The effect of low dose thyroid replacement therapy in patients with episodic migraine and subclinical hypothyroidism: A randomised placebo-controlled trial

Abstract

Introduction

Migraine is a common headache syndrome associated with various other comorbidities. Thyroid replacement in migraine patients with hypothyroidism improves headaches; however, thyroid hormone replacement in subclinical hypothyroidism is debatable, and its efficacy is not known.

Objective and methodology

Results

We assessed 87 patients for analysis; no patients were lost to follow-up. There was a decrease in all parameters evaluated (headache frequency, severity, duration, MIDAS score, MIDAS grade) at three months of follow-up in the treatment group compared to placebo group. There was a significant decrease in headache frequency and severity in the levothyroxine group compared to the placebo group at three months of follow-up. Also, the follow-up MIDAS score (mean ± SD: 6.30 ± 2.455 scores vs. 8.45 ± 5.757 scores) was significantly decreased by treatment at three months follow-up.

Conclusion

Treatment of subclinical hypothyroidism effectively reduces migraine headaches, and it is logical to check thyroid function status in patients presenting with migraine headaches. However, a larger randomised controlled trial is required to prove the efficacy of levothyroxine in migraine with subclinical hypothyroidism.

Keywords

Migraine sub-clinical hypothyroidism levothyroxine randomized clinical trial hypothyroidism

Introduction and background

Migraine is a common, disabling, recurrent headache syndrome associated with other symptoms of neurologic dysfunction in varying admixtures (1). The third edition of the International Classification of Headache Disorders (ICHD-3) classified migraine into various subtypes (1). As per GBD 2016 reports the global age standardized prevalence is 14.4% overall: 18.9% for women, and 9.8% for men (2). Chronic migraine is less common than episodic migraine but is associated with higher disability (3). Migraine is associated with other comorbidities: cardiovascular diseases including stroke, myocardial infarction; sleep disturbances; psychiatric illnesses such as depression, anxiety, panic disorder, neurological complications; fibromyalgia; asthma; and temporomandibular joint disorders (4). Due to inconsistent findings, the relationship between thyroid disorders and migraine has gained attention in recent years (5). Several studies have shown a link between hypothyroidism and migraines and how treating hypothyroidism might improve migraine severity (6 –8). The role of thyroid replacement therapy and the response to headaches in such patients is also well established (6 –8). However, the underlying mechanism is still not clear (5). Subclinical hypothyroidism is biochemically defined as an elevated thyroid stimulating hormone (TSH) combined with a serum-free thyroxine (T4) level within the population reference range (9). The incidence of subclinical hypothyroidism varies among populations. It ranges from 3 to 15%, with a higher incidence associated with increasing age, female sex, and a suboptimal iodine status (10 –12). Recent studies suggested that migraine is more frequent in patients with subclinical hypothyroidism also (5,13,14), It is unknown whether thyroid replacement therapy in migraine patients with subclinical hypothyroidism is effective. This study assessed the efficacy of low fixed-dose thyroid replacement therapy as an add-on treatment in patients with migraine headaches with subclinical hypothyroidism.

Material and methods

This prospective, single-centre, quasi-randomised interventional study was conducted on patients visiting the General Medicine and Neurology outpatient department at a tertiary center in India between September 2018 and June 2019. The institutional ethical committee approved the study. A sample size of 87 patients was calculated based on assumptions from a previous study in children (15), with a confidence interval of 95% and α error at 0.05 and power of 80. After written informed consent, all patients with ages ranging from 18 to 50 years who fulfilled the episodic migraine criteria according to International Classification of Headache Disorders-III (ICHD-3) (1) were diagnosed with subclinical hypothyroidism (TSH level 4.5–10.0 mIU/L and normal free T4 level measured twice six weeks apart) with negative anti-thyroid peroxidase antibody (TPO) levels were included in the study. We excluded patients with any form of thyroid disease as revealed by clinical examination or past medical records, patients with abnormal neurological examination, pregnant, with chronic illnesses known to affect thyroid hormone levels like chronic kidney disease or other systemic illness, with regular drug intake known to affect thyroid status of the patient.

Randomisation

Patients were quasi-randomised into two arms (based on the day of the outpatient visit), the intervention arm and the control arm (placebo) (Figure 1). The intervention arm received 25 µg of levothyroxine supplementation. Both groups continued or received treatment for prophylaxis of migraine Both groups continued or received treatment for prophylaxis of migraine. We advised patients to take levothyroxine on an empty stomach an hour before food in the morning. Also, medications causing interference with levothyroxine absorption (calcium and iron salts, proton pump inhibitors, etc.) were avoided or taken four hours or more after levothyroxine ingestion. The potential risks and benefits of either intervention were clearly explained to patients.

Figure 1.

Randomisation.

A detailed history of headache, including characteristics, frequency of attack, duration of each attack, the severity of attacks (on a visual analogue scale), associated features, analgesic intake, response to medications, aggravating and relieving factors, were recorded. Patients and relatives were told to keep a headache diary for these same characteristics. Disability in Migraine Disability Assessment Score (MIDAS) and MIDAS grade were noted during the outpatient visit. Serum-free thyroxin (FT4), thyroid stimulating hormone (TSH), and anti-TPO levels, in addition to routine haematological and biochemical parameters, were measured. FT4 and TSH levels were repeated after three months of follow-up.

Outcome measures

The primary outcomes were: a reduction in headache duration (hours), frequency, severity, and MIDAS score after three months of the randomisation. We also assessed MIDAS grades after three months of randomisation.

Statistical analysis

The demographic, clinical, and laboratory findings of the levothyroxine and control groups patients were compared using the Chi-square test or Fisher exact for categorical and student “t” test or Mann Whitney u test for continuous variable. Continuous and normally distributed data are expressed as mean. There were no significant differences ± standard deviation, while continuous and skewed data are expressed as median (range). The paired Student”s test and the Wilcoxson test were used for paired samples. Statistical analysis was done using the software SPSS version 22.0, and a p-value of <0.05 was considered significant. The correlation analysis was done between TSH normalisation and headache reduction indices as well as between plasmatic levels of TSH/ft4 and the clinical characteristics of migraine.

Results

A total of 87 adult patients with migraine with subclinical hypothyroidism were evaluated. Of them, 82 (94%) patients were female, and 5 (6%) were male. Forty-three patients were quasi-randomised into the levothyroxine group and 44 patients into the placebo group. There were no significant differences between age, TSH levels, headache severity, and MIDAS score between the two arms at baseline (Table 1).

Table 1.

Baseline characteristics of patients in the two arms.

Parameters	Thyroxine(N = 43)	Placebo(N = 44)	p-value
Age, mean ± SD	34.56 ± 10.731	32.84 ± 9.231	0.425
Age of onset
Female, no. (%)	41 (95)	41 (93)	0.43
Nausea, no. (%)	37 (86)	35 (80)	0.42
Vomiting, no. (%)	5 (12)	10 (23)	0.17
Photophobia, no. (%)	28 (65)	33 (75)	0.31
Phonophobia, no. (%)	21 (49)	30 (68)	0.07
Aura, no.(%)	2 (5)	3 (7)	0.17
Location of headache, no.(%)
Lateralised	39 (91)	39 (89)	0.75
Global	4 (9)	5 (11)
Headache frequency, mean ± SD	12.98 ± 6.36	13.57 ± 6.50	0.33
Headache severity, mean ± SD	7.70 ± 2.042	7.73 ± 2.027	0.95
Headache duration (hours), mean ± SD	25.16 ± 11.866	22.91 ± 12.718	0.40
MIDAS score, mean ± SD	23.44 ± 11.179	23.11 ± 11.736	0.89
MIDAS grade, mean ± SD	3.47 ± 0.505	3.43 ± 0.587	0.78
TSH level, mean ± SD	7.388 ± 1.5182	7.483 ± 1.4740	0.77

MIDAS: Mgraine Disability Assessment Score; SD: Standard Deviation; TSH: Thyroid Stimulating Hormone.

Outcomes

We screened 545 migraine patients and assessed 87 patients for analysis; no patients were lost to follow-up. There was a decrease in all parameters evaluated (headache frequency, severity, duration, MIDAS score, MIDAS grade) at three months of follow-up in the treatment group compared to placebo group. There was a significant decrease in headache frequency and severity in the levothyroxine group compared to the placebo group at three months of follow-up. Also, the MIDAS score (mean ± SD: 6.30 ± 2.455 scores vs. 8.45 ± 5.757 scores) was significantly decreased by treatment at three months follow-up. MIDAS grade was also considerably reduced in the intervention group. Even though headache duration was also reduced in the levothyroxine group, we could not find any statistically significant difference (Table 2). 87% of patients had normal TSH levels on repeat testing at three months. None of the patients progressed to overt hypothyroidism. We obtained the correlation of TSH with MIDAS Presentation, Duration Head Presentation, MIDAS Six Months and Difference Duration for each group. Furthermore, we performed the test to check the significance of the correlation coefficient. In other words, we have performed a test to decide whether the linear relationship in the sample is strong enough to use to model the relationship in the population. To perform this test, we obtained the t-statistic (correlation $r$ and sample size $n$ ) and corresponding p-value.

Table 2:

Comparison of primary outcome variables at three months between intervention and placebo arms.

Parameters	Thyroxine(N = 43)	Placebo(N = 44)	p-value
Headache frequency (mean ± SD)	1.67 ± 0.78	3.28 ± 1.71	0.001
Headache severity (mean ± SD)	2.05 ± 1.29	3.20 ± 1.77	0.001
Headache duration (hours), mean ± SD	1.93 ± 0.55	1.99 ± 0.58	0.630
MIDAS score (mean ± SD)	6.30 ± 2.46	8.45 ± 5.76	0.026
MIDAS grade (mean ± SD)	1.49 ± 0.63	1.84 ± 0.83	0.029

MIDAS: Mgraine Disability Assessment Score; SD: Standard Deviation.

A p-value greater than indicates an insignificant correlation. We observed that almost all the correlation of TSH with MIDAS Presentation, Duration Head Presentation, MIDAS Six Months and Difference Duration for each group is about 0.1. This indicates there is a very negligible linear relationship. Also, all the p-value greater than an insignificant linear relationship (Supplementary Table 1). Besides these, we also observed that almost all the correlation of TSH/fT4 with each group's MIDAS Presentation, Duration Head Presentation, MIDAS Six Months and Difference Duration were insignificant except the correlation between TSH/fT4 and MIADS presentation of the placebo group. The p-value (0.035) less than indicates a significant linear relationship (Supplementary Table 2).

Discussion

To our knowledge, this is the first study in adults evaluating the efficacy of a low fixed dose of levothyroxine as an add-on therapy in patients with migraine headaches with subclinical hypothyroidism.

Many studies have shown an association between migraine and hypothyroidism and improvement of migraine symptoms after the treatment of hypothyroidism (5 –8). Although many studies assessed this, the mechanism behind this is still unclear (5). A case-control study by Khan et al. (16) found that subclinical hypothyroidism was present in 22% of patients with primary headache disorders and overt hypothyroidism in 7.2%. Also, hypothyroidism was more common in chronic tension-type headaches and chronic migraine. Furthermore, even though not statistically significant, they observed that the frequency of hypothyroidism in patients with primary headache disorder was higher among females.

Recent studies also suggested migraines are more frequent in patients with subclinical hypothyroidism (5,13,14). Subclinical hypothyroidism is biochemically defined as an elevated serum thyroid-stimulating hormone (TSH) level combined with a serum-free thyroxine (T4) level within the population reference range (9). Most patients may be asymptomatic or present with non-specific vague symptoms, and most have serum TSH levels <10 mU/L (9). In a study by Rubino et al. (5), the prevalence of lifetime migraine (both with and without aura) was significantly higher in subclinical hypothyroidism patients than in controls.

Most guidelines and experts recommend treating patients with subclinical hypothyroidism if serum TSH concentration is ≥10 mU/L in people <75 years old and those ≥75 years old if there is a high risk of cardiovascular disorders (17 –19). However, treating asymptomatic patients with TSH values between 4.5 and 10 mU/L is always a topic of debate. The European Thyroid Association (ETA) guidelines (20) published in 2013 suggest the treatment of patients with subclinical hypothyroidism if TSH < 10 mU/L and if symptoms of hypothyroidism are present. They recommend observing and repeating TSH after six months if there are no symptoms. In elderly patients >70 years of age, ETA recommends just observation. Various factors favour levothyroxine treatment in patients with TSH levels between 4.5–10 mIU/l. These include the presence of goiter, young patient, pregnancy, infertility, ovulatory dysfunction, childhood, adolescence, psychiatric illness like depression, bipolar disorder, smoking, cardiovascular risk factors, dyslipidemia, and presence of antithyroid antibodies (21). If the decision is to treat subclinical hypothyroidism, then oral levothyroxine, administered daily, is the treatment of choice. A weight-related dose of levothyroxine should be used for patients without cardiac disease, approximating 1.5 µg/kg/day. However, a small dose, 25 or 50 µg daily, should be started in older patients and patients with cardiac disease. Every 14–21 days, the levothyroxine dose should be increased by 25 µg/day until a total replacement dose is reached (20). In our study, we used a low fixed dose of levothyroxine (25 µg/day) as there are no specific guidelines about the dose of levothyroxine in migraine patients as there are no trials or good published studies available.

However, the exact biological mechanisms underlying the association between subclinical hypothyroidism and migraine are unknown. Furthermore, there are no studies on the effect of the treatment of subclinical hypothyroidism on the frequency or severity of migraine in adults. This study found a significant decrease in headache frequency per month, headache severity, MIDAS score, and MIDAS grade in the levothyroxine group compared to the placebo group at three months of follow-up. We also found a decrease in headache duration in the levothyroxine group; however, it was not statistically significant.

A quasi-experimental study by Mirouliaei et al. (15) evaluated the effect of subclinical hypothyroidism with levothyroxine for two months on 25 children with migraine headaches. This is the only study published until now on the effectiveness of treatment of subclinical hypothyroidism in paediatric migraine patients. They reported that the monthly frequency and severity of headaches were significantly decreased by treatment with levothyroxine. However no similar studies have been published in the adult population till now. Moreover a cross-sectional study by Lima Carvalho et al. (7) observed that levothyroxine effectively reduced headaches attributed to hypothyroidism (HAH) in patients with subclinical hypothyroidism and with overt disease.

An abstract presented in Congress of the European Academy of Neurology (EAN) 2017 of a cross-sectional study (22) included 45 consecutive patients with migraine without aura and subclinical hypothyroidism attending a single outpatient headache clinic. Treatment of subclinical hypothyroidism (50 to 100 µg/day) effectively reduced both the frequency and severity of migraine attacks which was statistically significant.

Though our study did not have any correlation between headache indices, including MIDAS, with either TSH or TSH/FT4 ratio, the effect in the levothyroxine group is difficult to explain. However, the small sample size could have been one of the reasons.

Our study had many limitations. First, this was a quasi-randomised trial. A randomised controlled trial would be better to investigate the effectiveness of the treatment of subclinical hypothyroidism in reducing the frequency and severity of migraine headaches. Second, we used a low fixed dose of levothyroxine. We did not use the weight per kg dose as there was no current recommendation of levothyroxine dosage in subclinical hypothyroidism for this indication. Therefore, a further study with weight per kg dosing of levothyroxine would have been better. Third, we did not consider the levels of TSH after treatment and normalisation at the time of outcome assessment. Fourth, only patients referred to a tertiary care centre took part in the study, and hence patients with mild disease were few. This made it difficult to expand the results to all categories of migraine patients. Our study”s strength is that this is the first placebo-controlled interventional study in adult patients and included 87 patients.

Conclusion

Treatment of subclinical hypothyroidism effectively reduces migraine headaches, and it is logical to check thyroid function status in patients presenting with migraine headaches. The early diagnosis and treatment of subclinical hypothyroidism in migraine patients may help to reduce migraine episodes and avoid prolonged use of prophylactic migraine drugs, thus reducing side effects and improving quality of life. However, a larger randomised controlled trial is required to prove the efficacy of levothyroxine in migraine with subclinical hypothyroidism.

Clinical implications

It is known that thyroid replacement in migraine patients with hypothyroidism leads to improvement in headaches.

The replacement of thyroid hormone in migraine patients with subclinical hypothyroidism is debatable and its efficacy is not known.

The results of this study suggest that patients with migraine and subclinical hypothyroidism might benefit from low dose of thyroid replacement.

Based on the outcome of the study it might be reasonable to check thyroid function status in patients presenting with migraine headaches.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024231182684 - Supplemental material for The effect of low dose thyroid replacement therapy in patients with episodic migraine and subclinical hypothyroidism: A randomised placebo-controlled trial

Supplemental material, sj-pdf-1-cep-10.1177_03331024231182684 for The effect of low dose thyroid replacement therapy in patients with episodic migraine and subclinical hypothyroidism: A randomised placebo-controlled trial by Priya Dev, T.T. Favas, Rishab Jaiswal, Mareena Cyriac, Vijaya Nath Mishra and Abhishek Pathak in Cephalalgia

Footnotes

Author contribution

AP- Study design, study supervision, and manuscript writing; PD- Data collection and manuscript writing; TTF- Data collection and manuscript writing; MC- Manuscript writing; VNM- Manuscript editing; RJ- Data collection.

Availability of supporting data

Raw data will be with first author and corresponding author, which can be provided on request. Supporting literature for our study is present in references.

Declaration of conflicting interests

The authors do not have any conflict of interest to disclose in terms of research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research: This research was supported by Institution of Eminence (IOE) grant BHU (grant number 42872) received by A. Pathak.

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