Olfactory abnormalities in patients with migraine: a narrative review of a symptom commonly overlooked by neurologists

Nausea, vomiting, photophobia, and phonophobia are common concomitant symptoms in patients with migraine and provide valuable information for headache specialists during consultations. Clinical observations have identified various olfactory abnormalities in patients with migraine, such as osmophobia, olfactory hallucinations, hyperosmia and hyposmia, which are often overlooked by neurologists. These olfactory abnormalities may interact with the trigeminal vascular system, parasympathetic nervous system, and cortical spreading depression. This review aimed to examine the mechanisms underlying olfactory abnormalities in patients with migraine and the clinical correlations between these abnormalities and migraine. Additionally, olfactory training is highlighted as a promising non-pharmacological treatment for migraine.

Migraine; Osmophobia; Olfactory hallucinations; Hyperosmia; Hyposmia; Anosmia

[1] Han SA, Kim JK, Cho DY, Patel ZM, Rhee CS. The olfactory system: basic anatomy and physiology for general otorhinolaryngologists. Clinical and Experimental Otorhinolaryngology. 2023; 16: 308–316.

[2] Fatuzzo I, Niccolini GF, Zoccali F, Cavalcanti L, Bellizzi MG, Riccardi G, et al. Neurons, nose, and neurodegenerative diseases: olfactory function and cognitive impairment. International Journal of Molecular Sciences. 2023; 24: 2117.

[3] Hummel T, Liu DT, Müller CA, Stuck BA, Welge-Lüssen A, Hähner A. Olfactory dysfunction: etiology, diagnosis, and treatment. Deutsches Ärzteblatt International. 2023; 120: 146–154.

[4] Hernandez AK, Landis BN, Altundag A, Fjaeldstad AW, Gane S, Holbrook EH, et al. Olfactory nomenclature: an orchestrated effort to clarify terms and definitions of dysosmia, anosmia, hyposmia, normosmia, hyperosmia, olfactory intolerance, parosmia, and phantosmia/olfactory hallucination. ORL. 2023; 85: 312–320.

[5] Gupta J, Gaurkar SS. Migraine: an underestimated neurological condition affecting billions. Cureus. 2022; 14: e28347.

[6] Fornazieri MA, Neto AR, de Rezende Pinna F, Gobbi Porto FH, de Lima Navarro P, Voegels RL, et al. Olfactory symptoms reported by migraineurs with and without auras. Headache. 2016; 56: 1608–1616.

[7] Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. The Lancet. Neurology. 2019; 18: 795–804.

[8] Coleman ER, Grosberg BM, Robbins MS. Olfactory hallucinations in primary headache disorders: case series and literature review. Cephalalgia. 2011; 31: 1477–1489.

[9] Stankewitz A, May A. Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology. 2011; 77: 476–482.

[10] Frimpong-Manson K, Ortiz YT, McMahon LR, Wilkerson JL. Advances in understanding migraine pathophysiology: a bench to bedside review of research insights and therapeutics. Frontiers in Molecular Neuroscience. 2024; 17: 1355281.

[11] Imai N, Osanai A, Moriya A, Katsuki M, Kitamura E. Classification of odors associated with migraine attacks: a cross-sectional study. Scientific Reports. 2023; 13: 8469.

[12] Nassini R, Materazzi S, Vriens J, Prenen J, Benemei S, De Siena G, et al. The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain. 2012; 135: 376–390.

[13] Kunkler PE, Ballard CJ, Oxford GS, Hurley JH. TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. Pain. 2011; 152: 38–44.

[14] Zhang L, Kunkler PE, Knopp KL, Oxford GS, Hurley JH. Role of intraganglionic transmission in the trigeminovascular pathway. Molecular Pain. 2019; 15: 1744806919836570.

[15] Kunkler PE, Zhang L, Johnson PL, Oxford GS, Hurley JH. Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure. Pain. 2018; 159: 540–549.

[16] Kunkler PE, Zhang L, Pellman JJ, Oxford GS, Hurley JH. Sensitization of the trigeminovascular system following environmental irritant exposure. Cephalalgia. 2015; 35: 1192–1201.

[17] Genovese F, Bauersachs HG, Gräßer I, Kupke J, Magin L, Daiber P, et al. Possible role of calcitonin gene-related peptide in trigeminal modulation of glomerular microcircuits of the rodent olfactory bulb. The European Journal of Neuroscience. 2017; 45: 587–600.

[18] Daiber P, Genovese F, Schriever VA, Hummel T, Möhrlen F, Frings S. Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction. European Journal of Neuroscience. 2012; 37: 572–582.

[19] Benemei S, Eleonora R, Geppetti P. Trigeminal nerve and phantosmia in primary headaches. Cephalalgia. 2012; 32: 85.

[20] Burstein R, Jakubowski M. Unitary hypothesis for multiple triggers of the pain and strain of migraine. The Journal of Comparative Neurology. 2005; 493: 9–14.

[21] Lo Cascio S, Correnti E, D’Agostino S, Capizzi M, Marino A, Meli R, et al. Cranial autonomic symptoms and migraine: what relationship and what meaning? A review. Journal of Integrative Neuroscience. 2022; 21: 166.

[22] Demarquay G, Royet JP, Mick G, Ryvlin P. Olfactory hypersensitivity in migraineurs: a H215O-PET study. Cephalalgia. 2008; 28: 1069–1080.

[23] Demarquay G, Lothe A, Royet JP, Costes N, Mick G, Mauguière F, et al. Brainstem changes in 5-HT1A receptor availability during migraine attack. Cephalalgia. 2011; 31: 84–94.

[24] Silva-Néto RP, Peres MFP, Valença MM. Odorant substances that trigger headaches in migraine patients. Cephalalgia. 2013; 34: 14–21.

[25] Gossrau G, Frost M, Klimova A, Koch T, Sabatowski R, Mignot C, et al. Interictal osmophobia is associated with longer migraine disease duration. The Journal of Headache and Pain. 2022; 23: 81.

[26] Albanês Oliveira Bernardo A, Lys Medeiros F, Sampaio Rocha‐Filho PA. Osmophobia and odor‐triggered headaches in children and adolescents: prevalence, associated factors, and importance in the diagnosis of migraine. Headache. 2020; 60: 954–966.

[27] Kelman L. Osmophobia and taste abnormality in migraineurs: a tertiary care study. Headache. 2004; 44: 1019–1023.

[28] Sjöstrand C, Savic I, Laudon-Meyer E, Hillert L, Lodin K, Waldenlind E. Migraine and olfactory stimuli. Current Pain and Headache Reports. 2010; 14: 244–251.

[29] Zanchin G, Dainese F, Mainardi F, Mampreso E, Perin C, Maggioni F. Osmophobia in primary headaches. The Journal of Headache and Pain. 2005; 6: 213–215.

[30] Çiçekli E, Ozturk Mungan S, Orhan G. Evaluating the frequency of osmophobia in tension-type headache: a comparative study on migraine. Cureus. 2024; 16: e66558.

[31] Paparella G, Clemente L, Scannicchio S, Delussi M, De Tommaso M. Sex Differences in the expression of central sensitization symptoms in migraine: an observational study. Journal of Women’s Health. 2024; 33: 1656–1664.

[32] Zanchin G, Dainese F, Trucco M, Mainardi F, Mampreso E, Maggioni F. Osmophobia in migraine and tension-type headache and its clinical features in patients with migraine. Cephalalgia. 2007; 27: 1061–1068.

[33] Sousa-Santos PM, Moura CGF, Fontenele JL, Lima NC, Santos RA, Silva-Néto RP. Headache and osmophobia in gas station workers exposed to gasoline odor. European Neurology. 2020; 83: 259–262.

[34] Terrin A, Mainardi F, Lisotto C, Mampreso E, Fuccaro M, Maggioni F, et al. A prospective study on osmophobia in migraine versus tension-type headache in a large series of attacks. Cephalalgia. 2020; 40: 337–346.

[35] Imai N, Matsumori Y. Different effects of migraine associated features on headache impact, pain intensity, and psychiatric conditions in patients with migraine. Scientific Reports. 2024; 14: 22611.

[36] De Carlo D, Toldo I, Dal Zotto L, Perissinotto E, Sartori S, Gatta M, et al. Osmophobia as an early marker of migraine: a follow-up study in juvenile patients. Cephalalgia. 2012; 32: 401–406.

[37] Sampaio Rocha-Filho PA, Gherpelli JLD. Premonitory and accompanying symptoms in childhood migraine. Current Pain and Headache Reports. 2022; 26: 151–163.

[38] Meşe Pekdemir E, Tanik N. Clinical significance of osmophobia and its effect on quality of life in people with migraine. Acta Neurologica Belgica. 2022; 123: 1747–1755.

[39] Sciruicchio V, D’Agnano D, Clemente L, Rutigliano A, Laporta A, de Tommaso M. Clinical correlates of osmophobia in primary headaches: an observational study in child cohorts. Journal of Clinical Medicine. 2023; 12: 2939.

[40] Park SP, Seo JG, Lee WK. Osmophobia and allodynia are critical factors for suicidality in patients with migraine. The Journal of Headache and Pain. 2015; 16: 529.

[41] Ahmed MA, Donaldson S, Akor F, Cahill D, Akilani R. Olfactory hallucination in childhood primary headaches: case series. Cephalalgia. 2014; 35: 234–239.

[42] Kelman L. The aura: a tertiary care study of 952 migraine patients. Cephalalgia. 2004; 24: 728–734.

[43] Tiriticco M, Vanotti A, Mantica D, Coppola A. Migraine with exclusive olfactory aura: case report and literature review. Headache. 2020; 60: 2544–2547.

[44] Partovi O, Tolebeyan AS. Various presentations of the olfactory hallucination in two patients with migraine disease: case report. Frontiers in Neurology. 2022; 13: 992763.

[45] Demarquay G, Royet JP, Giraud P, Chazot G, Valade D, Ryvlin P. Rating of olfactory judgements in migraine patients. Cephalalgia. 2006; 26: 1123–1130.

[46] Kayabaşoglu G, Altundag A, Kotan D, Dizdar D, Kaymaz R. Osmophobia and olfactory functions in patients with migraine. European Archives of Oto-Rhino-Laryngology. 2016; 274: 817–821.

[47] Kandemir S, Pamuk AE, Habipoğlu Y, Özel G, Bayar Muluk N, Kılıç R. Olfactory acuity based on brief smell identification test (BSIT®) in migraine patients with and without aura: a cross-sectional, controlled study. Auris, Nasus, Larynx. 2022; 49: 613–617.

[48] Efendioğlu MK, Orhan EK, Şen C, Sönmez S, Orhan KS, Baykan B. Olfactory function assessment of migraine patients by using the Sniffin’ sticks test: a clinical study. American Journal of Otolaryngology. 2024; 45: 104076.

[49] Marmura MJ, Monteith TS, Anjum W, Doty RL, Hegarty SE, Keith SW. Olfactory function in migraine both during and between attacks. Cephalalgia. 2014; 34: 977–985.

[50] Grosser K, Oelkers R, Hummel T, Geisslinger G, Brune K, Kobal G, et al. Olfactory and trigeminal event-related potentials in migraine. Cephalalgia. 2000; 20: 621–631.

[51] Doğan A, Bayar Muluk N, Şahan MH, Asal N, Inal M, Ergün U. Olfactory bulbus volume and olfactory sulcus depth in migraine patients: an MRI evaluation. European Archives of Oto-Rhino-Laryngology. 2018; 275: 2005–2011.

[52] Hirsch AR. Olfaction in migraineurs. Headache. 1992; 32: 233–236.

[53] Snyder RD, Drummond PD. Olfaction in migraine. Cephalalgia. 1997; 17: 729–732.

[54] Pieniak M, Höfer B, Knipping J, Faria V, Richter M, Schriever VA, et al. Children and adolescents with primary headaches exhibit altered sensory profiles—a multi-modal investigation. The Journal of Headache and Pain. 2024; 25: 111.

[55] Pieniak M, Oleszkiewicz A, Avaro V, Calegari F, Hummel T. Olfactory training—thirteen years of research reviewed. Neuroscience & Biobehavioral Reviews. 2022; 141: 104853.

[56] Faria V, Dulheuer J, Joshi A, Wahl H, Klimova A, Haehner A, et al. Impact of a 12-week olfactory training programme in women with migraine with aura: protocol for a double-blind, randomised, placebo-controlled trial. BMJ Open. 2023; 13: e071443.

[57] Gossrau G, Zaranek L, Klimova A, Sabatowski R, Koch T, Richter M, et al. Olfactory training reduces pain sensitivity in children and adolescents with primary headaches. Frontiers in Pain Research. 2023; 4: 1091984.

[58] Birte-Antina W, Ilona C, Antje H, Thomas H. Olfactory training with older people. International Journal of Geriatric Psychiatry. 2017; 33: 212–220.

[59] Gossrau G, Baum D, Koch T, Sabatowski R, Hummel T, Haehner A. Exposure to odors increases pain threshold in chronic low back pain patients. Pain Medicine. 2020; 21: 2546–2551.