Association between postzoster neuralgia and tinnitus: A retrospective population-based cohort study

Abstract

Tinnitus, characterized by the perception of sound without external stimuli, has not been extensively studied in relation to postzoster neuralgia (PZN) using large-scale, real-world data. This study aimed to explore the potential correlation between tinnitus and PZN. This study utilized data from the National Health Insurance Service – National Sample Cohort, a nationwide population-based database. The PZN group was selected from a cohort of 1 million individuals randomly extracted from the National Health Insurance Service – National Sample Cohort database. A non-PZN group was obtained through propensity score matching, taking several variables into consideration. The primary endpoint was the diagnosis of tinnitus. The PZN group comprised 3417 individuals, with an equal number of individuals in the non-PZN (control) group. The overall hazard ratio (HR) for tinnitus in the PZN group was 1.35 (95% confidence interval [CI]: 1.18–1.55). Subgroup analysis showed an adjusted HR of 0.77 (95% CI: 0.67–0.9) for tinnitus in males, 1.99 (95% CI: 1.53–2.59) in the middle-aged group (40–59 years), and 2.37 (95% CI: 1.83–3.08) in the older age group (≥60 years). Additionally, the adjusted HRs for developing tinnitus were higher in patients with comorbidities, including anxiety (1.46 [95% CI, 1.18–1.82]), hearing loss (3.34 [95% CI, 2.56–4.36]), and sleep disorders (1.48 [95% CI, 1.14–1.949]). Long-term follow-up revealed that the incidence of tinnitus was 1.35 times higher in the PZN group compared to the control group. Moreover, older age, female sex, anxiety, hearing loss, and sleep disorders were identified as factors that increase the risk of developing tinnitus.

1. Introduction

Tinnitus, defined as the perception of sound in the absence of any external auditory stimuli, is a prevalent and often debilitating condition affecting a significant portion of the global population. The etiology of tinnitus is multifactorial, involving complex interactions between auditory and non-auditory pathways.^[1,2] Recent research has increasingly focused on the association between tinnitus and various neuropathic pain conditions, which share common pathophysiological mechanisms such as central sensitization and neural plasticity.^[3,4]

One such condition is postzoster neuralgia (PZN), a chronic pain syndrome that arises as a complication of herpes zoster. PZN is typically characterized by persistent, often severe pain following the resolution of the shingles rash, significantly impairing the quality of life.^[1,3] Despite the well-documented impact of PZN on patients, the potential relationship between PZN and tinnitus has not been extensively studied, particularly using large-scale, real-world data.^[4]

Herpes zoster involving the cranial nerves, including herpes zoster oticus and Ramsay Hunt syndrome, has been associated with various audiovestibular sequelae such as sudden sensorineural hearing loss (HL), vertigo, and facial palsy. Several clinical and epidemiologic studies have reported an increased risk of HL after herpes zoster infection.^[5] In these reports, tinnitus has usually been mentioned only as an accompanying symptom of cochlear damage rather than as a primary, long-term outcome. Moreover, to the best of our knowledge, no large-scale population-based cohort study has specifically evaluated the long-term risk of incident tinnitus among patients with PZN. By focusing on tinnitus as an independent outcome beyond overt HL, our study is designed to address this gap in the literature.

Therefore, we investigated the correlation between PZN and tinnitus. Utilizing data from the National Health Insurance Service – National Sample Cohort (NHIS-NSC), a comprehensive nationwide database, this study aimed to evaluate the incidence of tinnitus in individuals diagnosed with PZN compared to a matched control group. By exploring this association, we seek to provide new insights into the risk factors for tinnitus development in PZN patients, thereby contributing to a broader understanding of both conditions and informing future therapeutic strategies.

2. Methods

2.1. Database and type of study

This study used the NHIS-NSC database. This is a database of 1 million individuals constructed by random sampling 2% of a total of 50 million people in the Republic of Korea, and is a representative sample cohort with evenly distributed sex, age, economic status, and residential areas. This database includes demographic data with diagnostic code based on the International Classification of Diseases, 10th revision (ICD-10), treatment history, patients’ visit date, and medications. However, as this database is based on administrative claims, diagnoses were not validated by direct clinical assessment, and information regarding disease severity, duration, or symptomatology was unavailable.

2.2. Study population with PZN group

The definition of the patient cohort for PZN was based on the ICD-10 diagnostic code G530 diagnosed between 2002 and 2004. The definition of target disease for tinnitus is ICD-10 code H931. There were 3 exclusion criteria: patients with records for both tinnitus and PZN in whom tinnitus was diagnosed prior to or simultaneously with the PZN diagnosis; patients under 20 years of age; patients diagnosed with PZN during the period 2005 to 2013.

The starting point for the PZN group was the date of PZN diagnosis, and the end point was set as the date of first diagnosis of tinnitus if a record of tinnitus diagnosis existed or December 31, 2013 if a record for tinnitus diagnosis did not exist. Although these criteria aimed to reduce the risk of reverse causation, the possibility of shared underlying neuropathic or psychiatric profiles remains.

2.3. Propensity score (PS) matching and selection of the control (non-PZN) group

The control group was assembled by 1:1 PS matching considering eleven independent variables (age, sex, residential area, economic status, history of hypertension (HTN), history of diabetes mellitus (DM), history of chronic kidney disease (CKD), history of HL, history of depression, history of sleep disorder, and history of anxiety. PS matching was performed using a ‘greedy nearest neighbor’ algorithm with a 1:1 ratio. After 1:1 PS matching, baseline characteristics were summarized as frequencies and percentages for categorical variables. Covariate balance between the PZN and non-PZN groups was primarily assessed using standardized mean differences (SMDs), with an absolute SMD < 0.1 considered indicative of adequate balance. Because SMDs are not affected by sample size, they are recommended over hypothesis testing for evaluating covariate balance after PS matching. For transparency, we additionally calculated chi-square tests comparing the distribution of each categorical variable between the PZN and non-PZN. Although most variables met this criterion, slight imbalances were noted in some covariates such as DM and CKD. The study population was divided into 3 age groups (young age, <40; middle age, 40–59; old age, ≥60 years). The residential area was also divided into 3 groups based on home residence population density (Seoul, the largest metropolitan region in South Korea; other metropolitan cities in South Korea; and small cities and rural areas). Other variables were divided into 2 categories, and were as follows: male or female; based on the 10th quintile for economic status: the lower 70% is low economic status and the upper 30% is high economic status; history/no history of HTN; history/no history of DM; history/no history of CKD; history/no history of HL; history/no history of depression; history/no history of sleep disorder; history/no history of anxiety; history/no history of anxiety.

The starting point for individuals in the control group was the date of their 1st visit to any hospital between 2002 and 2004 and the end point was decided as the date of 1st diagnosis of tinnitus if there was a record of tinnitus diagnosis or December 31, 2013 if there was no record of tinnitus diagnosis.

2.4. Outcome variables and statistical analysis

The unadjusted hazard ratio (HR) is a value considering only 2 variables, 1 independent, and 1 dependent, without considering other variables. The HR in the Cox proportional-hazards model was obtained by taking the difference between the start point and end point. When considering the relationship between 1 independent variable and the dependent variable, the adjusted HR was obtained by considering all other variables. The risk ratio or relative risk was obtained as the ratio of the probability of an outcome in the PZN group to the probability of an outcome in the non-PZN group. The cumulative HR was obtained through Kaplan–Meier survival analysis, and the R 3.5.3 statistical program (R Foundation for Statistical Computing, Vienna, Austria) was used to analyze the results. The SAS program (SAS Institute Inc., Cary) was also used for analysis of the NHIS-NSC database.

2.5. Subgroup analysis

In subgroup analyses, we examined whether the association between PZN and tinnitus differed according to sex (male vs female), age (<40, 40–59, ≥60 years), residential area (Seoul, metropolitan, rural), economic status (lower 70% vs upper 30%), and the presence or absence of comorbid HTN, DM, CKD, depression, anxiety, HL, and sleep disorder. For each subgroup, adjusted HRs and 95% confidence intervals (CIs) were estimated using Cox proportional-hazards models that included PZN status and the same set of covariates as in the main analysis, except for the stratifying variable.

2.6. Ethical considerations

All studies were conducted and designed in accordance with the Declaration of Helsinki using NHIS-NSC database. The research was also approved by the Institutional Review Board of Jeonbuk National University Hospital (IRB file number 2022-01-033). Informed consent was waived by the Institutional Review Board which approved the study.

3. Results

Of the 1 million cohort samples, a total of 6834 individuals (3417 in the PZN group and 3417 in the non-PZN group) were followed up for a total of 9 years from January 2005 to December 2013.

3.1. Validation of PS matching

Table 1 shows the results obtained for PS matching between the experimental group (PZN) and the control group (non-PZN) for independent variables. Most standardized mean differences (SMDs) were below the commonly accepted threshold of 0.1, indicating acceptable balance between the groups. Although DM remained slightly more prevalent in the PZN group than in the non-PZN group (9.3% vs 6.9%, P < .001; SMD = 0.087) and CKD showed a borderline imbalance (P = .081; SMD = 0.042), the absolute differences were small. For all other covariates, there were no statistically significant differences between the groups (all P ≥ .05). From Figure 1, the distributions of the PZN and non-PZN groups appear similar, supporting that PS matching was generally successful. Nevertheless, the possibility of residual confounding due to minor covariate imbalances cannot be completely ruled out.

Table 1.

Baseline characteristics of PZN and matched non-PZN groups after PS matching and covariate balance diagnostics.

Variable	Study (PZN) group (n = 3417)	Control (non-PZN) group (n = 3417)	SMD	P-value
Sex			0.004	.864
Male	1982 (58.0%)	1989 (58.2%)
Female	1435 (42.0%)	1428 (41.8%)
Age			0.003	1.000
Young < 40	627 (18.3%)	625 (18.3%)
Middle: 40–59	1250 (36.6%)	1255 (36.7%)
Old ≥ 60	1540 (45.1%)	1537 (45.0%)
Residential area			0.009	.997
Rural	1910 (55.9%)	1895 (55.5%)
Metropolitan	860 (25.2%)	865 (25.3%)
Seoul	647 (18.9%)	657 (19.2%)
Economic status			0.001	.981
Low < 70%	1506 (44.1%)	1505 (44.0%)
High ≥ 70%	1911 (55.9%)	1912 (56.0%)
HTN			0.034	.165
No	2915 (85.3%)	2955 (86.5%)
Yes	502 (14.7%)	462 (13.5%)
DM			0.087	<.001
No	3099 (90.7%)	3180 (93.1%)
Yes	318 (9.3%)	237 (6.9%)
CKD			0.042	.081
No	3354 (98.2%)	3372 (98.7%)
Yes	63 (1.8%)	45 (1.3%)
Depression			0.021	.378
No	3258 (95.3%)	3273 (95.8%)
Yes	159 (4.7%)	144 (4.2%)
Anxiety			0.001	.964
No	3157 (92.4%)	3158 (92.4%)
Yes	260 (7.6%)	259 (7.6%)
Hearing loss			0.009	.697
No	3330 (97.5%)	3335 (97.6%)
Yes	87 (2.5%)	82 (2.4%)
Sleep disorder			< 0.001	1.000
No	3259 (95.4%)	3259 (95.4%)
Yes	158 (4.6%)	158 (4.6%)

SMD values represent standardized mean differences between the PZN and non-PZN groups after PS matching (absolute SMD < 0.1 was considered indicative of acceptable balance).

P-values are derived from Pearson chi-square tests comparing the distribution of each covariate between the 2 groups.

CKD = chronic kidney disease, DM = diabetes mellitus, HTN = hypertension, PZN = postzoster neuralgia, SMD = standardized mean difference.

Figure 1.

Validation of propensity score matching. DM = diabetes mellitus; HTN = hypertension; PZN = postzoster neuralgia.

3.2. Incidence rate and HR for tinnitus

Table 2 shows the relationship between the 12 independent variables for tinnitus and 3 statistics: 10,000-person-years (incidence rate), unadjusted HR, and adjusted HR. The incidence rate (incidence per 10,000-person-years) is a measure of the frequency with which a disease occurs over a specified time period. Figure 2 and Table 2 show that the adjusted HR for tinnitus in the PZN group was 1.35 (95% CI: 1.18–1.55), that is, the incidence of tinnitus was 1.35 times higher in the PZN group compared with the control group.

Table 2.

Incidence rates and hazard ratios for tinnitus by group and clinical characteristics.

Variable	Study group total	Number of cases	Incidence per 10,000-person-years	Adjusted HR (95% CI)	Unadjusted HR (95% CI)
Total	6834	828
Group
Control (Non-PZN)	3417	382	102.71	1	1
Study (PZN)	3417	446	145.66	1.35 (1.18–1.55)	1.37 (1.19–1.57)
Sex
Male	2863	290	101.34	0.77 (0.67–0.9)	0.74 (0.64–0.85)
Female	3971	538	137.26	1	1
Age
Young < 40	1252	70	54.89	1	1
Middle 40–59	2505	295	118.58	1.99 (1.53–2.59)	2.16 (1.67–2.81)
Old ≥ 60	3077	463	153.40	2.37 (1.83–3.08)	2.81 (2.19–3.62)
Economic status
Low < 70%	3011	354	118.28	1	1
High ≥ 70%	3823	474	125.12	1.05 (0.92–1.21)	1.06 (0.92–1.22)
Residential area
Metropolitan	1725	208	121.06	1.00 (0.85–1.19)	0.97 (0.82–1.14)
Rural	3805	472	125.26	1	1
Seoul	1304	148	114.28	0.93 (0.77–1.12)	0.91 (0.76–1.1)
HTN
No	5870	671	114.92	1	1
Yes	964	157	166.63	1.17 (0.98–1.41)	1.46 (1.22–1.73)
DM
No	6279	751	120.45	1	1
Yes	555	77	141.00	0.95 (0.75–1.22)	1.17 (0.93–1.48)
CKD
No	6726	815	122.09	1	1
Yes	108	13	122.83	0.89 (0.52–1.56)	1.01 (0.58–1.74)
Depression
No	6531	780	120.15	1	1
Yes	303	48	165.98	0.94 (0.7–1.29)	1.38 (1.03–1.85)
Anxiety
No	6315	729	115.85	1	1
Yes	519	99	202.66	1.42 (1.15–1.78)	1.75 (1.42–2.16)
Hearing loss
No	6665	767	115.32	1	1
Yes	169	61	467.70	3.35 (2.57–4.37)	4.01 (3.09–5.2)
Sleep disorder
No	6518	765	117.98	1	1
Yes	316	63	212.24	1.48 (1.14–1.94)	1.8 (1.39–2.33)

Incidence per 10,000-person-years was calculated as the number of incident tinnitus cases divided by the total person-years of follow-up, multiplied by 10,000.

Adjusted HRs were estimated using Cox Proportional-Hazards models including PZN status and all covariates listed in the table.

CI = confidence interval, CKD = chronic kidney disease, DM = diabetes mellitus, HR = hazard ratio, HTN = hypertension, PZN = postzoster neuralgia.

Figure 2.

Overall cumulative hazard ratio for tinnitus in the postzoster neuralgia group.

3.3. Subgroup analysis

In the subgroup for demographic factors, the adjusted HR was 0.77 (95% CI: 0.67–0.90) in the subgroup of male patients compared with female patients. For age groups, middle-aged people (age 40–59 years) showed adjusted HR (1.99; 95% CI, 1.53–2.59), old aged people (age ≥ 60 years) showed adjusted HR (2.37; 95% CI, 1.83–3.08) when comparing with young aged people (<40 years) (Fig. 3).

Figure 3.

Cumulative hazard ratio plot for subgroups: sex, residential area, social economic status, and age.

Furthermore, patient comorbidities were also significantly associated with the prospective development of tinnitus (anxiety: HR, 1.42; 95% CI, 1.15–1.78; HL: HR, 3.35; 95% CI, 2.57–4.37; and sleep disorder: HR, 1.48; 95% CI, 1.14–1.94). However, the risk of tinnitus in patients with HTN, DM, CKD and depression were statistically meaningless (Fig. 4).

Figure 4.

Forest plot of cumulative hazard ratio (mean with 95% confidence interval) for each factor.

4. Discussion

The findings of this study provide strong evidence for a significant association between PZN and an increased risk of developing tinnitus. The primary observation that individuals with PZN have a 1.35 times higher risk of tinnitus compared to the control group supports the hypothesis that neuropathic pain conditions like PZN may contribute to tinnitus onset or exacerbation.^[1,2] This association is particularly pronounced in older adults, where the risk increases significantly with age, and in individuals with comorbidities such as anxiety, HL, and sleep disorders.^[3,6]

Previous studies on otologic complications of herpes zoster have mainly focused on HL, facial palsy, and vestibular dysfunction, particularly in the context of herpes zoster oticus and Ramsay Hunt syndrome.^[5] In contrast, tinnitus has seldom been evaluated as a distinct, long-term outcome, and available reports are limited to small case series or cross-sectional observations in patients with acute infection. Our findings extend the existing literature by demonstrating, in a nationwide cohort, that patients with PZN have a 35% higher risk of subsequently developing tinnitus compared to PS matched controls, even after adjusting for baseline HL and other comorbidities. These results suggest that neuropathic mechanisms associated with PZN may contribute to tinnitus independently of clinically overt HL.

The correlation between PZN and tinnitus is consistent with existing literature suggesting that chronic pain conditions can influence auditory processing and lead to tinnitus. The higher adjusted HR for tinnitus in older adults and middle-aged individuals reflects the known age-related susceptibility to both tinnitus and neuropathic pain, likely due to degenerative changes in the auditory and nervous systems.^[4,7]

This study also highlights the impact of comorbid conditions on the risk of tinnitus. Anxiety, HL, and sleep disorders significantly elevated the likelihood of tinnitus in PZN patients, potentially through mechanisms such as central sensitization and neural plasticity changes.^[8] Central sensitization, where the central nervous system becomes overly responsive to stimuli following nerve injury, may amplify both pain and auditory signals, leading to tinnitus.^[9] Additionally, damage to sensory neurons in PZN could cause maladaptive changes in neural connections, affecting auditory processing pathways and further increasing tinnitus risk.^[2,10] However, the associations with anxiety and sleep disorders should be interpreted cautiously, as these conditions may also develop as a consequence of chronic tinnitus symptoms, rather than serving as true predisposing risk factors. In this context, reverse associations are plausible and may partially account for the observed HRs. Interestingly, although the post-matching distribution of sex appeared well-balanced (SMD = 0.004), the sex-stratified analysis revealed a significantly lower HR in males (HR = 0.77), raising the possibility of effect modification. This finding suggests that sex may interact with the exposure–outcome relationship and warrants further investigation in future studies using interaction terms or stratified modeling. It should also be noted that multiple subgroup comparisons were performed without statistical correction for multiplicity, which increases the risk of type I error. Therefore, the subgroup findings should be interpreted with caution and considered hypothesis-generating rather than confirmatory.

Moreover, inflammatory responses associated with herpes zoster infection might also contribute to tinnitus development. The virus induces a strong inflammatory reaction in the affected nerves, which can lead to ongoing neural damage even after the acute infection has resolved, potentially disrupting normal auditory processing.^[11,12]

Lastly, the psychological stress associated with chronic pain conditions like PZN might exacerbate the perception of tinnitus. Chronic pain is often accompanied by heightened levels of anxiety and stress, which are known to intensify tinnitus symptoms.^[13,14] This psychological component may serve to both trigger and perpetuate tinnitus in individuals already vulnerable due to nerve damage from PZN.

Given the increased risk of tinnitus in this population, clinicians should be vigilant in monitoring for auditory symptoms in patients with PZN, especially those who are older or have associated comorbidities. Early identification and intervention could potentially mitigate the impact of tinnitus on quality of life.^[15]

While this study benefits from a large, population-based cohort and robust methodology, there are limitations that should be acknowledged. The diagnoses of PZN and tinnitus were based solely on ICD-10 codes from administrative claims data, without clinical validation. As such, the presence, duration, and severity of either condition could not be confirmed. The reliance on ICD-10 codes for identifying PZN and tinnitus may not fully capture the clinical nuances of these conditions, such as the severity of neuralgia or tinnitus, which limits the granularity of the analysis. Consequently, this study could not analyze the correlation between the severity of neuralgia and tinnitus. Additionally, the observational nature of the study limits the ability to establish causality. Although PS matching was used to minimize confounding, residual confounding from unmeasured factors (such as baseline tinnitus susceptibility, psychological distress severity, or medication use) may still influence the results. Moreover, despite excluding cases in which tinnitus preceded or coincided with PZN diagnosis, the possibility of reverse causation remains due to shared neuropathic and psychiatric vulnerabilities. It is plausible that early, subclinical tinnitus or psychological factors may have contributed to both the experience of pain and the eventual diagnosis of PZN. Thus, the associations observed in this study should be interpreted as correlational rather than causal. In addition, because the dataset did not include objective clinical parameters, clinician assessments, or audiometric results, the interpretation of clinical impact is limited to diagnostic coding alone. Further research is needed to explore the underlying pathophysiological mechanisms connecting PZN and tinnitus, as well as to identify potential biomarkers for early detection and targeted treatment.^[16,17]

5. Conclusion

This study provides valuable evidence of an increased risk of tinnitus in individuals with PZN, particularly among older adults and those with certain comorbidities. These findings highlight the importance of comprehensive management strategies that address both neuropathic pain and auditory symptoms in patients with PZN. As our understanding of the relationship between PZN and tinnitus continues to evolve, further research will be essential in developing targeted interventions to improve outcomes for these patients.

Author contributions

Conceptualization: Cha Dong Yeo, Jong Seung Kim, Eun Jung Lee.

Data curation: Cha Dong Yeo, Haeng-Jin Lee.

Formal analysis: Sein Lee.

Methodology: Haeng-Jin Lee, Jong Seung Kim.

Supervision: Eun Jung Lee.

Validation: Sein Lee, Jong Seung Kim.

Writing – original draft: Cha Dong Yeo, Haeng-Jin Lee, Sein Lee, Jong Seung Kim, Eun Jung Lee.

Writing – review & editing: Cha Dong Yeo, Haeng-Jin Lee, Sein Lee, Jong Seung Kim, Eun Jung Lee.