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Abstract

Background

Tension-type headache (TTH) is the most common type of primary headache. Its etiology has not been clearly elucidated, and conflicting results have been reported in studies on oxidative stress. Uric acid is a molecule with antioxidant properties and is the end product of purine catabolism. Total oxidant-antioxidant status may potentially play an important role in the pathophysiology of chronic TTH. In this study, we investigated whether there was a difference in uric acid levels, an oxidative stress marker, between patients with tension-type headache and healthy controls.

Methods

The study was designed retrospective observational case–control study. The diagnosis of chronic TTH was made according to the diagnostic criteria established by the International Classification of Headache Disorders. A total of 164 people, including 94 patients with chronic tension-type headache and 70 healthy controls were included in the study. Hemoglobin, blood urea nitrogen (BUN), creatinine, albumin, and serum uric acid levels were studied from the serum of the participants. The Kolmogorov Smirnov Normality test, Mann–Whitney U test, and binary logistic regression test were used for statistical analysis.

Results

There was no statistically significant difference between our control and patient groups in terms of age and BUN (p = 0.069 and p = 0.547). The serum albumin (p = 0.000), creatinine (p = 0.047), and hemoglobin levels (p = 0.000) in our patient group were found to be significantly low compared to the healthy control group. The serum uric acid levels in the TTH and control groups were 4.28 ± 1.16 and 5.32 ± 1.31 mg/dL, respectively (p = 0.000). Lower uric acid levels correlate with an increased likelihood of TTH presence in both males and females.

Conclusion

We demonstrated that serum uric acid levels in TTH patients were lower than in controls. Further studies with larger populations are needed to determine whether uric acid plays a protective role in the etiology of TTH by reducing oxidative stress.

Keywords

primary headache antioxidant mechanism nitric oxide oxidative stress pain

Introduction

Tension-type headache (TTH) is the most prevalent type of primary headache, with approximately 80% of the population experiencing TTH at least once in their lifetime.¹ The annual incidence of TTH is 4.1%, and the rate is three times higher in women than in men.² Based on the frequency of pain, the International Classification of Headache Disorders, Third Edition (ICHD-3) divided TTH into three categories: frequent episodic TTH (≥ 12 and < 180 days/year), infrequent episodic TTH (pain frequency < 1/month or mean < 12 days/year), and chronic TTH (≥ 15 days per month on average for more than 3 months (≥ 180 days per year).³

The mechanisms involved in the occurrence of TTH are still not clearly understood. Its pathogenesis is known to involve both peripheral (pericranial myofascial tissue sensitivity) and central nervous system mechanisms (central nervous system sensitivity development).⁴ The episodic form is generally thought to be associated with peripheral mechanisms, while the chronic form is associated with central mechanisms.⁵

Nitric oxide (NO) is an important neuromodulator in the pain mechanism of chronic TTH.⁶ It plays a role in central sensitization at the spinal level and in hemodynamic changes contributing to pain and is classified as a reactive oxygen species (ROS).⁷ Serum uric acid is a natural antioxidant in the human body. As the end product of endogenous and exogenous purine catabolism, it protects erythrocytes from lipid peroxidation and hemoglobin from peroxide oxidation. At normal levels, it scavenges toxic reactants, exhibits endogenous antioxidant activity,^8,9 prevents the reaction of superoxide with nitric oxide, and inhibits peroxynitrite formation.¹⁰ Disruption of the balance between ROS and the antioxidant defense system has been suggested to play a role in the development of chronic pain syndromes.¹¹ The relation between uric acid and migraine,¹² which is a type of primary headache and shares similar pathophysiological mechanisms with chronic TTH, has been investigated, and uric acid levels were shown to be decreased in patients with migraine.

The present study was performed to investigate serum uric acid levels in patients with TTH in comparison with healthy controls.

Materials and methods

Study design

A total of 164 individuals were included in this retrospective observational case–control study, consisting of 94 patients diagnosed with chronic TTH and 70 healthy controls. The participants were selected from among those presenting to the Neurology Clinic of Inonu University between January 2020 and December 2022. Demographic features, chronic diseases, and blood parameters of both TTH and control groups were obtained retrospectively from medical records.

Participants and eligibility criteria

The study included patients diagnosed with chronic TTH by a neurologist in accordance with the ICHD-3 diagnostic criteria.³ The control group consisted of subjects who had never had recurrent primary headaches and with a negative family history of primary headaches. The controls were frequency-matched to patients with TTH according to age and comorbidities.

The exclusion criteria for both groups were as follows: history of autoimmune disease, chronic infection, severe heart failure, metabolic disorder, obesity or severe liver or renal failure, inflammatory diseases, malignancy, smoking/alcohol use, polycythemia, and use of medications that affect uric acid levels (such as allopurinol, losartan, various diuretics, including hydrochlorothiazide, furosemide, and ethacrynic acid) within 2–4 weeks prior to the assessment.

The required sample size was calculated as 94 cases and 70 controls using the G*Power program based on the 95% confidence interval (CI), 80% power, 0.5 control case rate, and mean and standard deviation of previous studies.

Biochemical and hematological blood sample analysis

Samples of 2 mL of venous blood were collected from participants in both the patient and control groups using potassium-EDTA tubes. Separator gel tubes were left for 20 min and then centrifuged for 10 min at 5000 rpm to separate serum. Hemoglobin level was measured using an automated hematology analyzer system (Sysmex Corporation, Kobe, Japan) utilizing a fully automated nephelometric method. Biochemical tests—blood urea nitrogen (BUN), creatinine, albumin, and uric acid—were performed with a spectrophotometric measurement closed system using a Cobas 8000 series c702 modular analyzer (Roche, Basel, Switzerland) in our laboratories.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics 26.0 (IBM, Armonk, NY, USA). In all analyses, a two-tailed P-value <0.05 was taken to indicate statistical significance. The normality of continuous variables was assessed using the Kolmogorov–Smirnov test for sample sizes ≥50. Differences between patients with TTH and healthy controls were evaluated using the independent samples t test for parametric variables and the Mann–Whitney U test for nonparametric variables.

Binary logistic regression analyses were conducted to assess associations between biochemical variables (BUN, creatinine, hemoglobin, uric acid) and the likelihood of TTH, adjusting for age, sex, and clinical parameters. The results are reported as the unstandardized coefficient (B), standard error, odds ratio (Exp(B)), and P-value. In addition, the association between uric acid level and TTH by sex was evaluated using the same binary logistic regression analysis, with results presented in terms of unstandardized coefficient (B), standard error, odds ratio (Exp(B)), and P-value.

The predictive ability of serum uric acid level was assessed by receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC) was calculated to evaluate the predictive performance.

Results

The TTH and control groups consisted of 94 (57.3%) and 70 (42.7%) participants, respectively. The TTH group consisted of 70 women (74.5%) and 24 men (25.5%) with a mean age of 52.88 ± 12.06 (35–84) years, while the control group included 35 women (50%) and 35 men (50%) with a mean age of 49.07 ± 9.15 (36–76) years.

Albumin, BUN, creatinine, uric acid, and hemoglobin levels in the TTH and control groups are shown in Table 1 and Figure 1. The mean albumin, hemoglobin, and creatinine levels were significantly lower in the TTH group compared to the control group (P = 0.000, P = 0.000, and P = 0.047, respectively). The mean uric acid level was 4.28 ± 1.16 mg/dL in the TTH group and 5.32 ± 1.31 mg/dL in the control group, and the difference was significant (P = 0.000). BUN levels were not significantly different between the two groups (P = 0.547) (Table 1, Figure 1).

Figure 1.

Sociodemographic characteristics and laboratory outcomes of the groups between patient and control group.

Table 1.

Sociodemographic characteristics and laboratory outcomes of the groups (mean ± SD/median range).

	Control n = 70 (42.7%)	Patient n = 94 (57.3%)	Total n = 164 (100%)	p
Age (years)	49.07 ± 9.15/47.5–40	52.88 ± 12.06/50–49	51.26 ± 11.05/49.5–49	0.069
Albumin (g/dl)	4.41 ± 0.38/4.4–2	4.17 ± 0.50/4.15–3.4	4.28 ± 0.47/4.3–3.4	0.000*
BUN (mg/dl)	13.63 ± 10.42/12.6–91.1	14.47 ± 7.41/12.81–42.2	14.11 ± 8.80/12.6–91.1	0.547
Creatinine (mg/dl)	1.11 ± 1.50/0.9–12.79	0.79 ± 0.17/0.78–1	0.93 ± 0.99/0.8–12.85	0.047*
Uric acid (mg/dl)**	5.32 ± 1.31/5.35–8	4.28 ± 1.16/4.3–5.2	4.72 ± 1.33/4.8–9.5	0.000*
Hemoglobin (g/dl)**	14.46 ± 1.53/14.45–6.6	13.20 ± 1.78/13.35–10.8	13.74 ± 1.79/13.8–10.8	0.000*
Gender (male(n)/female(n))	35/35	24/70	59/105	0.000*

BUN: blood urea nitrogen.

*Statistically significant at the 0.05 level. **t-test. All other variables were analyzed with Mann–Whitney U-test.

In binary logistic regression analysis, serum uric acid level showed a significant independent association with TTH after adjusting for sex, age, BUN, creatinine, and hemoglobin (P < 0.001). Higher uric acid levels were strongly associated with reduced odds of TTH. Uric acid remained a critical predictor of TTH, even after accounting for the influence of other biochemical variables (Table 2).

Table 2.

Binary logistic regression analysis of biochemical variables adjusted for demographic and clinical parameters.

	Unstandardized coefficients(B)	Standard error	Exp(B)	p
Age (years)	0.072	0.021	1.074	0.001*
Gender	−1.885	0.685	0.152	0.005*
BUN (mg/dl)	0.066	0.032	1.068	0.040
Creatinine (mg/dl)	−5.464	1.626	0.004	0.001*
Hemoglobin(g/dl)	−0.711	0.190	0.491	0.000*
Uric Acid (mg/dl)	−0.899	0.219	0.407	0.000*

BUN: blood urea nitrogen.

Statistically significant at the 0.05 level. Binary logistic regression is used.

As shown in Table 3, uric acid levels showed a significant negative association with TTH in both male (B = −0.528, P = 0.007) and female (B = −0.936, P = 0.003) patients, indicating that lower uric acid levels are associated with a higher likelihood of TTH in both sexes. The reduction was more pronounced in female patients, with an odds reduction of 61%, compared to 41% in male patients.

Table 3.

Association between uric acid and patient/control group by gender.

	Gender	Unstandardized coefficients (B)	Standard error	Exp(B)	p
Uric acid	Male	−0.528	0.197	0.590	0.007*
	Female	−0.936	0.320	0.392	0.003*

Statistically significant at the 0.05 level. Binary logistic regression is used.

The Youden index maximization approach was applied, and ROC curve analysis was performed to determine a blood uric acid level capable of differentiating between the TTH group and the control group. As shown in Figure 2, the AUC of the uric acid ROC curve was 71.90 (95% CI: 0.549–0.702). ROC curve analysis for the TTH group showed that the ideal diagnostic uric acid cutoff value was 3.885 mg/dL at which point the accuracy was 63%, with sensitivity and specificity of 92.9% and 40.4%, respectively (Table 4).

Figure 2.

Uric acid level ROC curve chart.

Table 4.

The sensitivity and specificity of uric acid.

	Uric acid
Cutoff	3.885
Specificity	40.40%
Sensitivity	92.90%
Accuracy	63%
Area under the curve (AUC)	71.90%
95% CI	0.549–0.702
p	0.000*

Statistically significant at the 0.05 level.

Discussion

The results of the present study showed that patients with chronic TTH had considerably lower serum uric acid levels than the control group. To our knowledge, there have been no previous studies of the association between TTH and uric acid levels.

TTH is one of the primary headache types, with the highest social cost in clinical practice. Its incidence increases in the productive age range of 30 to 39 years, after which it begins to decrease in both sexes.²

There is a lack of information regarding the pathophysiology of TTH. Continuous nociceptive input from peripheral myofascial structures has been suggested to induce central sensitization and lead to the conversion of episodic to chronic TTH.^13–15 Increased general pain sensitivity and heightened excitability of the central nervous system are observed in chronic TTH. This neuronal excitability may result in enhanced facilitation and reduced inhibition of pain transmission at the level of the spinal dorsal horn/trigeminal nucleus, further contributing to increased pericranial muscle activity.^16,17 In addition, centrally acting molecular factors have been implicated in the pathogenesis of chronic TTH. Neurons are sensitive to exogenous and endogenous injuries mediated by ROS.^18,19 Consequently, oxidative stress plays a significant role in the development of TTH.¹¹ There have been many studies of the relation between oxidative stress and TTH.^20–24 Unlike episodic TTH, a role for the NO mechanism has been emphasized in the etiology of chronic TTH.⁶ Increased NOS activity in platelets was reported in patients with chronic TTH, reflecting central upregulation of NOS activity, specifically in neurons in the spinal dorsal horn, trigeminal nucleus, and supraspinal structures.²⁵ In chronic TTH, reduced NO levels have been shown to decrease pain and muscle hardness,^26,27 while elevated levels of several inflammatory mediators (interleukin (IL)-1β, IL-8, and IL-10) have been reported in small case–control studies of patients with chronic TTH.^28,29 Uric acid neutralizes peroxynitrite, a harmful molecule formed by the reaction between NO and superoxide radicals.^30,31 This antioxidant effect of uric acid protects NO from degradation by superoxide radicals, thereby indirectly supporting the bioavailability of NO and potentially enhancing NO-mediated vasodilation.³² In addition, uric acid regulates the inflammatory response by inhibiting the production of inflammatory mediators, thus significantly reducing the formation of free radicals.³³ One of the most interesting aspects of the antioxidant function of uric acid is its potential role in neuroprotection.³⁴ Uric acid has been implicated in regulating central nervous system functions, such as sleep, activity, mood, social interaction, impulsivity, and intelligence.^35,36 In addition to its antioxidant and neuroprotective properties, uric acid may reduce the sensitivity of myofascial nociceptors and heightened excitability of the central nervous system by regulating sleep, mood, and inflammation. Therefore, it may contribute to the etiology of chronic TTH in multiple ways, unlike episodic TTH.

The relations between uric acid and various chronic neurological diseases, such as migraine, Meige syndrome, diabetic polyneuropathy, Alzheimer's disease, and Parkinson's disease, have been investigated.^12,37–40 Our results were consistent with those of studies in other diseases. Increased pain perception, NO-related neuromodulation, and structural and functional brain abnormalities and trigeminal pathways are known to be central mechanisms associated with chronic TTH, which also show similarities to those observed in chronic migraine.⁴¹ Central sensitization is thought to play a key role in the pathophysiology of both conditions.⁴² The influence of uric acid on the NO pathway and its impact on hypersensitivity may contribute to the pathophysiology of both migraine and chronic TTH. As NO is concentrated in the spinal dorsal horn, trigeminal nucleus, and supraspinal structures in TTH, and as the trigeminal system also plays a role in the pathophysiology of migraine, we hypothesized that the oxidative effects of uric acid may particularly affect the trigeminal system.

The uric acid level had a clear effect on TTH disease status in women, while this effect was less obvious in men. Previous studies showed that the prevalence of TTH is higher in women than in men.⁴³ Investigation of the underlying reasons for this difference showed that one of the main clinical features of TTH, mechanical pain hypersensitivity, is more pronounced in women than in men, and the pain threshold to pressure is lower in women.⁴⁴ In patients with TTH, pressure pain sensitivity has been shown to be particularly intense in the trigeminal region. Recent studies demonstrating the relations between muscle trigger points and central sensitization, which is a primary mechanism in chronic TTH, supported this pain model.⁴⁵ Oxidative stress is also known to play a significant role in the initiation, exacerbation, and dissemination of these pain conditions.²⁰ In the present study, the relation between low uric acid levels and TTH was demonstrated more clearly in female than male patients. Another study showed that malondialdehyde level, a marker of oxidative stress, was higher in female patients with TTH compared to males.²²

Tayyebi et al. and Gur-Ozmen et al. reported increased risk and frequency of migraine in patients with iron deficiency anemia.^46,47 Our study showed that patients with TTH had lower hemoglobin levels. Yazar et al. reported that albumin levels were lower in patients diagnosed with migraine than in controls, and albumin levels were also lower during migraine attack periods than in the interictal period.⁴⁸ Our study also showed that albumin levels were significantly lower in patients with TTH than controls. Low albumin levels have been associated with poor prognosis in various conditions, including stroke and myocardial infarction, and have been shown to be correlated with increased oxidative stress.^49,50 In light of these associations, our findings were consistent with those in the literature.

Uric acid levels can be assessed in peripheral blood using a cost-effective and easily accessible test. In TTH, we reported that the uric acid levels had a diagnostic accuracy of 63%, sensitivity of 92.9%, and specificity of 40.9%, and we found a cutoff value for identification of TTH, of 3.885 mg/dL. The results of ROC curve analysis showed that uric acid had high sensitivity for TTH, but its low specificity and moderate accuracy suggested that it may be better utilized alongside other diagnostic methods. On the other hand, we were unable to find a previous report with which to compare our findings.

The results obtained in our study should encourage the exploration of new therapeutic approaches for TTH and the review of existing antioxidant treatments. For example, the potential effects of increasing uric acid levels through antioxidant supplements or dietary modifications could be investigated. Particularly in female patients diagnosed with TTH, information on the roles of lifestyle changes and nutrition (e.g., a diet rich in antioxidants) in the management of headaches could be provided. This may enhance patient engagement in their treatment and improve their sense of control over their health.

This study had several limitations. The focus of the study on patients with chronic TTH and the small sample size limited its generalizability. Therefore, future studies should aim to include patients with episodic TTH, to clarify the relationship between uric acid and the mechanisms underlying TTH. Additionally, studies with larger sample sizes, balanced gender distribution, standardized timing for blood sample collection, and control of dietary and lifestyle factors will provide clearer results.

In conclusion, oxidative stress is known to play an important role in the formation, increase, and spread of chronic TTH. Although our findings indicated an association between low uric acid levels and TTH, further large-scale studies are needed to investigate the role of oxidative stress in the pathophysiology of TTH, to establish whether uric acid can be used as a biomarker for its diagnosis or for monitoring of prognosis.

Public health relevance

Uric acid is a substance that exhibits antioxidant properties by removing superoxide, a reactive oxygen species, from the cell, inhibiting the reaction between superoxide and nitric oxide, and reducing the production of peroxynitrite.

Lower uric acid levels may indicate a role in tension-type headache (TTH) pathophysiology by affecting oxidative stress mechanisms, inflammation, and neuroprotection.

Modifying uric acid levels may lead to new therapeutic approaches in the treatment of TTH.

Footnotes

Acknowledgements

We would like to thank the patients and their relatives who participated in the study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval and patient consent

The Inonu University Ethics Committee received approval for our research with protocol number 2023/4390.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fatma Ebru Algul

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Association between serum uric acid levels and chronic tension-type headache: A case–control study

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

Study design

Participants and eligibility criteria

Biochemical and hematological blood sample analysis

Statistical analysis

Results

Discussion

Public health relevance

Footnotes

Acknowledgements

Declaration of conflicting interests

Ethics approval and patient consent

Funding

ORCID iD

References