Potential therapeutic role of calcitonin gene-related peptide medications for tinnitus

Abstract

Tinnitus is defined as the perception of sound without an external stimulus. It is classified as a subjective phenomenon described as ringing, buzzing, or hissing in the ears. Tinnitus often co-occurs with migraine, as both conditions originate from disturbances of the central nervous system, specifically the auditory and trigeminal nerve pathways. The overlap in populations and pathophysiological similarities between tinnitus and migraine provide strong evidence for overlap between the conditions and a shared potential for therapy. Calcitonin gene-related peptide (CGRP) medications are a recent development in migraine treatment that have proven to be effective prophylactic agents. CGRP medications work by blocking CGRP’s inflammatory role in migraine formation, a physiological process that may also be involved in the loudness of tinnitus. This narrative review aims to provide an overview of the role of CGRP in migraine and tinnitus and discuss managing CGRP and central sensitization as a potential therapeutic role in tinnitus.

Lay Summary: Tinnitus is the perception of sound, like ringing or buzzing, without any external noise and often occurs alongside migraine. Both conditions are linked to disturbances in the brain’s auditory and nerve pathways. Research suggests that since they share common causes, treatments for migraine could also help treat tinnitus. One promising treatment is the use of calcitonin gene-related peptide (CGRP) medications, which are effective in preventing migraine by blocking inflammation caused by CGRP. This review explores the connection between CGRP, migraine, and tinnitus, and discusses the potential of CGRP-based treatments to manage tinnitus.

1. INTRODUCTION

Tinnitus is widely described as the perception of sound without external stimulus. It is classified as a subjective phenomenon described as ringing, buzzing, or hissing in the ears.¹ It affects approximately 16 million adults in the United States and is particularly prevalent among veterans.^1,2 Additionally, approximately 2.6 million young people aged 12 to 19 have also encountered tinnitus in their lives.^3,4 Given its widespread occurrence and the disruptive nature of its symptoms, tinnitus imposes a socioeconomic burden. The pathogenesis of tinnitus is due to damage to cochlear hair cells or loss of synapses between hair cells and auditory nerves (synaptopathy).^1,2 This loss of sharpened sensory input leads to a reorganization of the tonotopic map in the auditory cortex which causes spontaneous neural firing that is perceived as tinnitus.^2,5

An alternative theory is that the perception of tinnitus involves disruption to the dorsal cochlear nucleus (DCN) which receives auditory input from the vestibulocochlear nerve and indirect somatosensory input from the trigeminal nerve.^1,6,7 The DCN is a “tinnitus generator” as it projects to the inferior colliculus, medial geniculate body, and auditory cortex.¹ On a cellular level, tinnitus is also associated with increased neural synchrony, changes in neurotransmission, and maladaptive plasticity.^1,7 The pathophysiology is tied to a complex interplay of both auditory and non-auditory structures.¹ The spontaneous nature of tinnitus can be attributed to both changes in trigeminal sensory input and auditory disruptions.^8,9 Studies have shown that the auditory system pathology involved in tinnitus can be modified, especially via ion channels (ie, potassium) and neurotransmitters (ie, CGRP).^10,11 Conditions that share these channels and pathways with tinnitus, such as migraine, may promote tinnitus progression in the setting of pathological alterations, as will be discussed later in this review.

A recent study has also suggested that tinnitus may be exacerbated or triggered by neurological disturbances, including those caused by viral infections like coronavirus disease 2019 (COVID-19).¹² Long COVID, a condition where symptoms persist long after the acute phase of COVID-19, has been associated with various neurological symptoms, including tinnitus.¹² A meta-analysis of patients with long COVID demonstrated that 4.5% of individuals are also diagnosed with tinnitus.¹² It is proposed that the link between long COVID and tinnitus involves central sensitization, as both tinnitus and long COVID patients share elevated levels of calcitonin gene-related peptide (CGRP)—a peptide involved in immune system modulation.¹² Patients with long COVID are found to have 30% higher levels of CGRP than patients without central sensitization conditions (ie, headache).¹² Specifically, patients with serum CGRP levels <1.26 ng/mL were found to have faster recovery times than patients with serum CGRP levels greater than 1.26, which was correlated with negative disease evolution that could promote chronic inflammation and auditory disturbances.¹³ This connection between viral infections and tinnitus highlights a potential link between the mechanisms of chronic inflammation and auditory disturbances, including the role of neuropeptides like calcitonin gene-related peptide (CGRP).^12,13 In long COVID patients, tinnitus has been reported as one of the many lingering symptoms, with shared pathophysiological mechanisms, such as central sensitization and neuroinflammation, potentially linking it to other sensory disturbances.¹²

2. MIGRAINE AND TINNITUS

Migraine and tinnitus frequently co-occur, with studies showing a significant overlap between these two conditions.^14–17 A study of National Health and Nutrition Examination Survey (NHANES) data found that among 12 969 patients surveyed, 36.6% of patients with tinnitus also reported experiencing migraine headaches.^3,14 This association was further confirmed by multivariate logistic regression analysis, which found that patients with tinnitus are more predisposed to have migraine.^3,8,14 This association has also been found by others.^9,17 The association between tinnitus and migraine extends beyond mere epidemiology and is supported by common triggers, such as stress,^14–17 sleep disturbances,^3,18 noise exposure,^9,19 dietary patterns,³ and changes in weather conditions.³ These factors not only exacerbate migraine attacks but can also worsen tinnitus symptoms, indicating a shared susceptibility to environmental stressors.^3,9,18–20

Both migraine and tinnitus pathophysiology involve disturbances of the central nervous system, specifically the auditory and trigeminal nerve pathways.⁸ There is evidence for a mechanistic link between migraine and dysregulation of the central auditory pathway.⁸ Migraine occurs through the activation of the peripheral and central trigeminal-vascular system, where neurons synapse with blood vessels and release neuropeptides such as CGRP, substance P, and neurokinin A^3,21 (Fig. 1). These peptides cause vasodilation, plasma leakage, and mast cell degranulation, creating a neuroinflammatory state in the meninges.^1,21,22

Fig. 1.

The role of CGRP and the trigeminal system in migraine pathophysiology.

The onset of a migraine involves cortical spreading depression, or altered electrical activity across the cortex, which results in inflammation in the intracranial meninges and activation of trigeminal meningeal nociceptors.^2,23 This inflammation leads to altered white matter microstructure in the trigeminal nerve root.²⁴ This central hypersensitivity is linked to the loudness of tinnitus, as trigeminal nerve activation leads to central sensitization and increased attention to the tinnitus, leading to a louder tinnitus. Additionally, the trigeminal nerve is connected to the arterial blood supply of the cochlea and, when activated, leads to alteration in cochlear blood flow and fluid extravasation in the cochlea.²⁵ Recent neuroimaging studies have shown altered white matter microstructure and increased neuroinflammation in the trigeminal nerve root, further supporting the role of the trigeminal system in migraine pathophysiology.²² This central hypersensitivity may be linked to tinnitus, as the trigeminal nerve is connected to the inner ear and may contribute to auditory dysfunction.^3,26 Recent preclinical work has indicated that systemic CGRP can modulate inner-ear function and increase sensory hypersensitivity. In wild-type mice, intraperitoneal CGRP increased auditory brainstem response, reduced vestibular sensory evoked potential amplitudes, and heightened sound-evoked startle and postural sway, which parallels phonophobia and balance issues in vestibular migraine (VM). These findings support a peripheral contribution of CGRP to auditory and vestibular hypersensitivity and align with our discussed mechanism.²⁷

CGRP is a neuropeptide found in the efferent synapses of hair cell organs like the cochlea, semicircular canal, and lateral line.²⁸ It is a lateral olivocochlear efferent neurotransmitter that is widely distributed throughout the central and peripheral nervous system and is released from nerve fibers that run along meningeal and cerebral arteries.^29,30 Importantly, CGRP plays a crucial role in the neurogenic inflammatory response and has been shown to be both necessary and sufficient for inducing migraine in some patients.^29,30 Finally, CGRP is involved in vasodilation and mast cell degranulation within meningeal vessels.^31,32

The neuroinflammatory state induced by CGRP and other inflammatory peptides can affect the vestibulocochlear system through direct action of CGRP in the inner ear and the vasodilation/vasospasm of the cochlear blood supply induced by trigeminal activation.²⁵ Elevated levels of the inflammatory peptides are seen in patients with tinnitus and other central sensitization conditions compared to unaffected patients.¹² Such elevated levels suggest that CGRP can contribute to the pathophysiology of tinnitus. CGRP is detectable through immunoreactivity in the neural fibers within the cochlea,^30,33,34 and its localization suggests that it is involved in efferent auditory pathways.^26,30,34 The activation of trigeminal meningeal nociceptors, along with general inflammation of the trigeminal nerve, and the vasospasm and vasodilation of the inner ear, may cause migraine-related cochlear changes.^1,25 Changes to cochlear blood flow and fluid extravasation within the cochlea mediated through trigeminal nerve activation may lead to hearing loss and tinnitus in patients with fleeting short tinnitus. Additionally and much more commonly, trigeminal activation leads to a central hypersensitivity process which may be the pathophysiological link between migraine and tinnitus loudness.² Given that CGRP-induced inflammation appears to potentially be involved with tinnitus, CGRP-antagonists, which have been found to be effective prophylactic agents in migraine headaches and VM treatment, also may show promise as a tinnitus treatment by acting on a potential pathway common to both migraine and tinnitus.^35,36 These treatments, such as CGRP antagonists, were the initial CGRP-based treatments developed to inhibit CGRP binding and subsequent signal transduction.^29,37 CGRP is expressed in both trigeminal neurons and the efferent synapses of hair cells in the cochlea and the semicircular canals.³⁸ This neuropeptide is believed to play a role in nociception and contribute to vasodilation.^36,38–40

The proposed pathophysiologic processes through which CGRP exacerbates tinnitus symptoms via a central sensitivity pathway are noted in Fig. 2. Research has indicated that central auditory neural hyperactivity resulting from hair cell damage is the underlying cause of tinnitus.^41,42 Furthermore, minor alterations in neurovascular or neurosecretory processes can potentially lead to symptoms in the inner ear.⁴³ Dilation of vessels in the inner ear may lead to fluid extravasation and changes to basilar membrane stiffness. This then may lead to decreased hearing that may be related to tinnitus. The spiral modiolar artery, which provides the main blood supply to cochlea, also has CGRP containing neurons overlying it.¹¹ CGRP has vasodilatory effects on the spiral modiolar artery, and these effects cause an impaired blood flow regulation that may contribute to tinnitus due to a temporary hearing loss.¹¹ Studies have demonstrated spontaneous DCN hyperactivity in animals with tinnitus.⁴⁴ This increase in activity occurs in the neurons associated with the pitch of the resultant tinnitus.⁴⁴ This neuroplastic reorganization within the DCN is thought to occur after cochlear damage and is why the DCN is titled as the “tinnitus generator.^44,45 Additionally, the DCN receives somatosensory input from the trigeminal nerve. Activation of the trigeminal nerve may lead to modulation of the tinnitus signal, leading to somatic tinnitus.

Fig. 2.

Mechanisms of migraine contributing to the perception of tinnitus.

3. CGRP MEDICATIONS AND TINNITUS

The relationship between tinnitus and migraine suggests that treatments commonly used for migraine may contain alternative approaches in treating tinnitus and other inner ear conditions.² Recently, other migraine prophylactics, when used in combination, were found efficacious in treating tinnitus.⁴⁶ CGRP has an excitatory role in the auditory system and has been tied to general increased activity and auditory hyperactivity. Administration of CGRP has been associated with increased cochlear blood flow and an increase in spontaneous neural activity.^30,47 A study of guinea pig cochlea found a greater amplitude of round window noise and whole nerve response to sound with CGRP infusion.⁴⁷ Merchan-Perez et al⁴⁸ described CGRP-like immunoreactivity in perivascular nerves surrounding main branches of the inner ear in the albino rat.

One relevant study investigated the efficacy of galcanezumab, a CGRP monoclonal antibody, in treating VM, a condition frequently associated with tinnitus.³⁶ Although tinnitus was not a direct outcome measure of this study, studies have shown that patients with VM have a three-fold increase in cochlear disorders (including tinnitus).²⁸ Additionally, both VM and tinnitus are characterized by increases in CGRP levels. This overlap in patients and CGRP levels allows for CGRP blockade considerations to be extended to tinnitus patients. In the randomized, double-blind, placebo-controlled trial, researchers found that galcanezumab significantly reduced VM-related symptoms, including dizziness and the frequency of “dizzy days”.³⁶ In the treatment group, the count of dizzy days per month decreased from 17.9 to 6.6, compared to the placebo group, where the reduction was much smaller (from 18 to 12.5 days).³⁶ Additionally, the Dizziness Handicap Inventory (DHI) score dropped by 22 points in the galcanezumab group.³⁶ This study shows the effectiveness of this CGRP antagonist in alleviating VM and other associated symptoms linked to CGRP elevation. Given CGRP’s role in other ear-related symptoms, this study’s positive results suggest that galcanezumab may be useful in alleviating other CGRP-associated symptoms, including tinnitus.

These findings suggest that CGRP medications, through their effects on neuroinflammation and sensory processing, may provide significant relief not only for migraine but also for tinnitus symptoms that arise from a similar pathophysiological process. In addition, a combination of medication and lifestyle changes appears to have the highest benefit in the clinical setting. By targeting the trigeminal and auditory pathways affected by CGRP, these treatments offer a dual benefit, reducing both the frequency of migraine attacks and improving tinnitus-related symptoms. Given the high efficacy-to-tolerability ratio of CGRP monoclonal antibodies, these therapies hold promise for patients with both migraine and tinnitus when combined with lifestyle and dietary changes, supporting their use in managing tinnitus as a migraine phenomenon.⁴⁰ CGRP monoclonal antibodies have shown a high efficacy-to-tolerability ratio for migraine patients when combined with lifestyle and dietary changes. Although CGRP efficacy was not directly tested in tinnitus patients, the frequent co-occurrence of tinnitus and migraine and high levels of CGRP in both conditions have led to studies proposing that migraine treatments, especially CGRP monoclonal antibodies, may be effective in treating migraine-associated tinnitus.^1,28 This indicates the need for a multifaceted treatment approach—involving pharmacological and lifestyle modifications—for patients with CGRP-associated conditions like tinnitus and migraine. It is important to note that the response to anti-CGRP monoclonal antibodies is heterogeneous. In a scoping review and meta-analysis, prior triptan responsiveness and migraine-typical features predicted better outcomes, while obesity, interictal allodynia, daily headache, greater numbers of prior preventive failures, and psychiatric comorbidities—especially depression—were associated with poorer response.⁴⁹ Given the frequent co-occurrence of psychiatric comorbidities in tinnitus, screening and concurrent management may be important when considering CGRP-pathway therapies.

4. TINNITUS AND ANTIDEPRESSANTS

Current tinnitus management centers around symptomatic improvement rather than curative therapy.¹ Tinnitus often coexists with conditions such as depression, anxiety, and chronic or episodic classical or atypical migraine, and it is also strongly associated with stress.¹ Antidepressants, both through serotonergic and antimuscarinic mechanisms, including the class of drugs known as selective serotonin reuptake inhibitors (SSRIs), have also proven effective when used to treat tinnitus in individuals with more severe phenotypes co-occurring with psychiatric conditions.^2,50 Notably, a recent randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of drug combinations involving verapamil-paroxetine (a combination including an SSRI) and nortriptyline-topiramate in patients with moderate to severe tinnitus. The study found that both drug combinations resulted in significant reductions in tinnitus severity, as measured by the Tinnitus Functional Index (TFI), compared to placebo, demonstrating their potential efficacy in tinnitus management.⁴⁶ Lifestyle modifications are an essential component of a multi-modal therapy and include improved sleep, stress management, dietary changes (such as avoiding migraine dietary triggers, preventing starvation and dehydration), and supplements like vitamin B2 and magnesium, have also positively impacted tinnitus symptoms.^1,2,38 Combinations of antidepressants and antiseizures, antidepressants and antihypertensives, and antiseizures and antihypertensives all can be used for the treatment of tinnitus as part of a comprehensive program which includes lifestyle and dietary changes. In addition, a combination of an anti-CGRP antibody or CGRP receptor blocker in combination with an antiseizure, antidepressant, or antihypertensive can also potentially be used to treat tinnitus. A combination of three drugs in any of these classes can also be used to treat tinnitus.

Further research is needed to understand how endogenous CGRP release in the auditory system influences tinnitus and how CGRP-blocking medications might affect auditory physiology. In a 2021 animal study, a CGRP receptor antagonist did not influence auditory nerve or outer hair cell outcomes.³⁰ However, in this mouse model, the success of this specific antagonist in blocking CGRP binding was unclear. It is probable that a successful blockage of CGRP could reduce subjective symptoms of auditory disturbance in tinnitus, especially if combined with lifestyle and dietary changes.

5. CONCLUSION

Tinnitus has a complex pathophysiology involving cochlear damage and altered neural activity in auditory and somatosensory pathways. Symptoms may be exacerbated by neuroinflammatory effects of viral infections, consistent with central sensitization. Migraine and tinnitus frequently co-occur and share triggers and central nervous system disturbances, particularly along auditory and trigeminal pathways. CGRP, released during migraine attacks, can drive neuroinflammation and vascular and sensory changes that may contribute to tinnitus. Given their overlapping mechanisms, CGRP-targeted therapies developed for migraine are being explored as potential options for tinnitus by addressing central hypersensitivity and inflammation. However, evidence remains preliminary, and clinical trials are needed. Current tinnitus management emphasizes symptom relief through tailored combinations of pharmacologic treatments, such as SSRIs and antiepileptics, alongside lifestyle and dietary changes. Future studies should directly evaluate the effects of CGRP monoclonal antibodies on tinnitus outcomes to define efficacy and patient selection. Such work could both improve quality of life and refine our understanding of tinnitus mechanisms.