (ABR) testing. Five of the 17 case reports did not include any objective audiometric testing results to confirm the presence of HL, but either relied on patient report (Iqbal 2002a, b; Nicoucar 2005; Patell et al. 2021) or noted that audiometric testing was done but did not include the results in the publication (Ishiyama 2001). From the case reports/series, it appears that either chronic or acute ingestion of illicit drugs resulting in overdose (n = 8); acute ingestion without overdose (n = 1); prior chronic use and in treatment (n = 30); or prior chronic use followed by recovery, then relapsed with an overdose (n = 5), typically followed with a sudden bilateral sensorineural hearing loss (SNHL), and the degree of loss ranged across patients from mild to profound. Five of the case studies evaluated speech recognition, with reduced speech recognition thresholds (50 to 80 dB HL) and poor word discrimination scores (ranging from 4% to 56%) bilaterally (Ciorba et al.2009; Nair et al. 2010; Schweitzer et al. 2011; Aulet et al. 2014; Reich et al, 2021). In terms of HL recovery, 81.8% (36/44) of the patients who had HL recovered either partially or fully within a few days (Iqbal 2002a,b; Patell et al. 2021), one to two months (Ciorba et al. 2009; Schrock et al. 2008; Schweitzer et al. 2011) and up to two years (Antonopoulous et al. 2012); however, the extent of recovery is unclear as post-recovery audiometric data were not always provided in these cases. Many of the patients in the case reports also received steroids, vasoactive substances, or anti-viral medication before discharge, potentially facilitating some hearing restoration (e.g., Schrock et al. 2008; Stenner et al. 2009; Nair et al. 2010; Shaw et al. 2011; Antonopoulous et al. 2012; Aulet et al. 2014; Patell et al. 2021). The reported period of recovery for individuals who relapsed and overdosed ranged anywhere from three weeks (Ishiyama et al. 2001), to one (Polpathapee et al. 1984) to two (Schrock et al. 2008; Schweitzer et al. 2011) months, and up to two years (Antonopoulous et al. 2012). Seven patients who misused heroin or cocaine, particularly in combination with other drugs, had HL that was deemed permanent regardless of medical management (Polpathapee et al. 1984; Sharma 2001; Kortequee et al. 2005; Nicoucar et al. 2005; Nair et al. 2010; Schweitzer et al. 2011; 2012; Reich et al. 2021), and in one case, it was unknown whether hearing recovered (Fowler & King 2008). Sixteen individuals who used cocaine, ecstasy, heroin, and multi-substances also reported associated symptoms of unilateral or bilateral tinnitus.

Cohort Studies

There were only two cohort studies identified on the topic of HL and illicit drugs (Weich et al. 2012; Mokhtarinejad et al. 2021) with a total of 32 participants showing HL and/or abnormal auditory function (see Table 1B). Of those 32 participants, Mokhtarinejad et al. (2021) identified that 12 were men and 3 were women, whereas the sex or gender was not specified in Weich et al. (2012). Mokhtarinejad et al. 2021 was a cross-sectional cohort study that compared pure-tone average thresholds (PTAs), speech recognition, and distortion-product otoacoustic emissions (DPOAE; pass/fail) between 95 patients with illicit drug overdose or chronic use to 44 healthy individuals without substance-use histories. When adjusting for age, sex, and smoking history, there was association between combined ‘stimulants’ (terminology used by the authors, which included amphetamine and methamphetamine) and non-prescription opioids (unspecified) and SNHL, with 15-fold increased risk of SNHL in participants who misused illicit drugs. They also reported a higher incidence of HL in participants who used opioids and opioids with stimulants, versus stimulants alone. Overall, SNHL was identified in 15 out of the 95 people with known substance-use histories as compared to one participant in the healthy group (n=44). In the 15 participants with SNHL, 13 had failed a DPOAE screening and their SRT ranged from 15–40 dB HL. The severity of the loss was typically mild, except for one participant who had a moderate SNHL. The authors did not discuss HL recovery. Weich et al. (2012) was another cross-sectional cohort study reviewed, which compared hearing outcomes in 17 people who were former chronic users of either marijuana (as an illicit drug) or crack/cocaine. In that study, the authors did not describe their results in the context of the groups (based on substance), so it is unknown how each respective drug affected hearing outcomes. Using only the PTAs as criteria for HL, the authors denoted that 5/17 participants had HL that varied from mild to profound and was deemed unilateral or bilateral, and permanent. Twelve of the individuals had normal PTAs but abnormal ABR latencies, and six participants reported tinnitus (Weich et al. 2012).

Vestibular Findings

Case Reports/Series

Eight of the 17 case reports/series that were discussed above in the hearing section also addressed vestibular function (refer to Table 1A). Across these case reports/series, 50% (4/8) total patients, who all identified as males or men, reported vertigo or balance symptoms, or were reported to have VL based on vestibular test results: two cases from heroin and two cases involving poly-substances including an illicit drug. For the cases that did have patients reporting vestibular or balance symptoms, one patient reported “vertigo” following heroin injected into the neck (Kortequee et al. 2005), while another patient reported “general unsteadiness” from an ecstasy and methadone overdose (Sharma et al. 2001). In Ishiyama et al. (2001), it was reported that the patient experienced temporary bilateral VL after chronic heroin use that was followed by abstinence and then relapse with an overdose; however, no vestibular test results were noted. In fact, objective testing was rarely used to confirm vestibular function and was only presented in three of eight case reports/series that discussed vestibular function (Nicoucar et al. 2005; Schrock et al. 2008; Stenner et al. 2009). Nicoucar et al. (2005) reported on a patient who was receiving methadone treatment and experienced an intralabyrinthine hemorrhage following the ingestion of cocaine and alcohol. The patient presented with a sudden SNHL and left labyrinthine weakness based on laboratory findings. The authors noted that within three weeks, the patient’s vestibular symptoms had subsided likely due to physiological vestibular compensation; however, because the patient was on methadone treatment and was also misusing illicit drugs and alcohol, it is unknown if the VL was related to one specific substance or the combination of them.

Vestibular testing performed was also specific to caloric or a horizontal headshake nystagmus test. Of those cases, caloric and headshake testing results were all deemed normal in patients who misused cocaine (Nicoucar et al. 2005; Stenner et al. 2009) and heroin (Schrock et al. 2008). In two reports, a diagnosis of VL was excluded based on the patient only denying they had vestibular (e.g., vertigo) or balance symptoms (Ciorba et al. 2009; Schweitzer et al. 2011).

Cohort Studies

Like the auditory system, there were very few cohort studies (n = 3) on the topic of illicit drugs and the vestibular system. Across these studies, 13.6% of total participants (10/73) were identified to have central and/or peripheral vestibular dysfunction. At least four were identified as men (Moreira et al. 2012), while the other studies did not indicate sex or gender. In a cross-sectional study, Demer et al. (1989) utilized objective vestibular testing with water caloric and electrooculogram saccade, optokinetic, and smooth pursuit recordings in nine people who previously misused cocaine and nine age-matched people who were considered controls and denied substance use. The authors confirmed normal peripheral and central vestibular function in all participants. Comparatively, Moreira et al. (2012), evaluated vestibular function using objective clinical vestibular-balance test measures in 47 men who chronically used a combination of illicit drugs (cocaine/crack and marijuana as an illicit drug) with or without alcohol, as compared to a control group without drug or alcohol histories (n = 47). In that study, nearly 57% of the participants who used illicit drugs with or without alcohol self-reported “dizziness or imbalance” and had higher postural instability on posturography. While unclear what exact test parameters were used, only 8.5% (4/47) of the participants who used illicit drugs with or without alcohol had abnormal peripheral vestibular hypofunction based on caloric and rotary chair testing. These results may suggest differential effects of substances on the vestibular end-organs and potential sparing of semicircular canal function, atypical of vestibulotoxic medications. Interestingly, the authors showed a positive relationship between the duration of illicit drug use (months to years) and sway velocity during a vestibular-specific balance condition where the participant’s eyes were closed and standing on foam. The results suggested that the longer time a person had spent using illicit drugs correlated to more imbalance, particularly when proprioceptive and visual cues were removed, and the participant could only rely on their inner-ear inputs. Weich et al. (2012) reported dizziness symptoms and peripheral VL in 6/17 participants with illicit drug use of crack/cocaine or marijuana as an illicit drug; however, they provided no further details on vestibular testing or results.

Prescription Opioids

Table 2A and 2B summarize the resulting 28 unique studies that reported HL and/or VL stemming from prescription opioid misuse. Of the 28 studies, 27 of them discussed associated HL with the misuse of prescription opioids. Vestibular status was discussed in 13 of the 28 case reports/series/cohort studies (Table 2A-B). The most common prescription opioids reported were morphine-based (Kopec & Nelson 2012; Boyle & Rosenbaum 2013; MacDonald et al. 2015;Leache et al. 2016); codeine-based (Ho et al. 2007; Ntranos et al. 2017); propoxyphene (Darvon^®; Lupin et al. 1976; Harrell et al. 1978); methadone (e.g., Bayat et al. 2019) or other synthetic opioid (Helander et al. 2014); or opioids combined with acetaminophen/paracetamol, such as Vicodin^® (hydrocodone with acetaminophen; Friedman et al. 2000; Oh et al. 2000; Novac et al. 2015), codeine and acetaminophen (Blakley & Schilling 2008; Freeman et al. 2009), Percocet^® (oxycodone and acetaminophen; Rigby & Parnes 2008), or Darvocet^® (or co-proxamol, which is dextropropoxyphene and acetaminophen; Ramsay 1991).

Table 2A.

Literature summary of hearing and vestibular outcomes from prescription opioid drug misuse by case report/series/chart review.

Substance Class & Type	Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Opioids
Morphine	Kopec & Nelson (2012)	Case Report	Chronic or acute use w/overdose	IN/–	Yes*†	Sudden, Bilateral	–	–
Morphine	Leache et al. (2016)	Case Report	Chronic or acute use w/ overdose	PO/120 mg	Yes*	Sudden, Mod-Severe to Profound Bilateral (permanent)	–	–
Oxymorphone	Boyle & Rosenbaum (2013)	Case Report	Chronic or acute use w/ overdose	IN/–	Yes*†	Sudden, Bilateral	–	–
Oxymorphone	MacDonald et al. (2015)	Case Report	Acute ingestion w/o overdose	IN/30 mg	Yes*	Sudden, Bilateral	–	–
Oxycodone	Ntranos et al. (2017)	Case Report	Chronic or acute use w/ overdose	PO/34 tab	Yes*†	Sudden	–	–
Hydrocodone	Ho et al. (2007)	Case Series n = 5	Chronic use w/o overdose	PO/10 – 300 mg	Yes	Progressive, Profound Bilateral (permanent)	–	–
Propoxyphene (Darvon®)	Harell et al. (1978)	Case Report	Chronic use w/o overdose	PO/1000 mg qd	Yes	Progressive, Profound Bilateral (permanent)	No*	–
Propoxyphene hydrochloride	Lupin et al. (1976)	Case Report	Acute ingestion w/o overdose	PO/1560 mg qd	Yes	Sudden, Normal to Severe Bilateral (permanent)	Yes	Peripheral Bilateral VL
Methadone	Ghasemi et al. (2019)	Case Report	Chronic or acute use w/ overdose	PO/40 mg	Yes	Sudden, Mod-severe Bilateral (permanent)	–	–
Methadone	Repple et al. (2021)	Case Report	Chronic or acute use w/ overdose	IV/2.55 mg	Yes*†	Sudden, Moderate Bilateral	Yes†*	–
Methadone	Saifan et al. (2013)	Case Report	Chronic or acute use w/ overdose	PO/80 mg	Yes	Sudden, Mild-moderate Bilateral (permanent)	–	–
Methadone	Shaw et al. (2010)	Case Report	Chronic or acute use w/overdose	PO/–	Yes*†	Sudden, Bilateral	–	–
Methadone	Van Gaalen et al. 2009	Case Report	Chronic or acute use w/ overdose	PO/75 mg	Yes†	Sudden, Mod-Severe Bilateral	No*	–
Methadone	Vorasubin et al. (2013)	Case Report	Chronic or acute use w/ overdose	PO/90 mg	Yes	Sudden, Severe, Bilateral (permanent)	No*	–
MT-45 Synthetic Opioid	Helander et al. (2014)	Case Series n = 9	Chronic or acute use w/ overdose	PO, IV, IN/6–100 mg	Yes*† (n = 3/9)	Sudden, Bilateral (permanent n = 1)	Yes* (n = 4/9)	–
Opioid + Acetaminophen
Vicodin® (hydrocodone + acetaminophen)	Friedman et al. (2000)	Review n = 12	Chronic use w/o overdose	PO/10 – 60 tab	Yes	Sudden/Rapid Progressive, Bilateral Profound (permanent)	Yes* (n = 2/12)	–
Vicodin® (hydrocodone + acetaminophen)	Novac et al. (2015)	Case Report	Chronic or acute use w/overdose	–	Yes*	Profound, Unilateral (permanent)	–	–
Vicodin® (hydrocodone + acetaminophen)	Oh et al. (2000)	Case Series n = 2	Chronic use w/o overdose	PO/15 tab qid; 35 tab qd	Yes*	Rapid Progressive, Profound Bilateral (permanent)	Yes (n = 1/2)	Normal Caloric and Rotary Chair
Codeine + acetaminophen	Blakley & Schilling (2008)	Case Series n = 3	Chronic use w/o overdose	PO/300 mg 2qd	Yes	Progressive, Profound Bilateral (permanent)	Yes (n = 3/3)	Absent Caloric
Codeine phosphate + acetaminophen	Freeman et al. (2009)	Case Series n = 10	Chronic use w/o overdose	PO/4–20 tab, 30–500mg	Yes*	Sudden/Rapid Progressive, Profound Bilateral (permanent)	No*	Normal VNG
Percocet® (oxycodone + acetaminophen)	Rigby & Parnes (2008)	Case Report	Chronic use w/o overdose	PO/5 mg oxy; 325 mg acetaminophen	Yes	Progressive, Profound Bilateral (permanent)	No*	Normal VNG
Co-proxamol (Darvocet®)	Ramsay (1991)	Case Report	Chronic use w/o overdose	PO/ 30 qd	Yes*	Progressive, Severe Bilateral (permanent)	–	–
Poly- or Unspecified Opioids
Methadone + marijuana	Christenson & Marjala (2010)	Case Series n = 2	Chronic use w/o overdose	–	Yes†*	Sudden, Bilateral	–	–
Various opioids + heroin, oxycodone, methadone, tramadol	Mozeika et al. (2020)	Review n = 41	–	PO, IN, IV/–	Yes* (n = 19/41)	Unilateral (n = 1), Bilateral (n = 40), (permanent n = 4)	–	–

PO= oral

IV= intravenous

IN= intranasal

qd= once a day

qid= four times a day

tab= tablet

tx= treatment

^{– =}Author(s) did not address or provide evidence of test results

^*self-reported only

^†full or partial recovery

ENG/VNG= electro/videonystagmography

VL= vestibular loss

Table 2B.

Literature summary of hearing and vestibular outcomes from prescription opioid drug misuse by cohort study.

Substance Class & Type	Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Opioids
Methadone	Bayat et al. (2019)	Cohort n = 27	Prior chronic use, in tx	30 mg	Yes* (n = 11/27)	Bilateral (permanent)	–	–
Poly- or Unspecified Opioids
Opioids + barbituates+ "sniffers" + alcohol	Jozefowicz-Korczynska et al. (1994)	Cohort n = 96 (+50 controls)	Prior chronic use, in tx	–	Yes* (n = 62/96)	–	Yes (n = 79/96)	Peripheral VL and Central Dysfunction
Opioids (unspecified)	Rawool & Dluhy (2011)	Cohort n = 23	Prior chronic use, in tx	–	Yes (n = 2/23)	–	–	–
Opioids (unspecified)	Kurnatowski & Garganisz (1996)	Cohort n = 62 (+50 controls)	Prior chronic use, in tx	–	–	–	Yes (n = 55/62)	Peripheral VL Central Dysfunction

PO= oral

IV= intravenous

IN= intranasal

qd= once a day

qid= four times a day

tab= tablet

tx=treatment

^{– =}Author(s) did not address or provide evidence of test results

^*self-reported only

^†full or partial recovery

ENG/VNG= electro/videonystagmography

VL= vestibular loss

Auditory Findings

Case Reports/Series/Chart Review

Across all case reports/series/chart review studies involving prescription opioids (see Table 2A), 72% (72 /100) of the total patients were reported to experience HL: 21 cases from opioids alone, 30 cases from opioids combined with acetaminophen, and 21 cases from poly-substances involving opioids or unspecified opioids. Of these patients, 39 cases where in males or men and 33 were in females or women. Out of the 72 patients, 15% (11/72) individuals who misused opioids presented with a sudden SNHL within hours after overdose (e.g., Kopec & Nelson 2012; Boyle & Rosenbaum 2013; Leache et al. 2016; excluding data from Helander et al., who did not specify use patterns for the three individuals who experienced HL). However, a higher incidence of people who chronically misused opioids over time but reportedly never overdosed (51% [37/72]) also experienced SNHL. A rapidly progressive SNHL was especially apparent in patients who misused opioids in combination with acetaminophen (e.g., Friedman et al. 2000; Oh et al. 2000). The degree of HL that was reported varied, however, many individuals experienced moderate to profound SNHL, and some had cookie-bite configurations, although this was less apparent compared to the findings for illicit drugs. Opioid-related HL was also rarely temporary, which is another notable difference from the reports for illicit drugs. Mozeika et al. (2020) was a retrospective chart review where opioid-related HL was identified in 19 individuals through the New Jersey Poison Center. Substances included heroin, oxycodone, methadone, and tramadol and the HL was found to be temporary in seven people, and permanent in 12. Approximately, 58% (42/72) of patients were identified with permanent HL, even after steroid management in some instances, and several became cochlear implant recipients (Friedman et al. 2000; Oh et al. 2000; Ho et al. 2007; Blakely & Schilling 2008; Freeman et al. 2009; Novac et al. 2015). Importantly, all patients who experienced HL with misuse of prescribed opioids (most notably hydrocodone, oxycodone, or codeine) in combination with acetaminophen had permanent and profound SNHL (e.g., Friedman et al. 2000; Freeman et al. 2009). Last, 40 out of the 72 patients reported bilateral or unilateral tinnitus.

Cohort Studies

There were three cohort studies that described HL involving the misuse of either unspecified opioids or poly-substances involving opioids (Jozefowicz-Korczynska et al. 1994; Rawool & Dluhy 2011; Bayat et al. 2019), where a total of 146 participants with prescription opioid misuse were evaluated for potential HL. Nearly 34% (50/146) of these participants identified as males or men and remainder sex/gender was not provided (Jozefowicz-Korczynska et al. 1994). Overall, 51% (75/146) of those participants were then identified to have SNHL (see Table 2B). Rawool and Dluhy (2011) evaluated hearing function in 23 young adults with a history of unspecified opioid misuse and/or occupational noise (no healthy comparison group was used). The authors identified two participants (ages 20 and 33), who did not have concomitant noise exposure, had a permanent bilateral cookie-bite SNHL that they likely attributed to opioid misuse; however, there was no pre-audiometric testing performed nor did this study rule out genetic or other causes of HL aside from noise exposure so the exact cause cannot be determined. Jozefowicz-Korczynska et al. (1994) also identified SNHL in 62 of 96 adults who chronically used opioids/barbiturates and who had not used opioids from anywhere from one to 18 months. Unfortunately, that study did not provide additional details on the degree or configurations of the HL measured. In one prospective study, Bayat et al. (2019) compared hearing function in 27 males with past chronic opioid misuse and who were receiving methadone maintenance treatment to 27 age- and gender-matched healthy controls. The authors found that those participants on methadone maintenance had significantly poorer hearing than the controls; however, the hearing outcomes were self-reported (i.e., reporting “being deaf” or “serious difficulty hearing”) rather than based on objective audiometric data. None of the cohort studies reported on the occurrence of tinnitus.

It is of note that six case reports and one cohort study were focused on methadone, propoxyphene, or a methadone synthetic, and its suspected cause of sudden SNHL following overdose or misuse. Methadone, propoxyphene, or buprenorphine are often prescribed as a treatment for pain and other opioid dependence; however, it is possible that HL occurs after misuse or overuse of it (e.g., Lupin et al. 1976; Christenson & Marjala, 2010; Bayat et al. 2019; Ghasemi et al. 2019).

Vestibular Findings

Case Reports/Series/Chart Review

Across the 11 case reports/series/chart review studies addressing the effects of misuse of prescription opioids and vestibular function (see Table 2A), 29% (12/42) patients were reported to experience VL or self-reported vestibular or balance symptoms: 6 cases from opioids alone and 6 cases from opioids combined with acetaminophen. Eight of the patients were male or men and 4 were females. For the case reports that resulted in patients experiencing SNHL, the authors reported changes in vestibular function; however, only a self-report from the patient was taken to confirm or deny vestibular or imbalance symptoms (e.g., Harell et al. 1978; Friedman et al. 2000; Van Gaalen et al. 2009). Although the test results themselves were not presented, Blakley and Schilling et al. (2008), Oh et al. (2000), and Lupin et al. (1976) reported using electronystagmography (ENG), caloric, and/or rotary chair to evaluate vestibular function. In these reports, it appears that permanent bilateral or unilateral peripheral VL can occur suddenly (Lupin et al. 1976), or progressively (Blakley & Schilling et al. 2008) in patients who misused either propoxyphene or codeine with acetaminophen. Comparatively, Oh et al. (2000) found that of the two patients in their report, one had profound SNHL with spared vestibular function as measured by normal caloric responses. Collectively, these case reports suggest that opioids may negatively affect the vestibular end-organs, yet the true incidence and prevalence may not be known given the lack of vestibular testing performed.

Cohort Studies

There were two cohort studies that investigated the association between opioid misuse and the vestibular system, with a total of 158 participants between the two studies. Overall, 84% (134/158) of participants were determined to have central and/or peripheral vestibular dysfunction (see Table 2B). Jozefowicz-Korczynska et al. (1994) was a cohort study that involved three groups of people who either misused alcohol (n = 223), misused non-specified opioids (n = 96; sex or gender was unknown), or did not use substances (n = 50). All underwent objective vestibular testing, including caloric and ENG. Of the 96 subjects who used opioids, 20 subjects showed signs of peripheral VL and 59 showed central vestibular indications, whereas 41/50 normal healthy controls had a normal vestibular evaluation. Kurnatowski & Garganisz (1996) objectively measured vestibular function in 62 male participants, who misused unspecified prescription opioids and who were in recovery anywhere from one to nine months, as compared to a healthy group who did not use substances. Using ENG ocular motility, caloric, rotary chair, and functional balance measures, it was concluded that 69% of people (43/62) who misused opioids had signs of central vestibular dysfunction and 19% (12/62) had peripheral vestibular indications as compared to a normal control group of individuals who showed only 22% (11/50) and 10% (5/50) of central or peripheral vestibular indications, respectively. Interestingly, 38% of participants who misused opioids reported vestibular symptoms, highlighting a common disassociation between self-report of symptoms and physiologic vestibular dysfunction and similar what is known about the discordance between self-reported vestibular outcomes in patients with known vestibulotoxicity (Prayuenyong et al. 2018).

Alcohol

Research and clinical findings on the otologic effects of alcohol predated other forms of substance use and have a larger patient/participant base. Table 3A-B summarizes the 20 articles that focused on the effects of chronic alcohol use and hearing or vestibular function; two were single-case reports/case series (Shen 1993; Iqbal 2000b) and 18 were cohort studies (13 addressing auditory and 9 addressing vestibular function).

Table 3B.

Literature summary of hearing and vestibular outcomes from alcohol misuse by cohort study.

Reference	Study Type	Phase of Use	Delivery/Dose	Hearing Loss?	Hearing Results	Vestibular Loss?	Vestibular Results
Belle et al. (2007)	Cohort n = 37 (+ 35 controls)	Prior chronic use, in treatment or recovered	Long-term ingestion	Yes* (n = 25/37)	–	Yes* (n = 4/37)	–
Chu et al. (1982)	Cohort n = 66	Chronic use without overdose	Long-term ingestion	Yes n = 27/66 had prolonged ABR	Retrocochlear	–	–
Kumar & Patrick (2011)	Cohort n = 30 (+ 30 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	Yes* (n = 14/30)	Mild-Moderate High Frequency (permanent)	–	–
Niedziellska et al. (2001)	Cohort n = 30	Chronic use without overdose	Long-term Ingestion	Yes* (n = 22/30)	High Frequency Retrocochlear	–	–
Nordahl (1964)	Cohort n = 83	Chronic use without overdose	Long-term Ingestion	Yes (n = 14/83)	–	–	–
Ribeiro et al. (2007)	Cohort n = 40 (+35 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	Yes (n = 22/40)	Mild-Moderate High Frequency	–	–
Rosenhall et al. (1993)	Cohort n = 41	Chronic use without overdose	Long-term Ingestion	Yes* (n = 41/41)	High Frequency Bilateral	–	–
Spitzer & Newman (1987)	Cohort n = 14 (+14 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	No Variable ABR only	–	–	–
Spitzer & Ventry (1980)	Cohort n = 15 (+15 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	Yes* (n = 7/15)	Retrocochlear	–	–
Wheeler et al. (1980)	Cohort n = 52	Chronic use without overdose	Long-term Ingestion	Yes (n= 49/52)	Bilateral High Frequency (permanent)	–	–
Gołabek & Niedzielska (1984) >	Cohort n = 67	Prior chronic use, in treatment or recovered	Long-term ingestion	Yes (n = 93/134 ears)	High Frequency (permanent) Retrocochlear (n = 21 ears)	–	–
Verma et al. (2006)	Cohort n = 20 (+30 controls)	Chronic use without overdose	Long-term Ingestion	Yes* (n =18/20)	High Frequency (n = 10) Retrocochlear (n = 8)	Yes (n = 9/20)	Peripheral VL
Jozefowicz-Korczynska et al. (1994) #	Cohort n = 223 (+50 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	Yes* (n = 130/223)	–	Yes (n = 142/223)	Peripheral VL and Central Dysfunction
Holm et al. (1983)	Cohort n = 13	Prior chronic use, in treatment or recovered	Long-term Ingestion	–	–	Yes (n = 9/13)	Peripheral VL and Central Dysfunction
Sasa et al. (1981)	Cohort n = 33 (+16 controls)	Chronic use without overdose	Long-term Ingestion	–	–	Yes† (n = 33/33)	Peripheral VL and Central Dysfunction
Schmidt et al. (2010)	Cohort n = 32 (+32 controls)	Chronic use without overdose	Long-term Ingestion	–	–	Yes (n= 29/33)	Abnormal Balance
Ledin (1995)	Cohort n = 11 (+12 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	–	–	Yes (n = 11/11)	Abnormal Balance
Ledin & Odkvist (1991)	Cohort n = 11 (+12 controls)	Prior chronic use, in treatment or recovered	Long-term Ingestion	–	–	Yes (n = 8/11)	Central Dysfunction, Abnormal Balance

PO= oral

IV= intravenous

IN= intranasal

qd= once a day

qid= four times a day

tab= tablets

tx= treatment

^{– =}Author(s) did not address or provide evidence of test results

^*self-reported only

^†full or partial recovery

ENG/VNG= electro/ videonystagmography

VL= vestibular loss

^#duplicate study from Table 1

^>not included in the total counts due to e*ar data only

Auditory Findings

Case Reports/Series/Chart Review

Out of the case studies, 100% (3/3) of patients, who were all males, were reported to experience sudden HL (see Table 3A). Iqbal (2002a) reported on a patient who had long-term alcohol and amphetamines misuse but who was in recovery. This patient experienced a sudden bilateral HL that recovered, although an audiogram was never reported to verify the onset or improvement in hearing. Shen (1993) reported on two patients with past chronic alcohol misuse histories, in recovery, and then who relapsed. The HL was indicated to be sudden with tinnitus, and reportedly recovered for both patients, but no documented hearing testing was provided.

Cohort Studies

Of the 13 cohort studies identified, 57% (369/651) total participants were identified to have HL and/or abnormal tests of retrocochlear function (e.g., ABRs, acoustic reflexes). Gołabek & Niedzielska (1984) only reported the incidence of HL based on the number of ears affected versus participants, so their data were not included in these totals, as it was unclear which participants had abnormal findings. The vast majority of HL or abnormal auditory function was identified in 30% (198/651) of people with prior chronic use and who were in treatment or recovered and followed by 26% (171/651) of people who had chronic sustained use. Of the 13 cohort studies, six studies did not describe sex or gender demographics, four studies had both males and females but did not describe their results as a function of sex or gender (Rosenahall et al. 1993; Ribero et al.,2007; Schmidt et al. 2010) and the remaining five studies only had cohorts of men or males. Only three of the papers discussed that the HL observed in their participants was permanent in nature, while all of the studies were performed in people with long-term use of alcohol exposure, so it may be likely that chronic alcohol-induced HL is permanent. Nordhal (1964) was one of the first large cohort studies (n = 83) to investigate the relation between alcohol and HL. While 14/83 male subjects were found to have HL that could be linked to alcohol misuse, the authors could not separate the confounder that many of their participants had prior noise exposure. Similarly, while Ribeiro et al. (2007) did find higher high frequency HL in participants with past chronic alcohol misuse histories (n = 40) as compared to a control group who had no past noise exposure, they could not conclude whether auditory thresholds in participants with alcohol misuse were higher than thresholds in a separate control group who were exposed to noise. Spitzer and Ventry (1980) also did not detect significant hearing differences between healthy controls and people who identified as misusing alcohol; however, they did determine that those who used alcohol had 7–13 dB higher thresholds from 4 kHz to 8 kHz compared to controls, and there were likely more indications of retrocochlear impairments given that these participants had absent acoustic reflexes in frequencies with normal thresholds and poorer scores for the staggered spondaic word test and synthetic sentence identification test compared to controls. Comparatively, several other studies did find that chronic alcohol misuse leads to a permanent high frequency SNHL (e.g., Golabek & Niedzielska 1984; Kumar & Patrick 2011) that was typically bilateral in nature (e.g., Wheeler et al.1980; Rosenhall et al. 1993; Iqbal 2002a); however, audiometric findings were not always reported or included in the article itself.

Wheeler et al. (1980) found that 49/52 of their study’s male participants (>60 years of age) with a diagnosed alcohol misuse disorder had symmetrical bilateral SNHL most evident from 2 kHz to 8 kHz. Interestingly, the authors also found that the duration of their participants’ alcohol consumption positively correlated to their severity of HL. When accounting for age, 78% of the participants who had reported drinking 10 years or more showed a greater than 20 dB average high-frequency SNHL as compared to participants who reported drinking less than 10 years. This suggests that more severe alcohol use patterns may contribute to increased risk of hearing deficits. Verma et al. (2006) also reported hearing and vestibular function in three groups of people who: (a) had long-term alcohol dependence (mean, 16 years), (b) only socially drank, and (c) had complete alcohol abstinence. A total of 90% (18/20) adults in the long-term alcohol group had SNHL of various configurations, with the most elevated thresholds at 4 kHz to 8 kHz as compared to those who socially drank, 13% (2/15), and those who were abstinent from alcohol, 6% (1/15). Lastly, Bellé et al. (2007) identified that 20 participants with long-term alcohol dependence have also reported associated otologic symptoms of aural fullness or tinnitus, as compared to 11 of the healthy controls.

While the nature of the alcohol-induced HL appears to be mostly sensory, it appears it can be neural, as suggested by studies that have shown abnormal acoustic reflex and ABR testing (e.g., Chu et al. 1982; Golabek & Niedzielska 1984; Niedziellska et al. 2001). Verma et al. (2006) also identified abnormal ABR findings in 40% (8/20) people who had long-term alcohol dependence, as noted by prolonged absolute waves III and V latencies and interpeak latency of I-V. Similarly, in their study, Spitzer and Ventry (1980) identified that 46% (7/15) of their participants who misused alcohol for more than 10 years presented with bilaterally absent acoustic reflexes and poor Staggered Spondaic Word Test and Synthetic Word Identification scores, despite normal speech discrimination and normal audiometric thresholds, aligning with abnormalities consistent with brainstem site-of-lesion. However, in a follow up study, Spitzer and Newman (1987) also found that 14 people with past chronic alcohol misuse had more variable auditory brainstem evoked responses, but no negative changes on peak latencies or amplitudes.

Vestibular Findings

Case Reports/Series/Chart Review

As shown in Table 3A, there was only one case series that reported vestibular effects in patients with chronic alcohol misuse. Shen (1993) reported on two male patients in recovery, and then who relapsed with alcohol. Vestibular and imbalance symptoms were reported in both patients (2/2), but no documented vestibular testing was reported or provided.

Cohort Studies

There were eight cohort studies that investigated the effects of alcohol misuse on the vestibular system (see Table 3B), with 64% (245/381) total participants identified to have vestibular dysfunction. Exact numbers for sex and gender were unknown or unclear for two studies (Verma et al. 2006; Bellé et al. 2007), while the remaining studies were only performed in males or men. Schmidt et al. 2010 did have both males and females but did not describe the results accordingly, so the incidence by sex or gender is unclear. Bellé et al. 2007 reported that four out of their cohort of participants with alcohol misuse histories had VL, but no objective testing was provided. The remaining studies addressed the effects of chronic alcohol misuse on vestibular and balance function using objective measures (Sasa et al. 1981; Holm et al. 1983; Ledin & Odkvist 1991; Jozefowicz-Korczynska et al. 1994; Ledin 1995; Verma et al. 2006; Schmidt et al. 2010). Using ENG, caloric, rotary chair, and/or balance function measures, these studies identified that long-term alcohol use can affect semicircular canal function, but more commonly the brainstem-mediated central vestibular pathways (Sasa et al. 1981; Holm et al. 1983; Ledin & Odkvist 1991; Jozefowicz-Korczynska et al. 1994; Ledin 1995; Verma et al. 2006; Schmidt et al. 2010). Overall, Sasa et al. (1981) reported a higher incidence of vestibular abnormalities in males with a chronic alcohol disorder (n = 33) as compared to a healthy control group. Most notably, 18.1% of subjects had a peripheral vestibular loss, 36% had central vestibular abnormalities, and 46% showed combined peripheral and central abnormalities. The authors also found that participants who had a drinking history of <30 years and who were younger were more likely to have peripheral vestibular effects, whereas those with combined central and peripheral loss were typically seen in older subjects with a long history of alcohol use (>30 years). The authors followed up with seven of their participants three years after they had not used alcohol and found that almost half of the participants had complete resolution of their vestibular findings or had a reduction in abnormalities to just presenting with central vestibular impairments, suggesting some level of recovery with abstinence.

Jozefowicz-Korczynska et al. (1994) also identified that nearly 53% of their male participants who had an alcohol use disorder but were in treatment presented with central vestibular dysfunction, whereas only 10% had peripheral vestibular findings. This was consistent with other studies using similar methods that also found a greater proportion of central cerebellar indications, consistent with abnormal smooth pursuit and optokinetics (Holm et al. 1983; Ledin & Odkvist 1991) and balance performance, particularly in challenging visual and somatosensory conditions (Ledin & Odkvist 1991; Ledin 1995). Comparatively, Schmidt et al. (2010) reported on the vestibular function of 32 adults enrolled in Alcoholics Anonymous and 32 healthy matched controls. The authors concluded that there was no difference in ENG results between groups, but participants in the alcohol group had poorer dynamic posturography, making them a higher risk of fall. Collectively, these findings suggest there are likely differential effects based on the duration of alcohol use, timing of use, and type/severity of vestibular dysfunction.

DISCUSSION

General Conclusions Based on Existing Literature

This systematic review explored the associations between substance misuse and hearing and vestibular effects to establish the current knowledgebase and identify the gaps which would warrant further systematic work. In summary, of the 67 unique studies reviewed, 21 (33%) reported ototoxicity related to illicit drug misuse, 28 studies (42%) reported ototoxicity from prescription opioids, and 20 studies (30%) reported HL and/or VL related to chronic alcohol misuse (note that two studies fell within more than one category). Overall, substance misuse and SUDs may be risk factors for sudden or gradual and either temporary or permanent HL and/or VL, particularly with long-term misuse and/or overdoses.

HL associated with illicit drug use varied in severity and presentation, where HL associated with amphetamine and cocaine was typically sudden, bilateral, and reportedly temporary, whereas HL from the combination of a stimulant and an opioid – most commonly cocaine and heroin – often presented with a more severe HL in the mid-frequency range (cookie-bite HL). A closer look at the substance combinations in these studies suggests that there could be a higher risk for permanent HL when an illicit opioid (typically heroin) is used in conjunction with a stimulant (typically cocaine or amphetamine), although additional prospective studies are needed. Vestibular function associated with illicit drug use suggested intact function; however, more vertigo or imbalance symptoms were noted, particularly with more polysubstance illicit drug use. HL associated with opioids was typically sudden or rapidly progressive, bilateral, moderately severe to profound, and in almost all cases permanent. HL was profound and permanent in all reported cases stemming from misuse of prescription opioids combined with acetaminophen, with most patients in the case reports ultimately becoming cochlear-implant recipients. VL associated with opioids occasionally resulted in central and/or peripheral VL, particularly when opioid misuse was over a long period and when coupled with other substances. HL associated with chronic alcohol misuse often resulted in high-frequency sudden or progressive SNHL, or even retrocochlear dysfunction, and the severity may be associated with longer use patterns (Golabek & Niedzielska 1984; Niedziellska et al. 2001; Ribeiro et al. 2007; Kumar & Patrick 2011). VL associated with alcohol misuse most often resulted in central vestibular dysfunction and balance impairments, and the duration of alcohol use may positively correlate to greater deficits.

Limitations to the Evidence and Knowledge Gaps

Lack of objective measures

While the existing literature may point to certain trends in how different substance classes associate to different degrees and types of HL/VL, this systematic review revealed that there are significant limitations on this topic. A notable limitation is the lack of objective test measures used to describe hearing or vestibular effects from substance misuse, particularly in the case reports. Several case reports did not present audiometric data, but instead relied only on the patient’s subjective account to determine if HL was present or that their hearing had recovered (e.g., Iqbal, 2002a; Ciorba et al. 2009; Bayat et al. 2019). While these case reports provide valuable clinical perspective, the lack of objective hearing results in the case reports weakens our analysis of the true incidence of substance misuse on hearing. Tsimpida et al. 2020 recommended that self-report measures should not be considered reliable measures of hearing acuity based on misreporting. In that study, authors saw a discordance between subjective self-reporting and objective screening of HL and found that factors including lower socioeconomic factors and unhealthy lifestyle (e.g., alcohol misuse) were largely associated with inaccuracies and underestimation of self-identification of HL in people who did in fact show HL on objective screening. Similarly, Ardeshirrouhanifard et al. (2022) published a large-scaled cohort study involving cancer survivors with ototoxicity and showed that 65% (n = 902/1386) of their participants underestimated their hearing difficulty as compared to audiometric-defined HL, and factors including lower education and older age associated with more underreporting. This may be especially relevant for persons with a SUD who may or may not be under the influence at the time they are asked to subjectively assess their symptoms. It is also possible that people with SUDs may not functionally notice a change in hearing especially if the HL is in the high frequencies and progressively worsening versus sudden. Comparatively, sudden or rapidly progressive hearing losses are more likely to be self-reported as noted in several of the case reports which likely increases reporting bias. Overall, the evidence in this review is compromised given the high reliance on subjective or perceptual symptoms. Without sufficient results from objective hearing measures, there is still an unclear depiction of the true incidence of HL, temporary versus permanent effects, or perhaps HL in the extended high-frequency range (a hallmark of ototoxicity) in a SUD population.

Similarly, several of the case reports indicated no change in vestibular status based on the patienťs self-report, such as “no dizziness, problems with balance, or vertigo” (e.g., Ciorba et al. 2009; Schweitzer et al. 2011). While asking for a self-report of dizziness symptoms is feasible, it alone may not be informative to rule out vestibular dysfunction for this population. Recent literature in individuals with cisplatin-based vestibulotoxicity suggest that vestibular impairment is often missed by clinicians when only relying on symptom report because patients often underreport (Prayuenyong et al. 2018; Prayuenyong et al. 2020). Peripheral vestibular involvement could be underlying but go unnoticed functionally if the person was centrally compensating, especially in the case of progressive bilateral vestibular dysfunction (van de Berg et al., 2015) as compared to sudden onset, or if the patient or healthcare provider assumes that the dizziness symptoms are due to acute effects of the substance as opposed to a newly developed vestibular impairment (Prayuenyon et al. 2018). Additionally, specific types of VL may be undetected in a substance-misuse population because published studies did not test the peripheral vestibular system in its entirety. Animal data suggest that both otoliths and semicircular canals could be affected equally by ototoxicity (Burns & Stone 2017). Among 31 studies that reported vestibular findings in individuals with SUDs, only 17 incorporated vestibular tests including caloric test, balance test, headshaking nystagmus, and rotary chair test (e.g., Lupin et al. 1976; Oei et al. 2004). Although valuable to the vestibular test battery, these assessments solely measure horizontal semicircular canal function, are multi-sensory, and/or cannot isolate the integrity of the otolith organs and the inferior aspect of the vestibular nerve innervated by the saccule and posterior semicircular canal function. Therefore, using self-reporting tools or only relying on broad test measures to identify VL also likely underestimates the true amount of people who misuse substances and who also have underlying vestibular deficits.

In general, there was far less information on how substance misuse or SUDs affects the vestibular system, which limits our understanding of how substances similarly or differentially affect the cochlear and vestibular apparatus in humans. Comparatively, animal studies (feline, frog, and rat models) have been performed to determine the effects of opioids, amphetamine, and alcohol on the vestibular system, which may provide insight on potential mechanisms for future work. There appears to be inhibitory effects on the medial vestibular nucleus with D-amphetamine (Kirsten & Sharma 1976), opioids (Sulaiman & Dutia 1998), and ethanol (Ishihara et al. 1998), and on the acetylcholine receptors of vestibular hair cells (Lioudyno et al. 2000) with morphine.

Low study quality

A substantial limitation to the existing literature is the reliance on a significant number of case reports to systematically review the evidence and low sample sizes of the limited cohort studies available. Of the 67 studies reviewed, 42 were single-case reports or case series with no study design. Typically, because of the highly variable risk of bias from case reports and series, they are excluded from systematic reviews to avoid applying a common high risk-of-bias grading (Viswanathan et al. 2012); however, when limited systematic research exists on a topic, the inclusion of case reports and studies can provide an initial hypothesis, clinical perspective, and set the stage for future work (Nissen & Wynn, 2014). Since 60% of the studies presented here were case reports and series, this review did not include a risk-of-bias assessment because standardized risk-of-bias tools specific for case reports/series are not well established and do not directly assess risk of bias. The JBI checklist could be used for case reports/series, but it does not explicitly address bias in reporting of results (Glasgow et al. 2020), and there is limited scoring guidance as compared to the other risk-of-bias tools used for randomized control trials or cohort studies (i.e., there are no recommended thresholds for low, moderate, high risk of bias; Munn et al. 2020). Rather, it is recommended that discussions of study quality for case reports and series make an overall judgment about methodological quality based on the specific clinical scenario (Murad et al. 2018). consider the possible biases based on the topic and design and evaluate the potential importance for each study (Viswanathan et al. 2012), which the authors have attempted to extensively provide in this review. While the inclusion of the case reports and series in this review is an important initial step for our field, the interpretation of hearing and vestibular findings related to SUDs should be translated with caution and with an understanding that there is often high bias associated with using evidence from single-study case designs or small sampled studies.

Unaccounted contribution of health comorbidities

Most studies did not consider how concomitant health co-morbidities affected individual study findings especially for extraneous factors that could have contributed to pre-existing HL/VL outside of substance misuse itself. Of the 67 papers reviewed, only 12 of the studies (all cohort studies) excluded participants or accounted for confounding effects that could cause progressive HL/VL, specifically noise-exposure, head trauma, Wernicke encephalopathy, smoking, congenital HL, and/or previous exposure to ototoxic medications (e.g., Nordahl, 1964; Spitzer & Ventry 1980; Holm et al. 1983; Spitzer & Newman 1987). No study utilized genetic testing to rule out possible HL/VL etiologies. It is then possible that patients in the reports or participants in the remaining cohort studies could have had underlying HL/VL that was not accounted for in the results or should not be attributed causal to substance misuse. Patients with SUDs have a significantly higher prevalence of type 2 diabetes, obesity, cancer, and chronic kidney, liver, lung, and cardiovascular diseases, many of which are unmanaged (Wang et al. 2021). It is possible that pre-existing health complications already predispose a person to early-onset HL/VL or increase the risk of someone with a SUD developing HL/VL. This may especially be true for the patients described to have rhabdomyolysis and subsequent renal dysfunction following overdose from an illicit drug or misuse of prescription opioids. None of the papers that we reviewed prospectively controlled for renal dysfunction, but eight case reports did discuss the concomitant factor of renal dysfunction in their patient (e.g., Sharma 2001; Aulet et al. 2014; Patell et al. 2021), and later discussed in this review.

Inability to assess sex and gender factors

Importantly, the existing literature did not discuss the implications of sex and/or gender on test results, which limits our ability to assess and identity the biological sex and social gender constructs on hearing or vestibular outcomes in a SUD population. Many of the cohort studies only included males or men (e.g., Wheeler et al. 1980; Jozefowicz-Korczynska et al. 1994; Iqbal, 2002a, b; Rawool & Dluhy, 2011; Moreira et al. 2012; Bayat et al. 2019), with only one cohort study controlling for sex as a biological variable in their analysis (Mokhtarinejad et al. 2021). It is possible that there is a preponderance of males or men because authors of those studies recruited from inpatient SUD programs specific for men, which suggests potential selection bias in the methodology. The exclusion of women or females is relevant because women with SUDs are significantly less likely than men to seek treatment and tend to underutilize health-related services for fear of stigma (Pinedo et al. 2020), which could exacerbate SUD health complications like HL/VL. While it is still controversial in humans, some animal studies also report that females are at a significantly higher risk for neurotoxicity of the spiral ganglion cells and brainstem due to estrogen, higher risk of oxidative stress, and have overall differences in metabolism (Kirkim et al. 2015; Corazzi et al. 2020). Others report that females have reduced risk of ototoxicity since estrogen provides protective effects on the hearing system (Nakamagoe et al. 2010; Hu et al. 2017). Overall, there appears to be mixed evidence on the implications of sex or gender on ototoxicity risks that may play a role in a SUD population and that needs to be further explored.

Substance use variability

A fourth barrier to the literature was variability in substance use patterns, especially the route of ingestion (i.e., oral pills, intranasal, intravenous), potency or dosage of the substance ingested, phase of use (e.g., chronic versus relapsed), and poly-substance misuse involvement, all of which likely led to differences in how hearing or vestibular function was affected. For many of the case reports, cocaine and heroin were delivered intravenously or intranasally; however, the exact potency and amount were relatively unknown. For opioids, many of the cases reported ingestion through oral pills, with varying dosages; however, some were noted to have been crushed and ingested intranasally. Intravenous and intranasal ingestion likely increases the risks for toxicity as these routes bypass the standard process of drug absorption (Campbell, 2007, p. 22), gives an immediate effect, and allows for rapid titration of a drug with 100% bioavailability (Brenner & Stevens 2018, p.7).

Substance misuse patterns also varied across studies, from an acute overdose, chronic misuse, chronic past misuse and then overdose, or chronic past misuse and then relapse. It is plausible that an abrupt stop or start of a substance, particularly after a withdrawal period can negatively trigger opioid receptors within the cochlea (Ishiyama et al. 2001). Some of the studies reported here showed HL/VL in patients who were on methadone treatment and then overdosed on other drugs, or patients who misused prescription opioids and acetaminophen (e.g., Nicoucar et al. 2005). Human studies have shown that there is a higher risk of HL with the combined use of other analgesics and acetaminophen (Curhan et al., 2010; Curhan et al., 2012; Lin et al., 2017), which may be linked to an oxidative stress mechanism (Yorgason et al., 2010; Kalinec et al., 2014; McGill et al., 2016). Given these concomitant drug uses, it is difficult to extrapolate whether the HL/VL was related to one specific substance versus the other or polysubstance use, confounding the results. Overall exposure levels and substance type may contribute to differential inner ear effects. Some studies discussed here showed positive correlations between years of illicit drug and alcohol misuse (Spitzer & Ventry 1980; Sasa et al. 1981; Moreria et al. 2012) and severity of HL or VL, where longer exposures led to greater severities of HL or VL. Chronic low-dose exposure of opioids in animal models do indicate more complex patterns of hair cells and afferent neuron damage (Sedo-Cabezon et al. 2014); however future human studies are needed to systematically study if more complex and longer durations of alcohol or other substances increase the odds of someone developing HL and/or VL.

Another shared finding in the existing literature was the high occurrence of poly-substance misuse, which is common in people with SUDs (Martin 2008). Recent 2019 data show that over 400,000 people who misuse prescription opioids also misuse heroin (Substance Abuse and Mental Health Services Administration 2019). While a reality, many of the papers discussed in this review did not consider poly-substance use, making it difficult to ascertain the systemic effects of each substance on the ear. Given some of the results in the reports involving poly-substances (e.g., Nicoucar et al. 2005; Moreria et al. 2012), one can only hypothesize that poly-substance misuse likely increases the risk of HL and/or VL and the severity of the damage, but the evidence does not fully exist. Related, we presented the results of the systematic review using three groupings/substance classes (i.e., illicit, prescription opioids, and alcohol), to provide some organization to what has been published in the literature and similar to many of the cohort and case series papers (e.g., Iqbal et al. papers) that organized the substances together in a similar manner. However, it is important to recognize that within these grouping/classes there is likely high heterogeneity regarding how each specific drug may affect portions of the hearing and vestibular systems.

Review Approach

While an in-depth systematic review (using our criteria) was carried out for the present report, it is possible that other nonspecific articles on the topic were missed due to the broad nature of substance misuse and array of journals in which these articles have been published. As an example, we found the article by Sangani et al. (2021) describing a case report of rhabdomyolysis, HL, and heart failure with kratom overdose as we were researching links between rhabdomyolysis and HL. Kratom was not a substance included in our original search because it is neither a prescribed opioid nor currently classified as an illicit drug in the United States but is used for pain relief, mood-altering effects, and opioid withdrawal. However, emerging evidence shows it is addictive and has been associated with significant toxic effects (Eggleston et al. 2019; Veltri & Grundmann 2019), including death (Corkery et al. 2019). Although marijuana recently has been legalized in some states within the U.S., we have classified it with the illicit drugs in the present study due to its legal classification at the time of the published studies reporting its effects. While the association between tobacco use and increased risk of HL is well documented (Cruickshanks et al. 1998; Lin et al. 2020), this review intentionally did not include tobacco because we wanted to focus on substances that can result in an overdose or misuse that could require in-patient treatment, and tobacco has not been associated with overdose. Lastly, our review incorporated a large publication window (1964–2021), which encompasses significant changes in scientific understanding and investigational methodology. As a result, the methods used to quantity vestibular and auditory function were variable based on the time of publication. While we did not exclude studies on this factor, the methodological inconsistencies could have affected the reliability and validity of the findings.

Potential HL/VL mechanisms per substance class

The limitations to the current work on substance misuse and ototoxicity suggest that much more prospective and systematic work is needed to truly elucidate the mechanisms on why substances could cause ototoxic effects. In some of the studies reported in this review, authors alluded to the potential mechanisms that might contribute to negative auditory and/or vestibular effects associated with substance misuse, as described below per substance class.

Illicit Drug Misuse

Although still uncertain, some of the studies reviewed above discussed a few hypothesized mechanisms for HL following illicit drug use. First, drugs like cocaine, heroin, and amphetamine may cause vasospasms and decreased blood flow, resulting in cochlear (Schrock et al. 2008; Ciorba et al. 2009) and/or temporal lobe ischemia that would coincide with the bilateral SNHL noted on clinical testing (Iqbal, 2002a). Heroin is known to exert potent effects on the cardiovascular system and is suspected to reduce blood flow to the cochlear-vestibular system, potentially leading to temporal lobe ischemia and hearing or vestibular deficits (Schrock et al. 2008). Cocaine is a fast K+ channel blocker known to increase cardiac arrhythmias; thus, it is probable that cocaine damages cochlear hair cell metabolism or blocks K+ channel functions that are necessary for cochlear homeostasis (Ciorba et al. 2009).

Second, animal studies have suggested that opioid receptors (mu, kappa, and delta) exist within the cochlea, and the activation of the kappa receptor on cochlear hair cells decreases afferent activity. Drug overdose may then cause overstimulation of kappa receptors and subsequent decreased afferent activity in the cochlea (Soto & Vega 2010), potentially explaining HL and poor speech understanding seen in these patients. For the cases in which patients who used illicit drugs chronically and then had a period of recovery (i.e., 3 weeks to 2 years), the sudden onset of the HL may be related to the cochlea’s opioid receptors becoming re-sensitized and/or hypersensitized following a particular withdrawal period (Ishiyama et al. 2001), e.g., when a person goes into withdrawal management for a SUD.

Third, several cases involving overdose of illicit drugs reported rhabdomyolysis upon admission to the emergency department (Sharma 2001; Aulet et al. 2014; Patell et al. 2021; Reich et al. 2021). Rhabdomyolysis is caused by muscle tissue breakdown, which releases myoglobulin into the blood, causing kidney damage. Given the structural similarities between kidney tubules and cochlear stria vascularis, it is possible that the mechanisms underlying rhabdomyolysis could also be a contributor to HL, as there have been reports in the literature of cases of concomitant rhabdomyolysis and HL secondary to other sources besides illicit drugs (e.g., bacterial infection in Tambyah et al. 1997 and Mikaberidz et al. 2013; opioids in Shaw et al. 2010 and Ghasemi et al. 2019; untreated hypothyroidism in Seo et al. 2019; and kratom in Sangani et al. 2021). Therefore, it is possible that HL in these cases was secondary to rhabdomyolysis (which was secondary to the drug overdose), rather than the HL directly resulting from the drug itself.

Lastly, illicit drugs, like heroin, are typically never 100% pure in nature and could be mixed with other substances such as heavy metals or quinine (Shrock et al. 2008; Antonopoulous et al. 2012), which are known to negatively affect outer hair cell motility and the mechanical response of the basilar membrane as shown in animal models (Zheng et al. 2001). Defined mechanisms for illicit drugs and VL are very much unknown. While future work is needed to elucidate the vestibular mechanisms and SUDs, SUD-related VL may follow similar patterns as described above given the shared vascular supply and similar sensory hair cells between the cochlea and vestibular-end organs. It is also possible that, like cisplatin-based vestibulotoxicity (Prayuenyong et al. 2018), the vestibular end organs may be more vulnerable than the cochlea to damage from substance misuse. Megalin is heavily present in the dark cells of the crista ampullaris and utricle but not in sensory cells of the organ of Corti or the spiral ganglion and is involved in the transport of cisplatin and susceptibility to cisplatin-induced vestibulotoxicity (Mukherjea & Rybak, 2011).

In our examination of the literature, a unique finding was that the HL reported from cocaine and/or heroin misuse often resulted in a mid-frequency or cookie-bite configuration, with the maximum loss occurring between 1 and 4 kHz, then rising to a lesser degree of loss in the higher frequencies (Hughes et al. 2022; see Figure 2). Although this audiogram configuration has classically been associated with hereditary hearing loss, such as Turner’s syndrome, it has been sporadically seen in other non-genetic etiologies, including early developing vestibular schwannomas (Shah et al. 2005; Birkenbeuel et al. 2019). A few case reports have reported a cookie-bite SNHL secondary to chronic carbon monoxide intoxication, which is thought to be caused by cochlear hypoxia and/or cranial nerve VIII damage (Baker & Lilly 1977; Mehrparvar et al. 2013; Li et al. 2020); however, an explanation as to why the mid-frequencies are most affected was not provided in these reports. The trend in this HL configuration suggests that there may be unique differences in how illicit substances affect the cochlea as compared to known ototoxic medications, which suggests that typical ototoxicity monitoring protocols (that focus on the extended high-frequency range) may not be appropriate in these cases.

Figure 2.

Individual pure-tone thresholds from seven case reports (13 ears total) following misuse of cocaine and/or heroin. Results show a characteristic mid-frequency or cookie-bite configuration, with the maximum loss occurring between 1 and 4 kHz, then rising to a lesser loss in the higher frequencies (adapted from Hughes et al. 2022).

Prescription Opioid Misuse

Unlike illicit drugs, prescription drugs like opioids and methadone are less likely to contain contamination from other unknown substances that could affect hearing or vestibular function. Rather, the mechanisms for opioid-related HL are likely direct toxicity to the cochlear opioid receptors, ischemia that then leads to cochlear hypoxia, and/or hypersensitization of the cochlear opioid receptors upon re-exposure after a period of opioid withdrawal (Ishiyama et al. 2001; Vorasubin et al. 2013). Some other possibilities include genetic predisposition and other health comorbidities. Familial and sporadic cases of aminoglycoside associated SNHL have been attributed to mitochondrial mutations, specifically the 12S ribosomal RNA gene often seen with damage to the inner ear tissue and HL (Prezant et al. 1993). Genetic predisposition may also explain patient variability. Specifically, genetic differences may explain why some people who misuse opioids develop ototoxic effects whereas others do not, or why some patients who used opioids chronically experience hearing or vestibular symptoms after their usual doses, while others develop HL/VL only after taking higher doses (Vorasubin et al. 2013). Lastly, there may be a relationship between the health complications that patients who misuse opioids experience and the onset of HL. As noted above for illicit drugs, there were several reports of opioid overdoses in which patients were reported to have developed concomitant transient kidney failure or dysfunction (Shaw et al. 2010; Leache et al. 2016; Ghasemi et al. 2019; Repple et al. 2021). The patients in Shaw et al. (2010) and Ghasemi et al. (2019) presented with rhabdomyolysis, which may have potentially caused both the HL and kidney failure. Although kidney failure was not explicitly stated for the patient in Repple et al. (2021), he did have extremely elevated creatine kinase levels, which are indicative of rhabdomyolysis. Likewise, the patient in Leache et al. (2016) had elevated creatinine and urea levels, which also indicate kidney dysfunction. It is speculated that the similarity between the channels and junctions between the stria vascularis and kidney tubules that filter fluid is a possible explanation for the concomitant dysfunction in both organ systems (Ghasemi et al. 2019). Like illicit drugs, distinct mechanisms for opioid use and VL are unspecified but are potentially comparable to proposed mechanisms for HL.

Alcohol Misuse

The mechanisms for alcohol-associated HL/VL vary, but it is most consistently accepted that there can be temporary or permanent demyelination changes to all levels of the hearing pathway, including the central auditory and central cerebellar vestibular pathways (Niedziellska et al. 2001; Verma et al. 2006). Some authors specify that alcohol, a central nervous suppressant slows down sensory processing or damages auditory connections over time, adversely altering the auditory central processing (Fitzpatrick & Eviatar 1980; Verma et al. 2006). For the vestibular system, conditions including Positional Alcohol Nystagmus and Wernicke-Koraskoff Syndrome are common in individuals who consume alcohol and result in positional nystagmus and ataxia (Bergstedt & Kus, 1968). Alcohol misuse can slow ocular motility, motor, proprioceptive, and visual processing, which then causes poor balance control (Schmidt et al. 2010). However, more permanent misuse leads to more damage along the brainstem and likely persistent HL or vestibular dysfunction.

Wolff and Gross (1968) performed a temporal bone histological analysis on people who chronically used alcohol and discussed that unilateral or bilateral cochlear and vestibular-end organ damage is also likely. The authors explored 16 temporal bones of eight individuals with a history of chronic alcohol misuse and found vascular disruptions to the stria vascularis and spiral ligament, intralabyrinthine hemorrhages, excess endolymphatic pressure, pathological damage to both the cochlear and vestibular peripheral ganglion cells, and atrophy of the crista and spiral ganglion cells in the basal turn of the cochlea, which may explain the marker of high-frequency SNHL and peripheral vestibular damage seen in alcohol misuse. It should be noted, however, that some of the temporal bones showed indications of temporal bone fracture and changes related to falls from intoxication, complicating some of the histological findings.

While less researched, it appears that prolonged use and/or withdrawal from alcohol use may also lead to otologic symptoms, specifically “auditory hallucinations” (i.e., fluttering, clicking) as described in Saravay and Pardes (1967). From the studies examined in this review, 2/7 patients in Iqbal (2002b) and 14 participants in the Spitzer and Newman (1987) cohort study reported auditory hallucinations as a complaint. In the same eight temporal bones of people who chronically used alcohol, Wolff and Gross (1968) also described atypical changes to the middle-ear cavity, particularly of fragmentation and fatty replacements to the tensor tympani and stapedial muscles. This finding aligns with the reports of abnormal acoustic reflexes by Niedziellska et al. (2001). Wolff and Gross (1968) concluded that these changes could represent muscle malnutrition that is often seen in alcoholism. Thus, the “auditory hallucinations” reported in people who misuse alcohol may be audible sounds pathologically produced by the stapedius and tensor tympani muscles contracting (Saravay & Pardes 1967).

Clinical implications

Since COVID-19, there are expected increases in SUDs across all age groups and a major risk for relapses for those in recovery due to psychosocial COVID-19 factors (e.g., isolation, anxiety, and depression; Yazdi et al. 2020). While it is clear from the results of this review that stronger evidence is needed to fully understand the role of substance misuse and ototoxicity, clinicians should become aware of the associations between substance misuse and potential impacts on the auditory and vestibular systems. This knowledge may help audiologists and otolaryngologists better manage patients at risk or with past substance misuse histories and signs of HL or VL. Clinicians could consider asking patients about past or current substance misuse in their case intake, particularly for people who present with sudden HL or dizziness, with no other apparent cause, and to rule out substance misuse as a possible contributor. This may be relevant given the rise in opioid misuse, association with a greater likelihood of prescription opioid and substance misuse with HL (McKee et al. 2019), and the more permanent effects of opioids on hearing as noted in the literature. Many more individuals who misuse substances may experience noticeable hearing or dizziness symptoms but are reluctant to seek medical care due to not having healthcare access, or they might not divulge their SUD due to fear of stigma or legality for using substances.

Audiologists and otolaryngologists may also recognize vestibular symptoms associated with inner-ear damage that otherwise would be overlooked in general healthcare visits. General healthcare providers interacting with patients with SUD may assume that common vestibular symptoms (e.g., nausea, vertigo) are related to acute side effects from the substance versus a developing vestibular impairment may not think to consult audiology or otolaryngology. Upon presentation of overdose, nystagmus is a common non-cardiac manifestation of alcohol, amphetamine, barbiturates, and hallucinogens that could be ignored (Verma et al. 2006), leading to modifiable risks like falls and subsequent head injury. Audiologists and otolaryngologists could play a vital role in recommending objective vestibular testing and vestibular rehabilitation. Lastly, audiologists and otolaryngologists can serve as a resource in managing the hearing or vestibular symptoms of patients who misuse substances and in referring to addiction specialists if there were concerns for a SUD. Of the 67 studies reviewed here, only 24 were published in international otolaryngology/audiology-specific journals, whereas the remaining papers were published in journals of addiction medicine, emergency medicine, psychiatry, pharmacology, toxicology, other journals that were specific to certain countries, or were peripheral to audiology or otolaryngology. This suggests that patients with SUDs and hearing or vestibular complaints are likely to enter the medical system from various entry points. Thus, multidisciplinary team management and consultation from otologic specialists are key in managing these types of patients. The variability in the journals’ disciplines also shows interest of non-otolaryngology and audiology specialties in ototoxicity, but perhaps points to gaps in knowledge regarding study design and suggests opportunities for multidisciplinary collaboration.

Opportunities for future work

HL and VL are prevalent and disabling chronic conditions that can impair communication, quality of life, and physical and mental health. However, as this review has highlighted, there is an association between chronic misuse of illicit drugs, prescription opioids, and alcohol and negative impacts to one’s hearing and/or vestibular system. Furthermore, there are likely patient and substance-use factors that contribute to who is most at risk. Thus, an in-depth understanding of the relation between substance misuse and otologic effects would benefit clinical practice. Future large-scaled systematic studies are warranted, which should encompass comprehensive behavioral and electrophysiological testing that evaluates both the peripheral and central components of the auditory and vestibular systems. A better understanding of the impacts of specific substances on hearing and vestibular function, along with possible associated health risks, will facilitate the development of clinical monitoring guidelines for hearing and vestibular function in people who misuse substances.

CONCLUSIONS

Findings from this systematic review suggest that substance misuse can associate with negative effects to the auditory and vestibular systems, and certain classes of drugs may have differential effects. Despite these trends, there are many notable gaps in the quality and validity of the existing studies’ design, methodology, and interpretation of results that need to be improved to enhance the evidence. Specifically, the overwhelming reliance on case studies and non-hypothesis-driven reports likely accounts for the significant variability in the existing literature. Additionally, there appears to be several patient-dependent factors that could contribute to the onset, type, and severity of HL/VL that complicate our ability to extrapolate consistent clinical findings. Nonetheless, given the consistent rise in SUD diagnoses since 2020 that affects people from diverse backgrounds, this is an important topic to understand for clinicians and researchers who may encounter patients with substance misuse histories.