Osmophobia in Patients With Migraine: A Systematic Review and Meta‐Analysis

ABSTRACT

Objective

To determine the prevalence of osmophobia and to better characterize experiences reported by patients with migraine.

Data Sources

CINAHL, Cochrane Library, PubMed, and SCOPUS.

Methods

The literature was searched for articles reporting prevalence of osmophobia in patients with migraine. Primary outcome measures included proportions (%) and odds ratio (OR) with 95% confidence intervals (CI).

Results

Fifty‐eight studies were included (n = 22,299 patients). The prevalence of osmophobia among patients with migraine was 47.8% [95% CI: 42.0%–53.6%]. Migraine attacks triggered by odor occurred in 40.1% [95% CI: 32.7%–47.8%] of patients with perfume as the primary trigger. Patients that experienced osmophobia were at greater risk of experiencing other sensory disturbances, such as photophobia, aura, and nausea (OR = 1.45, 1.66, 1.73, respectively, all p < 0.0001).

Conclusion

Osmophobia is a significant and underrecognized component of migraine. In this study, nearly half of patients with migraine reported osmophobia and over a third identified specific odorants, such as perfume or smoke, as a trigger of migraine attacks. Of note, true prevalence of osmophobia is hard to discern as studies were selected based on reporting of osmophobia. This study furthers the understanding that osmophobia can be a concomitant symptom in patients with migraine, and has association with other sensory disturbances, which may guide both diagnosis and management of migraine.

Summary

• Osmophobia is a significant but underrecognized component of migraine.

• The study highlights that nearly half of migraine patients experience osmophobia, and over a third have specific odors (such as perfume or smoke) as triggers.

• Patients with osmophobia are at a higher risk of experiencing other sensory disturbances, including photophobia, aura, and nausea.

• Osmophobia is linked with other sensory disturbances, which could aid in the diagnosis and management of migraine.

1. Introduction

Migraine is a chronic and often lifelong neurovascular disorder that affects over one billion people globally and has a 12%–13% 1‐year prevalence in the United States [1]. Diagnosis of migraine is based on clinical criteria from the third edition of the International Classification of Headache Disorders (ICHD‐3) with clinical features including recurrent headache attacks of unilateral location, pulsating quality, moderate to severe intensity, aggravation by routine physical activity, and association with symptoms of nausea, vomiting, photophobia, and phonophobia [2]. Migraines can be sub‐classified based on the presence or absence of aura, generally recognized as a reversible sensory, speech, or motor change accompanying the migraine [2]. Although not included among the diagnostic criteria, olfactory disturbance (OD) represents an additional sensory component of migraine.

Otolaryngologists see a large proportion of patients with complaints of headache as many people experience pain in their head, face, and neck [3, 4]. Headache is the most common presenting neurological symptom in a primary care setting and is often misdiagnosed [1, 5]. Facial pain or pressure can lead patients to believe that they have a “sinus headache” or may lead to misdiagnosis of headache secondary to chronic rhinosinusitis (CRS), especially when other symptoms present in tandem such as nasal congestion or rhinorrhea [3]. It can be difficult to differentiate the origin of a headache as migrainous or sinogenic in nature.

OD is a common manifestation of both rhinologic and sinogenic disease and is also experienced with migraine. OD has a myriad of different presentations, including hyposensitivity, hypersensitivity, aversion, and phantosmia. Osmophobia, a form of OD, is specifically an aversion to odors coinciding with a migraine, or simply a heightened sensitivity to odors during or preceding a migraine [6]. Additionally, many migraineurs report smells and odors as a trigger of their migraines [7]. The goal of this systematic review and meta‐analysis is to determine the prevalence of osmophobia in patients with migraine and further characterize osmophobia as an accompanying symptom with the hope of raising awareness to improve diagnostic accuracy of headache patients in an ENT setting. Furthermore, we will investigate other aspects of olfactory disturbance such as hyposmia and phantosmia as they relate to migraine.

2. Methods

2.1. Research Question

The question guiding this systematic review is “What is the prevalence of osmophobia in migraine patients?” We hypothesize that osmophobia is a prevalent symptom among patients suffering from migraine. The outcomes we compared were osmophobia, smell as a trigger for migraine, and the relationship of osmophobia and other migraine symptoms.

2.2. Search Criteria

This systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) [8]. A broad‐scoping literature search was conducted using PubMed (National Library of Medicine), Scopus (Elsevier), and CINAHL (EBSCO). A literature search designed for PubMed included keywords and medical subjected headings (MeSH) related to migraine, olfaction, osmophobia, phantosmia, and smell. The PubMed search strategy was applied to Scopus and CINAHL. Once the literature search was completed, articles were uploaded to Covidence systematic review software.

2.3. Study Selection

Two authors (E.E.B and A.H.S) independently screened articles for inclusion by title and abstract first, followed by full‐text review. Discrepancies between reviewers were resolved via discussion by the two reviewers. Inclusion criteria were (1) patients with a diagnosis of migraine and (2) inclusion of data on osmophobia and smell as a migraine trigger. Exclusion criteria were (1) animal studies, (2) studies not involving migraine patients, (3) case studies, (4) review articles, (5) articles with non‐extractable data, (6) studies without available English translation.

2.4. Study Appraisal

Each study was assigned a level of evidence according to the Oxford Center for Evidence‐Based Medicine criteria [9]. Randomized control trials were assessed for risk of bias via the Revised Cochrane risk‐of‐bias tool for randomized trials (RoB‐2), while nonrandomized control trials were assessed for risk of bias with the Risk of Bias in Non‐Randomized Studies‐of Interventions (ROBINS‐I) assessment tool [10, 11]. Case series, cross‐sectional, and case–control studies were assessed for risk of bias using the Joanna Briggs Institute (JBI) Critical Appraisal Tool checklist [12]. Two authors (E.E.B and A.H.S) independently assessed each study using a checklist, and all conflicting answers were reconciled discussion by the two reviewers. For studies using the ROBINS‐1 or ROB‐2 assessment, each aspect of risk of bias was assigned a grade of low, unclear, or high. For studies in which the JBI was utilized, each item was given a score of “1” for “yes” and “0” for “no,” “not applicable,” or “unclear.” The cross‐sectional checklist has eight questions and a score of 4 or higher was considered at low risk for bias.

2.5. Data Extraction

Two authors (E.E.B. and A.H.S.) independently extracted data into a standardized spreadsheet. Any conflicts or inaccuracies were resolved via discussion by the two reviewers. Extracted data included author name, year of publication, sample size, sample demographics, duration of disease, frequency of attacks, duration of attacks, and comorbidities. Outcome data included prevalence of osmophobia, odor as a migraine trigger, and symptoms associated with osmophobia.

2.6. Statistical Analysis

Meta‐analysis of proportions (gender, OD, odor as a trigger) was performed by Comprehensive Meta‐Analysis version 4 (Biostat Inc., Englewood, NJ, USA). Meta‐analysis of the odds ratio for osmophobia and other migraine symptoms, such as photophobia, phonophobia, and nausea, was performed with Cochrane Review Manager (RevMan) version 5.4 (The Cochrane Collaboration 2020, UK). Each measure (mean difference/proportion difference (Δ), proportions (Δ), odds ratio (OR), and 95% confidence interval (CI) was weighted according to the number of individuals affected. Heterogeneity among studies was assessed using I ² statistics with fixed effects (I ² < 50%) and random effects (I ² > 50%). In addition, a comparison of means and proportions, expressed as difference (Δ) and 95% CI, was done to compare outcomes between two groups. A p value of < 0.05 was considered indicative of a significant difference for all statistical tests.

3. Results

3.1. Search Results and Study Characteristics

The literature search yielded 1211 studies, of which 459 duplicates were removed. The remaining 752 articles underwent title and abstract screening. Full‐text review was performed on 119 studies and 61 studies were excluded. Reasons for exclusion included wrong outcomes, wrong measurement, improper study design, wrong patient population, non‐English text, and unavailable full text. At the conclusion of the review, 58 articles met the inclusion criteria [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70]. A PRISMA diagram detailing the systematic review is provided in Figure 1. A summary of the studies included is provided in Table 1.

Figure 1.

PRISMA diagram osmophobia in patients with migraine.

Table 1.

Summary of included studies.

Author year	OLE	Total n	Outcomes
Akarsu 2020	4	871	OP, OT
Akdal 2015	4	1742	OP
Aktürk 2019	4	177	ODC
Al‐Shimmery 2010	4	140	OT
Albayrak 2023	4	134	OP
Amery 1988	4	200	P, Hypo
Andress‐Rothrock 2010	4	1818	OT
Atalar 2024	4	200	OT
Baldacci 2015	4	1148	OP, ODC
Barbanti 2020	4	871	OP, OT
Baykan 2016	4	50	OP
Blau 1985	4	198	OP, OT
Borini	4	198	OP, OT
Chalmer 2019	4	346	OP
Chitsaz 2017	4	150	OP
Demarquay 2006	4	74	OT
Efendioğlu 2024	4	101	OP
Fornazieri 2016	4	113	OP, OT, P
Fukui 2008	4	200	OT
GöçmezYılmaz 2024	4	824	OP
Gossrau 2022	4	113	OT
Güven 2018	3	339	OP
Hemasian 2022	2	60	OP
Hirsch 1992	4	67	Hypo
Imai 2020	4	62	OP, ODC
Jürgens 2015	4	129	OP
Kandemir 2022	4	60	OP, OT
Karli 2005	4	56	OT, P
Kelman 2006	4	1009	OP, OT
Kutlu 2010	4	190	OT
Li 2024	4	555	OP
Lima 2011	4	96	OP, OT
Lovati 2015	4	673	OP
Mahmud 2022	3	18	OP
Meşe Pekdemir 2023	4	145	OP, ODC
Morillo 2005	4	798	OP
Nagaraj 2022	4	447	OP
Oguz‐Akarsu 2020	3	704	OP
Ozge 2015	4	351	OP
Park 2015	4	70	OP
Rocha‐Filho 2016	4	147	OP, ODC
Sacmaci 2020	4	106	OP
Silva‐Neto 2014	3	80	OP, OT
Silva‐Néto 2017	3	200	OP
Saisu 2011	4	158	OP, OT
Sousa‐Santos 2020	4	39	OP, OT
Spierings 2001	4	38	OT
Sulena 2020	4	1245	OT
Suzuki 2022	4	187	OP
Suzuki 2021	4	76	OP
Suzuki 2023	4	228	OP
Tanik and Bektas 2022	3	164	OP, ODC
Viana 2016	3	30	OP
Vuralli 2016	3	15	OP
Wang 2012	4	1809	OP, ODC
Yalın 2016	4	835	OP
Yaun 2021	2	44	OP
Zanchin 2005	4	569	OP

Abbreviations: Hypo, hposensitivity; ODC, osmophobia direct comparison; OLE, Oxford level of evidence; OP, osmophobia prevalence; OT, odor as a trigger; P, phantosmia.

Critical appraisal of studies indicated an acceptably low risk of bias for all studies included. Potential sources of bias were most pronounced with confounding, missing data, classification of interventions, and selective reporting in the nonrandomized studies (Figure 2). JBI assessment also found a low risk of bias for both case series, cohort, and cross‐sectional studies.

Figure 2.

ROBINS‐I risk of bias assessment.

All studies were considered low risk across all risk bias appraisal tools, and a funnel plot with Egger's test, 1.21 ([95% CI: −1.3, −3.6], p = 0.86) showed that 51 of 58 studies fell inside the funnel plot with little asymmetry, suggesting low publication bias (Figure 3) [71].

Figure 3.

Funnel plot.

3.2. Patient Characteristics

A total of 21,299 patients with migraine was included with a mean age of 37.7 (range: 16–82 [95% CI: 36.0–39.3]); 77.7% were female [95% CI: 74.6–80.5]. Patients had a mean disease duration of 13.3 years [95% CI: 11.5–15.3], the frequency of attacks was 9.6 [95% CI: 5.1–14.1] days per month, and the duration of attacks was 26.0 [95% CI: 19.9–32.2] hours.

3.3. Prevalence of Olfactory Dysfunction

The prevalence of osmophobia among patients with migraine was 47.8% [95% CI: 42.0%–53.6%]. In papers specifically reporting olfactory hypersensitivity during a migraine attack, the prevalence was 40.1% of patients [95% CI: 23.1%–58.5%]. Conversely, 13.2% of patients reported olfactory hyposensitivity or hyposmia [95% CI: 6.8%–21.3%]. Phantosmia was reported by 10.5% of patients [95% CI: 6.9%–15.3%]. Table 2 provides definitions of these conditions.

Table 2.

Definitions of olfactory dysfunction.

Terminology	Definition
Osmophobia	An aversion to odors coinciding with a migraine, or simply a heightened sensitivity to odors during or preceding a migraine [6].
Phantosmia	The perception of odor, usually unpleasant, when there are no odorants present [72].
Hyposmia	Reduction in olfactory function [73].
Anosmia	Complete loss of smell, with no functional olfactory ability [73].
Olfactory triggering	When a smell/odor provokes a migraine episode [7].

Additionally, odor was reported as a trigger of migraine in 40.1% [95% CI: 32.7%–47.8%] of patients. Perfume (65.0%) was the most reported trigger, followed by smoke (36.3%), household cleaners/bleach/chemicals (29.0%), and then food (18.6%). Differences in OD between gender are presented in Table 3.

Table 3.

Gender differences in olfactory disturbance.

	Gender	Proportion (%)	95% CI	% difference (significance)
Osmophobia prevalence	Female	65.7	50.0–79.8	17.6 (p < 0.0001)
	Male	48.1	33.6–62.7
Prevalence of odor as a trigger	Females	51.3	28.7–74.0	18.5 (p < 0.0001)
	Males	32.8	16.8–51.3

Patients who experienced osmophobia were at greater risk of experiencing photophobia, aura, and nausea (OR = 1.45, 1.66, 1.73, respectively, all p < 0.0001). Osmophobia was not correlated with an increased risk of phonophobia (OR = 1.18, p = 0.6).

4. Discussion

This study investigated the prevalence of osmophobia and other forms of OD in migraineurs. There is a global body of literature on migraine and associated symptoms; however, there is little information available regarding the true prevalence and characterization of OD experienced by migraineurs [74]. In this study, osmophobia was reported by nearly half of migraineurs with approximately 40% reporting odor as a trigger of their migraine attacks.

Many patients present to the otolaryngology clinic with symptoms that have overlap between migraine and sinus disease, thus creating difficulty in distinguishing pathologies [75]. A prior study of 2991 patients with either self‐diagnosed or physician‐diagnosed “sinus headache” showed that 88% of the population actually met the ICHD criteria for a diagnosis of migraine [76]. A prior study of 100 patients with self‐diagnosed “sinus headache” demonstrated that despite 56% and 25% of the population reporting nasal congestion and rhinorrhea, respectively, only 3% of the patients had headache secondary to rhinosinusitis [77]. Furthermore, the CHEER network study found that two‐thirds of the patients at the otolaryngology clinic that screened positive for migraine disease were previously undiagnosed [4]. They also noted that 32% of these migraine patients experienced unusual sensitivity to smells. The relationship between symptoms of headache and sinus disease, as well as patient perception of their symptoms, can make it difficult to determine the etiology. Knowledge of the relationship between OD and migraine will be helpful for otolaryngologists when considering a differential for a patient presenting with headache, facial pain, nasal congestion or rhinorrhea, and OD. The presence of osmophobia may guide clinicians toward a migraine diagnosis, as it is uncommon in conditions like CRS, where OD is common and typically presents as hyposmia or anosmia [78]. Therefore, it may prove advantageous for a clinician evaluating a patient with complaints of headache or facial pain to specifically ask about symptoms of osmophobia, as the patient may neglect to mention that symptom among the myriad of other symptoms they are experiencing.

The estimated female to male ratio of migraine is 3:1 worldwide [79]. Consistent with the literature, our migraine population was mostly women. The proportion of females with migraine that experience osmophobia was significantly more than the proportion of males. Female patients also reported odor as a trigger of their migraines more often than male patients. Data from the American Migraine Prevalence and Prevention Study showed that females with migraine were significantly more likely than males to report sensory symptoms such as nausea, photophobia, phonophobia, blurred vision, and visual aura [80]. Our study further validates the finding that females experience sensory symptoms associated with migraine, including osmophobia, more often than males.

To be diagnosed with migraine, in accordance with the current ICHD criteria, a patient must have at least one of the following associated symptoms: nausea/vomiting, photophobia, or phonophobia [2]. Our study found that patients with osmophobia were more likely to experience photophobia, nausea, and aura; however, there was no increased risk of phonophobia. Where photophobia, phonophobia, and nausea often occur during the migraine itself, auras are sensory disturbances that precede the migraine and are thought to be caused by a cascade of ions through the cortex stimulating a local inflammatory reaction [81]. It is apparent that these sensory migraine features are interrelated; osmophobia is one in which the underlying mechanism is not well understood [82, 83]. One theory is that the trigeminovascular thalamic neurons can project to the olfactory cortices and can lead to osmophobia [84]. The mechanisms by which odors may trigger migraine in sensitive individuals remain largely unknown. One proposed pathway involves odor‐induced inhibition of the trigeminal nuclear complex (TNC) in the brainstem, which may permit trigeminal nociceptive signals to access the central pain pathways of the nervous system [74]. Investigating the pathophysiology linking osmophobia to migraines will allow for better understanding of why and how patients experience these symptoms. It may also help direct treatment plans to address not only the symptoms, but the underlying cause.

The strength of this study is our novel investigation into the relationship of osmophobia in migraineurs. There are several limitations that should be considered when reviewing this study. First, some studies had variable definitions of osmophobia, although alluded to the unpleasant perception of an odor during an attack, which was otherwise non‐aversive or even pleasurable outside of the attack. Second, most studies utilized survey questions to determine the presence of osmophobia leading to the possibility of recall bias or patient misinterpretation of the question or their symptoms. Additionally, there is some selection bias within the studies. Certain studies only included patients with specific migraine features such as those with aura versus those without aura, or chronic versus episodic migraine, preventing us from determining the prevalence of osmophobia by subgroup. There was one study that selectively recruited patients with osmophobia for comparison to patients without osmophobia [15]. This study was not included in the overall study meta‐analysis for osmophobia prevalence, age, or demographic data; however, it was included in the odds ratio calculations along with the studies that stratified data on associated sensory symptoms between patients with and without osmophobia. No studies distinguished whether there was overlap between the group of patients reporting osmophobia and those reporting odor as a trigger; therefore, no conclusions could be made regarding the relationship between them. Finally, there is a lack of objective OD in the patient populations as only three studies provided smell testing scores, none of which were the same quantitative measures of olfactory perception and therefore could not be compared. Future studies should collect objective measures of the frequency and severity of osmophobia and other OD in migraine patients.

5. Conclusion

Our findings suggest that nearly half of migraine patients experience osmophobia, while odor acts as a migraine trigger in over a third of migraineurs. OD is an integral aspect of migraine, yet it remains poorly understood and requires further investigation.

Author Contributions

All authors were involved in project formation, data analysis, and manuscript preparation.

Ethics Statement

IRB approval was not required for this study as it was an analysis of publicly available, published data. The requirement for informed consent was not applicable as this was not a study of individual patients.

Conflicts of Interest

Shaun A. Nguyen is a member of World Journal of Otorhinolaryngology – Head and Neck Surgery (WJOHNS) editorial board and is not involved in the peer review process of this article. Zachary M. Soler: OptiNose (consultant), Sinusonic (consultant), Regeneron (consultant), Sanofi (consultant). Rodney J. Schlosser: OptiNose (consultant), Sinusonic (consultant), Medtronic (consultant), Stryker (consultant).

Supporting information

S1. Final Search Strategy. S2. ROBINS‐I Risk of Bias Assessment. S3. ROB‐2 Risk of Bias Assessment. S4. JBI Cohort Risk of Bias Assessment. S5. JBI Case Control Risk of Bias Assessment. S6. JBI Case Series Risk of Bias Assessment.

Data Availability Statement

Data can be accessed upon reasonable request to the corresponding author.