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Pathophysiology and Therapy of Associated Features of Migraine
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Migraine is a complex and debilitating disorder that is broadly recognised by its characteristic headache. The associated symptoms to migraine, apart from the painful component, are frequent, under-recognised and can be more deleterious than the headache itself. The clinical anamnesis of a headache patient should enquire about the associated symptoms, and treatment should be considered and individualised.

migraine pathophysiology nausea osmophobia phonophobia vertigo allodynia
Subjects: Neurosciences
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Update Date: 25 Sep 2022
Table of Contents

    1. Introduction

    Migraine has been traditionally associated with the core symptom, headache [1]. Photophobia and vomiting, two of the canonical symptoms associated with migraine [2], are also widely accepted features of the typical migraine attack, as understood classically by patients and physicians [3]. However, reducing the understanding of migraine to a few symptoms would be as simplistic, perhaps, as reducing Parkinson’s disease to tremors.
    The way that migraineurs deal with their attacks provides valuable information about hypersensitivity to sensorial stimulation, including avoiding movement, light, sounds, touch or smells [4]. These are usually subjective, unpleasant experiences, unshared by family, friends or colleagues. Consequently, migraine patients presenting associated symptoms as prominent features can usually be labelled as sensitive. The Greek translation for sensitive, Ευαίσθητος “evahistos”, can be separated into the following two parts: the prefix meaning good or well, and the rest meaning sense or perception. However, any positive connotation of the term has nowadays dissipated. Many of these “evahistic” manifestations can actually be the main symptom of the clinical picture in a patient with migraine, and imply a higher disability [5]. Migraine patients with sensory hypersensitivity may have more attention difficulties during daily activities [6], or more cranial autonomic symptoms associated to the headache [7], and the response to preventive treatments may vary [8]. Exogenous factors, such as stress, obesity, intestinal microbiota and even parental behaviour, have been speculated to play a role in the chronification and sensitization process [9][10][11][12].

    2. Nausea and Vomiting

    2.1. Nausea in Migraine and Conditions Related to Migraine

    Nausea is one of the symptoms associated with migraine that is considered canonical, according to the International Classification of Headache Disorders, 3rd Edition (ICHD-3) [2]. Ictal and interictal nausea has a high impact on quality of life and economic cost [13][14], and is the second most bothersome migraine symptom, reported in 28% of patients, exceeded only by photophobia [15].
    Up to half of the people with episodic migraine suffer from nausea in more than half of their headache episodes, and the attacks were accompanied by more headache symptoms and a higher impact, compared to patients with less frequency of nausea. The majority of those reporting high-frequency nausea were women [16] and had an increased risk of developing chronic migraine in 2 years [17].
    Having migrainous biology could result in patients having more disability when presenting with other disorders that are generally associated with nausea and vomiting.

    2.2. Neuroanatomy and Neuropharmacology

    There is a matrix of neuro-anatomical structures involved in the onset and control of nausea, as well as several neurotransmitters that have been the main targets of antiemetic and acute treatment schemes.
    Dopamine has been the main compound implicated in the pathophysiology of nausea associated with migraine, at least since the 1970s [18]. Patients with migraine are sensitive to dopaminergic pharmacological agents [19][20][21] and develop nausea and other classically considered dopaminergic symptoms, such as yawning, not necessarily accompanied by headache [19][21]. This propensity may entail a genetic predisposition, and a particular allelic distribution was found to be significantly different for the D2 dopamine receptor in a subpopulation of migraineurs with prominent dopaminergic symptoms [22]. Among the dopaminergic symptoms, nausea, unlike yawning, is considered post-synaptic, and is triggered by apomorphine and inhibited by domperidone, which targets D2 receptors [21]. Dopamine may also regulate headache pain, as dopaminergic neurons play a role in nociceptive control by modulating trigemino-vascular neurons [23].
    Serotonin also has a major role in nausea, with the receptor 5-hydroxytryptamine- 5-HT3 as the main target not only of modern antiemetic pharmacological compounds, but also of natural antiemetics used for centuries, such as the gingerol compounds contained in ginger [24].
    Hyporexia during headaches may be explained by the loss of appetite that can be observed during noxious dural stimulation, which activates the nucleus parabrachial and the ventromedial of the hypothalamus, and may be mediated by cholecystokinin [25]. However, nausea can also appear before the headache, during the premonitory phase, in almost a quarter of spontaneous attacks [26]. This percentage was doubled when headache attacks were triggered in a controlled environment [27].
    Another intriguing component in migrainous nausea is substance P. Neurokinin 1 (NK-1) receptor antagonists can inhibit vomit produced by central or peripheral stimuli [28], and its central action may be mediated by inhibiting the substance P emetic effect [29], which may take place predominantly in the locus coeruleus [30].
    Early pre-clinical experiments are good examples of the extent of anatomical structures that could be involved in the process of vomiting. Monkeys presented vomiting following the electrical stimulation of the olfactory tubercle, amygdala, septum, fornix and the thalamic ventral anterior nucleus [31]. In cats, lesions in the medulla abolished the characteristic pattern of respiratory motor nerve discharge, observed in vomiting [32], induced by emetic drugs and electrical vagal stimulation of abdominal afferents. This study suggested that the regions that control vomiting were localised between the obex and the retrofacial nucleus [33], both localized in the medulla.
    In human neuroimaging studies, some brainstem areas showed significant activation with a H215O positron emission tomography (PET) scan in the premonitory phase of migraine participants with nausea, including the periaqueductal grey, dorsal motor nucleus of the vagus, nucleus ambiguous and nucleus tractus solitarius [34], as shown in the following paragraphs. Following a rostral-caudal approach, among them, the mesencephalic periaqueductal grey (PAG) deserves a special mention [34].
    PAG has an important role in the descending modulation of the trigeminovascular processes [35]. PAG has been related to other autonomic sympathetic activity [36][37], emotional perception of pain and aversive behaviours [38][39] cough [40] and breathing control [41]. It is involved in modulating the descending pain pathways [42][43][44]. This modulation has recently been shown to be activated by mu opioids by means of presynaptic disinhibition and reducing GABAergic postsynaptic currents [45]. It is yet unknown whether this area is related to the chronification observed in migraineurs with frequent use of opioids, as commented on below.
    More caudal areas in the rostral dorsal medulla were involved, including the dorsal motor nucleus of the vagus [34], which may relax the lower esophageal sphincter [46].
    The nucleus tractus solitarius has connections with hypothalamic areas that play a role in autonomic control [47]. Both the nucleus tractus solitarius and dorsal motor nucleus of the vagus conform, along with the area postrema, the dorsal vagal complex, which is one of the main termination sites of the afferent fibres of the vagal nerve [48] and has a high distribution of dopamine D2–4 receptors [49]. The area postrema is one of the sensory circumventricular organs with a possible chemoreceptive function, situated outside the blood–brain barrier and connected to the hypothalamus, which is thought to be essential in controlling neuroendocrine functions [50], is rich in type D2 dopamine receptors [51] and is the brain area with the higher estimates of substance P [52].

    2.3. Treatment of Nausea

    The treatment of nausea during migraine attacks must be considered in every patient presenting with that symptom. When nausea does not respond to analgesic treatment, specific antiemetic treatment should focus on the pathways of the neurotransmitters described above (dopamine, serotonin, substance P) as main targets for treatment. Nevertheless, acute treatment can be essential in the management of nausea associated with migraine. NSAIDs could be effective in alleviating nausea in patients who have not taken any triptans [53] and there is a recent meta-analysis that supports gepants as an effective treatment for nausea in patients with episodic migraine [54]. Special attention must be paid to patients consuming opioids. Nausea is a recognised side effect following opioid use [55]. Patients with episodic migraines who are exposed to opioids have a twofold risk of migraine chronification [56], a likely reduction in the efficacy of triptans for acute treatment [57] and the issue of developing gastro-intestinal adverse events after long-term consumption [58].

    3. Osmophobia

    The perception of odour is certainly an extremely subjective experience, or we would all be wearing the same perfume. Being perhaps the less studied of the senses, the mechanisms behind the way a fragrance is perceived is not yet fully understood. A brief mention here is appropriate for two interesting theories that were proposed in the twentieth century, involving a lock-and-key system and vibrational wavelengths [59], which have not yet been fully developed.
    There are several substances whose consumption or inhalation has been popularly related to headaches [60][61][62][63]. Remarkably, Umbellularia californica is a type of tree, commonly known as “the headache tree” [64], which contains umbellulone, a ketone that was reported of being capable of triggering cluster headache-like attacks in a gardener with a history of cluster headaches [65]. It was later discovered that this mechanism was mediated by the activation of the transient receptor potential (TRP) ankyrin 1 (TRPA1) [66][67], followed by the release of calcitonin gene-related peptide (CGRP) [66]. CGRP is also released through the activation of vanilloid receptors, following stimulation with nitric oxide [68] or ethanol [69][70], one of the most relevant cluster headache triggers. TRPA1 has also been involved in the responses to some inhaled chemicals, including the smoke of cigarettes [71], chloride [72][73] hydrogen peroxide-containing substances [73] or formalin, the noxious compound largely used in pain models [74].
    It has been reported that up to 70% of migraineurs can develop a headache after the stimulation with some odorants, which happened around 25 minutes following the exposure [75], and there is a case report of migraine improvement following the imposition of mandatory masks in the workplace during the COVID-19 pandemic [76]. Increased sensitivity to smells can be part of the premonitory-like symptoms experienced by migraineurs; therefore, certain smells may be misinterpreted as the trigger for a migraine attack, which might not be a necessary factor for its occurrence [77][78]. As a consequence, the results of studies that assess migraine triggers have debatable interpretations.
    Nevertheless, the presence of osmophobia may be related to more florid migraine phenotypes and greater disability, and a scale has been developed recently for the quantification of quality of life related to osmophobia [79]. Migraineurs that present with ictal osmophobia may have more painful headaches [80][81]. Ictal and interictal osmophobia have been associated with a longer history of migraines or high frequency of the attacks, as well as other associated symptoms, such as cranial allodynia [82][83][84], suggesting a central sensitization process [85]. Vomiting can also be more common in the presence of osmophobia [81][83]. Osmophobic migraineurs may also have a higher prevalence of psychiatric comorbidities than those without it [80][86][87][88].
    Osmophobia has been proposed as a specific marker, helpful for the diagnosis of migraine [81][86][89][90][91][92][93][94]; however, it is not very sensitive [84]. Around half of the patients with migraines reported an increased sense of smell or reduced tolerability to smells [91][95]. Remarkable examples of patients reporting hyperosmia include the smell of a rose from more than 5 meters of distance, or soap from a different room, and the main scents triggers for osmophobia arose from food, specifically fried food and onions, cigarettes or self-care products, and perfume or paint specifically were reported as triggers [95]. More recently, forty percent of patients with chronic migraine reported osmophobia [96], and a similar number suggested odours or perfumes as potential triggers of a migraine attack [63].
    Paradoxically, despite their hypersensitivity to smells, migraineurs have a lower capability for the threshold, identification and discrimination of smells [97][98]. Patients with episodic migraine were found to have a similar olfactory acuity to controls, and furthermore, around one fifth of them developed hyposmia during the attack [99]. Taste abnormalities in migraineurs [95] are a matter of debate [100].
    Patients with migraine and osmophobia have neuroanatomical alterations. A significantly reduced volume of the olfactory bulb was observed in 1.5 Tesla MRI, compared to patients with other types of headache [101], and might be more pronounced on the left, in comparison with controls [102]. In migraineurs with reported hypersensitivity to odours, regional blood flow in a study using H215O-positron emission tomography was found to be increased in areas of the left piriform cortex and antero-superior temporal gyrus, as compared to controls, both with and without multiple odour stimuli [103]. During odour stimulation, blood flow was found to be decreased in bilateral fronto-temporo-parietal regions, as well as the posterior cingulate gyrus and right locus coeruleus [103]. Another study using fMRI to compare responses to the smell of roses found higher blood oxygen level-dependent activity in the amygdala and insular cortices of the amygdala and also in the midbrain, particularly the rostral pons. However, the smell of roses did not show significant interictal differences compared to the controls [104]. Activation of the amygdala and orbitofrontal cortex might be related, respectively, with the intensity and valence of the smell emotional experience [105]. The amygdala and cingulate cortex also showed abnormal activation in patients with multiple chemical sensitivity [106][107], which is associated with a high prevalence of headache [108] and was observed in up to 20% of migraineurs [109].
    Olfactory hallucinations or phantosmia is a hallmark of temporal lobe epilepsy, and currently a no man’s land when it presents in the form of aura. It is a rare symptom, with a reported prevalence of 0.66% in a headache center [110]. The majority of reported cases had normal electroencephalograms that were, however, taken during the interictal period, and usually respond to antiepileptic drugs.
    The reported cases showed that the episodes have an average duration of less than 10 min and the onset occurs prior to the migraine attack [110][111]. Patients with symptoms of phantosmia scanned with FLASH and eco-planar imaging MRI techniques showed increased activation of different brain areas associated with the process of the sense of smell, such as the prefrontal, cingulate, temporal or insular cortex MRI activation was inhibited by typical antipsychotics that perform its activity through a wide range of binding receptors [112]. Peripheral blocking activities can alleviate phantosmia [113].

    4. Neuro-Otological Manifestations

    In 1984, Kayan and Hood described how vestibulocochlear symptoms were frequently reported, in up to 60% of patients with migraine, and these can be important or disabling enough for the patient to be the primary reason for referral to a specialist. The incidence of neuro-otological symptoms for migraineurs seemed homogeneous throughout all ages in males, but had a peculiar distribution in females. For women who reported audiovestibular symptoms only when asked during the study, a positive skew distribution could be observed, with the peak situated in the 3rd decade. However, the female patients whose reason of referral was the presence of disabling audio-vestibular symptoms had a peak in the peri-menopausal 5th and 6th decades. This group with disabling symptoms had a higher incidence in males [114]. They compared 80 patients referred for vestibulocochlear symptoms with 500 patients with multiple sclerosis for benign positional vertigo and Méniere’s [114]. Only migraineurs described cochlear sensations, such as tinnitus, distortion of pitch, or hearing loss [114].
    The frequency of migraine in Méniere’s disease is higher than in normal subjects, and phonophobia has a high prevalence in these patients, independently of the presence of migraine headache [115].


    1. Willis, T.; Pordage, S. Two Discourses Concerning the Soul of Brutes, Which Is That of the Vital and Sensitive of Man: The First Is Physiological, Shewing the Nature, Parts, Powers, and Affections of the Same; and the Other Is Pathological, Which Unfolds the Diseases which Affect It and Its Primary Seat, to Wit, the Brain and Nervous Stock, and Treats of Their Cures: With Copper Cuts; Thomas Dring, Ch. Harper and John Leigh: London, UK, 1683.
    2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018, 38, 1–211.
    3. Gowers, W.R. A Manual of Diseases of the Nervous System, 3rd ed.; P. Blakiston, Son & Co.: Philadelphia, PA, USA, 1899; p. 1357.
    4. Goadsby, P.; Holland, P.; Martins-Oliveira, M.; Hoffmann, J.; Schankin, C.; Akerman, S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol. Rev. 2017, 97, 553–622.
    5. Suzuki, K.; Suzuki, S.; Shiina, T.; Okamura, M.; Haruyama, Y.; Tatsumoto, M.; Hirata, K. Investigating the relationships between the burden of multiple sensory hypersensitivity symptoms and headache-related disability in patents with migraine. J. Headache Pain 2021, 22, 77.
    6. Lévêque, Y.; Masson, R.; Fornoni, L.; Moulin, A.; Bidet-Caulet, A.; Caclin, A.; Demarquay, G. Self-perceived attention difficulties are associated with sensory hypersensitivity in migraine. Rev. Neurol. 2020, 176, 829–838.
    7. Danno, D.; Wolf, J.; Ishizaki, K.; Kikui, S.; Hirata, K.; Takeshima, T. Cranial autonomic symptoms in migraine are related to central sensitization: A prospective study of 164 migraine patients at a tertiary headache center. BMC Neurol. 2022, 22, 89.
    8. Pan, L.-L.H.; Wang, Y.-F.; Ling, Y.-H.; Lai, K.-L.; Chen, S.-P.; Chen, W.-T.; Treede, R.-D.; Wang, S.-J. Pain sensitivities predict prophylactic treatment outcomes of flunarizine in chronic migraine patients: A prospective study. Cephalalgia 2022, 11, 899–909.
    9. Stubberud, A.; Buse, D.C.; Kristoffersen, E.S.; Linde, M.; Tronvik, E. Is there a causal relationship between stress and migraine? Current evidence and implications for management. J. Headache Pain 2021, 22, 155.
    10. Westgate, C.S.J.; Israelsen, I.M.E.; Jensen, R.H.; Eftekhari, S. Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension. J. Headache Pain 2021, 22, 123.
    11. Kang, L.; Tang, W.; Zhang, Y.; Zhang, M.; Liu, J.; Li, Y.; Kong, S.; Zhao, D.; Yu, S. The gut microbiome modulates nitroglycerin-induced migraine-related hyperalgesia in mice. Cephalalgia 2022, 42, 490–499.
    12. Raibin, K.; Markus, T.E. Cutaneous allodynia in pediatric and adolescent patients and their mothers: A comparative study. Cephalalgia 2022, 42, 579–589.
    13. Lipton, R.B.; Buse, D.C.; Saiers, J.; Serrano, D.; Reed, M.L. Healthcare resource utilization and direct costs associated with frequent nausea in episodic migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study. J. Med. Econ. 2013, 16, 490–499.
    14. Gajria, K.; Lee, L.K.; Flores, N.M.; Aycardi, E.; Gandhi, S.K. Humanistic and economic burden of nausea and vomiting among migraine sufferers. J. Pain Res. 2017, 10, 689–698.
    15. Munjal, S.; Singh, P.; Reed, M.L.; Fanning, K.; Schwedt, T.J.; Dodick, D.W.; Buse, D.C.; Lipton, R.B. Most Bothersome Symptom in Persons with Migraine: Results from the Migraine in America Symptoms and Treatment (MAST) Study. Headache 2020, 60, 416–429.
    16. Lipton, R.B.; Buse, D.C.; Saiers, J.; Fanning, K.M.; Serrano, D.; Reed, M.L. Frequency and burden of headache-related nausea: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2013, 53, 93–103.
    17. Reed, M.L.; Fanning, K.M.; Serrano, D.; Buse, D.C.; Lipton, R.B. Persistent frequent nausea is associated with progression to chronic migraine: AMPP study results. Headache 2015, 55, 76–87.
    18. Sicuteri, F. Dopamine, the second putative protagonist in headache. Headache 1977, 17, 129–131.
    19. Bes, A.; Dupui, P.; Guell, A.; Bessoles, G.; Geraud, G. Pharmacological exploration of dopamine hypersensitivity in migraine patients. Int. J. Clin. Pharmacol. Res. 1986, 6, 189–192.
    20. Calabresi, P.; Silvestrini, M.; Stratta, F.; Cupini, L.M.; Argiro, G.; Atzei, G.P.; Bernardi, G. l-deprenyl test in migraine: Neuroendocrinological aspects. Cephalalgia 1993, 13, 406–409.
    21. Cerbo, R.; Barbanti, P.; Buzzi, M.G.; Fabbrini, G.; Brusa, L.; Roberti, C.; Zanette, E.; Lenzi, G.L. Dopamine hypersensitivity in migraine: Role of the apomorphine test. Clin. Neuropharmacol. 1997, 20, 36–41.
    22. Del Zompo, M.; Cherchi, A.; Palmas, M.A.; Ponti, M.; Bocchetta, A.; Gessa, G.L.; Piccardi, M.P. Association between dopamine receptor genes and migraine without aura in a Sardinian sample. Neurology 1998, 51, 781–786.
    23. Charbit, A.R.; Akerman, S.; Goadsby, P.J. Dopamine: What’s new in migraine? Curr. Opin. Neurol. 2010, 23, 275–281.
    24. Walstab, J.; Krüger, D.; Stark, T.; Hofmann, T.; Demir, I.E.; Ceyhan, G.O.; Feistel, B.; Schemann, M.; Niesler, B. Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons. Neurogastroenterol. Motil. 2013, 25, 439–447, e302.
    25. Malick, A.; Jakubowski, M.; Elmquist, J.K.; Saper, C.B.; Burstein, R. A neurohistochemical blueprint for pain-induced loss of appetite. Proc. Natl. Acad. Sci. USA 2001, 98, 9930–9935.
    26. Giffin, N.; Ruggiero, L.; Lipton, R.; Silberstein, S.; Tvedskov, J.F.; Olesen, J.; Altman, J.; Goadsby, P.; Macrae, A. Premonitory symptoms in migraine: An electronic diary study. Neurology 2003, 60, 935–940.
    27. Karsan, N.; Bose, P.R.; Thompson, C.; Newman, J.; Goadsby, P.J. Headache and non-headache symptoms provoked by nitroglycerin in migraineurs: A human pharmacological triggering study. Cephalalgia 2020, 40, 828–841.
    28. Watson, J.; Gonsalves, S.; Fossa, A.; McLean, S.; Seeger, T.; Obach, S.; Andrews, P. The anti-emetic effects of CP-99,994 in the ferret and the dog: Role of the NK1 receptor. Br. J. Pharmacol. 1995, 115, 84–94.
    29. Saria, A. The tachykinin NK1 receptor in the brain: Pharmacology and putative functions. Eur. J. Pharmacol. 1999, 375, 51–60.
    30. McLean, S.; Ganong, A.H.; Seeger, T.F.; Bryce, D.K.; Pratt, K.G.; Reynolds, L.S.; Siok, C.J.; Lowe, J.A.; Heym, J. Activity and distribution of binding sites in brain of a nonpeptide substance P (NK1) receptor antagonist. Science 1991, 251, 437–439.
    31. Robinson, B.W.; Mishkin, M. Alimentary responses to forebrain stimulation in monkeys. Exp. Brain Res. 1968, 4, 330–366.
    32. Grélot, L.; Milano, S.; Portillo, F.; Miller, A.D.; Bianchi, A.L. Membrane potential changes of phrenic motoneurons during fictive vomiting, coughing, and swallowing in the decerebrate cat. J. Neurophysiol. 1992, 68, 2110–2119.
    33. Miller, A.D.; Nonaka, S.; Jakus, J. Brain areas essential or non-essential for emesis. Brain Res. 1994, 647, 255–264.
    34. Maniyar, F.H.; Sprenger, T.; Schankin, C.; Goadsby, P.J. The origin of nausea in migraine-a PET study. J. Headache Pain 2014, 15, 84.
    35. Goadsby, P.J.; Holland, P.R. An Update: Pathophysiology of Migraine. Neurol. Clin. 2019, 37, 651–671.
    36. Pereira, E.A.; Lu, G.; Wang, S.; Schweder, P.M.; Hyam, J.A.; Stein, J.F.; Paterson, D.J.; Aziz, T.Z.; Green, A.L. Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain. Exp. Neurol. 2010, 223, 574–581.
    37. Green, A.L.; Hyam, J.A.; Williams, C.; Wang, S.; Shlugman, D.; Stein, J.F.; Paterson, D.J.; Aziz, T.Z. Intra-operative deep brain stimulation of the periaqueductal grey matter modulates blood pressure and heart rate variability in humans. Neuromodulation 2010, 13, 174–181.
    38. Luo, H.; Huang, Y.; Green, A.L.; Aziz, T.Z.; Xiao, X.; Wang, S. Neurophysiological characteristics in the periventricular/periaqueductal gray correlate with pain perception, sensation, and affect in neuropathic pain patients. Neuroimage Clin. 2021, 32, 102876.
    39. Aguiar, D.C.; Almeida-Santos, A.F.; Moreira, F.A.; Guimaraes, F.S. Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses. Acta Neuropsychiatr. 2015, 27, 97–105.
    40. McGovern, A.E.; Ajayi, I.E.; Farrell, M.J.; Mazzone, S.B. A neuroanatomical framework for the central modulation of respiratory sensory processing and cough by the periaqueductal grey. J. Thorac. Dis. 2017, 9, 4098–4107.
    41. Subramanian, H.H.; Balnave, R.J.; Holstege, G. The midbrain periaqueductal gray control of respiration. J. Neurosci. 2008, 28, 12274–12283.
    42. Oliveras, J.L.; Besson, J.M.; Guilbaud, G.; Liebeskind, J.C. Behavioral and electrophysiological evidence of pain inhibition from midbrain stimulation in the cat. Exp. Brain Res. 1974, 20, 32–44.
    43. Makovac, E.; Venezia, A.; Hohenschurz-Schmidt, D.; Dipasquale, O.; Jackson, J.B.; Medina, S.; O’Daly, O.; Williams, S.C.R.; McMahon, S.B.; Howard, M.A. The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey. J. Physiol. 2021, 599, 5243–5260.
    44. Wu, D.; Wang, S.; Stein, J.F.; Aziz, T.Z.; Green, A.L. Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception. Exp. Brain Res. 2014, 232, 527–534.
    45. Lau, B.K.; Winters, B.L.; Vaughan, C.W. Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway. Br. J. Pharmacol. 2020, 177, 2320–2332.
    46. Hyland, N.P.; Abrahams, T.P.; Fuchs, K.; Burmeister, M.A.; Hornby, P.J. Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets. J. Comp. Neurol. 2001, 430, 222–234.
    47. Kannan, H.; Yamashita, H. Connections of neurons in the region of the nucleus tractus solitarius with the hypothalamic paraventricular nucleus: Their possible involvement in neural control of the cardiovascular system in rats. Brain Res. 1985, 329, 205–212.
    48. Miller, A.D.; Leslie, R.A. The area postrema and vomiting. Front. Neuroendocrinol. 1994, 15, 301–320.
    49. Hyde, T.M.; Knable, M.B.; Murray, A.M. Distribution of dopamine D1–D4 receptor subtypes in human dorsal vagal complex. Synapse 1996, 24, 224–232.
    50. Jeong, J.K.; Dow, S.A.; Young, C.N. Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation. Metabolites 2021, 11, 494.
    51. Stafanini, E.; Clement-Cormier, Y. Detection of dopamine receptors in the area postrema. Eur. J. Pharmacol. 1981, 74, 257–260.
    52. Amin, A.H.; Crawford, T.B.; Gaddum, J.H. The distribution of substance P and 5-hydroxytryptamine in the central nervous system of the dog. J. Physiol. 1954, 126, 596–618.
    53. Lipton, R.B.; Schmidt, P.; Diener, H.C. Post Hoc Subanalysis of Two Randomized, Controlled Phase 3 Trials Evaluating Diclofenac Potassium for Oral Solution: Impact of Migraine-Associated Nausea and Prior Triptan Use on Efficacy. Headache 2017, 57, 756–765.
    54. Chan, T.L.H.; Cowan, R.P.; Woldeamanuel, Y.W. Calcitonin Gene-Related Peptide Receptor Antagonists (Gepants) for the Acute Treatment of Nausea in Episodic Migraine: A Systematic Review and Meta-Analysis. Headache 2020, 60, 1489–1499.
    55. Duthie, D.J.; Nimmo, W.S. Adverse effects of opioid analgesic drugs. Br. J. Anaesth. 1987, 59, 61–77.
    56. Bigal, M.E.; Serrano, D.; Buse, D.; Scher, A.; Stewart, W.F.; Lipton, R.B. Acute migraine medications and evolution from episodic to chronic migraine: A longitudinal population-based study. Headache 2008, 48, 1157–1168.
    57. Ho, T.W.; Rodgers, A.; Bigal, M.E. Impact of recent prior opioid use on rizatriptan efficacy. A post hoc pooled analysis. Headache 2009, 49, 395–403.
    58. Bonafede, M.; Wilson, K.; Xue, F. Long-term treatment patterns of prophylactic and acute migraine medications and incidence of opioid-related adverse events in patients with migraine. Cephalalgia 2019, 39, 1086–1098.
    59. Douek, E.E. Smell: Recent theories and their clinical application. J. Laryngol. Otol. 1967, 81, 431–439.
    60. Courteau, J.P.; Cushman, R.; Bouchard, F.; Quevillon, M.; Chartrand, A.; Bherer, L. Survey of construction workers repeatedly exposed to chlorine over a three to six month period in a pulpmill: I. Exposure and symptomatology. Occup. Environ. Med. 1994, 51, 219–224.
    61. Peatfield, R.C. Relationships between food, wine, and beer-precipitated migrainous headaches. Headache 1995, 35, 355–357.
    62. Wantke, F.; Focke, M.; Hemmer, W.; Bracun, R.; Wolf-Abdolvahab, S.; Gotz, M.; Jarisch, R.; Tschabitscher, M.; Gann, M.; Tappler, P.; et al. Exposure to formaldehyde and phenol during an anatomy dissecting course: Sensitizing potency of formaldehyde in medical students. Allergy 2000, 55, 84–87.
    63. Kelman, L. The triggers or precipitants of the acute migraine attack. Cephalalgia 2007, 27, 394–402.
    64. Barrett, S.A.; Gifford, E.W. Miwok Material Culture. Bull. Public Mus. City Milwaukee 1933, 2, 117–376.
    65. Benemei, S.; Appendino, G.; Geppetti, P. Pleasant natural scent with unpleasant effects: Cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia 2010, 30, 744–746.
    66. Nassini, R.; Materazzi, S.; Vriens, J.; Prenen, J.; Benemei, S.; De Siena, G.; La Marca, G.; Andrè, E.; Preti, D.; Avonto, C.; et al. The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain 2012, 135 Pt 2, 376–390.
    67. Zhong, J.; Minassi, A.; Prenen, J.; Taglialatela-Scafati, O.; Appendino, G.; Nilius, B. Umbellulone modulates TRP channels. Pflugers Arch. 2011, 462, 861–870.
    68. Strecker, T.; Dux, M.; Messlinger, K. Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. J. Vasc. Res. 2002, 39, 489–496.
    69. Nicoletti, P.; Trevisani, M.; Manconi, M.; Gatti, R.; De Siena, G.; Zagli, G.; Benemei, S.; Capone, J.A.; Geppetti, P.; Pini, L.A. Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig. Cephalalgia 2008, 28, 9–17.
    70. Trevisani, M.; Smart, D.; Gunthorpe, M.J.; Tognetto, M.; Barbieri, M.; Campi, B.; Amadesi, S.; Gray, J.; Jerman, J.C.; Brough, S.J.; et al. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat. Neurosci. 2002, 5, 546–551.
    71. Andre, E.; Campi, B.; Materazzi, S.; Trevisani, M.; Amadesi, S.; Massi, D.; Creminon, C.; Vaksman, N.; Nassini, R.; Civelli, M.; et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Investig. 2008, 118, 2574–2582.
    72. Fujita, F.; Uchida, K.; Moriyama, T.; Shima, A.; Shibasaki, K.; Inada, H.; Sokabe, T.; Tominaga, M. Intracellular alkalization causes pain sensation through activation of TRPA1 in mice. J. Clin. Investig. 2008, 118, 4049–4057.
    73. Bessac, B.F.; Sivula, M.; von Hehn, C.A.; Escalera, J.; Cohn, L.; Jordt, S.E. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J. Clin. Investig. 2008, 118, 1899–1910.
    74. McNamara, C.R.; Mandel-Brehm, J.; Bautista, D.M.; Siemens, J.; Deranian, K.L.; Zhao, M.; Hayward, N.J.; Chong, J.A.; Julius, D.; Moran, M.M.; et al. TRPA1 mediates formalin-induced pain. Proc. Natl. Acad. Sci. USA 2007, 104, 13525–13530.
    75. Silva-Néto, R.P.; Peres, M.F.; Valença, M.M. Odorant substances that trigger headaches in migraine patients. Cephalalgia 2014, 34, 14–21.
    76. Martins, B.; Costa, A. Migraine Improvement during COVID-19 Pandemic—A Case Report on the Wonders of a Mask. Headache 2020, 60, 2608–2609.
    77. Schulte, L.H.; Jürgens, T.P.; May, A. Photo-, osmo- and phonophobia in the premonitory phase of migraine: Mistaking symptoms for triggers? J. Headache Pain 2015, 16, 015–0495.
    78. Hoffmann, J.; Recober, A. Migraine and triggers: Post hoc ergo propter hoc? Curr. Pain Headache Rep. 2013, 17, 370.
    79. Tanik, N.; Bektas, M. Development of quality of life assessment questionnaire associated with osmophobia in people with migraine. Pain Med. 2021, 21, 1006–1014.
    80. Baldacci, F.; Lucchesi, C.; Ulivi, M.; Cafalli, M.; Vedovello, M.; Vergallo, A.; Prete, E.D.; Nuti, A.; Bonuccelli, U.; Gori, S. Clinical features associated with ictal osmophobia in migraine. Neurol. Sci. 2015, 36, 43–46.
    81. Albanês Oliveira Bernardo, A.; Lys Medeiros, F.; Sampaio Rocha-Filho, P.A. Osmophobia and Odor-Triggered Headaches in Children and Adolescents: Prevalence, Associated Factors, and Importance in the Diagnosis of Migraine. Headache 2020, 60, 954–966.
    82. Lovati, C.; Giani, L.; Capiluppi, E.; Preziosa, G.; D’Amico, D.; Mariani, C. O067. Osmophobia in allodynic migraine: Role of frequency of attacks and headache duration. J. Headache Pain 2015, 16 (Suppl. S1), 1129–2377.
    83. Lovati, C.; Lombardo, D.; Peruzzo, S.; Bellotti, A.; Capogrosso, C.A.; Pantoni, L. Osmophobia in migraine: Multifactorial investigation and population-based survey. Neurol. Sci. 2020, 41 (Suppl. S2), 453–454.
    84. Delussi, M.; Laporta, A.; Fraccalvieri, I.; de Tommaso, M. Osmophobia in primary headache patients: Associated symptoms and response to preventive treatments. J. Headache Pain 2021, 22, 109.
    85. Lovati, C.; Giani, L.; Castoldi, D.; Mariotti D’Alessandro, C.; DeAngeli, F.; Capiluppi, E.; D’Amico, D.; Mariani, C. Osmophobia in allodynic migraineurs: Cause or consequence of central sensitization? Neurol. Sci. 2015, 1, 145–147.
    86. Wang, Y.F.; Fuh, J.L.; Chen, S.P.; Wu, J.C.; Wang, S.J. Clinical correlates and diagnostic utility of osmophobia in migraine. Cephalalgia 2012, 32, 1180–1188.
    87. Park, S.P.; Seo, J.G.; Lee, W.K. Osmophobia and allodynia are critical factors for suicidality in patients with migraine. J. Headache Pain 2015, 16, 44.
    88. Saçmacı, H.; Cengiz, G.F.; Aktürk, T. Impact of dissociative experiences in migraine and its close relationship with osmophobia. Neurol. Res. 2020, 42, 529–536.
    89. Zanchin, G.; Dainese, F.; Mainardi, F.; Mampreso, E.; Perin, C.; Maggioni, F. Osmophobia in primary headaches. J. Headache Pain 2005, 6, 213–215.
    90. De Carlo, D.; Toldo, I.; Dal Zotto, L.; Perissinotto, E.; Sartori, S.; Gatta, M.; Balottin, U.; Mazzotta, G.; Moscato, D.; Raieli, V.; et al. Osmophobia as an early marker of migraine: A follow-up study in juvenile patients. Cephalalgia 2012, 32, 401–406.
    91. Rocha-Filho, P.A.; Marques, K.S.; Torres, R.C.; Leal, K.N. Osmophobia and Headaches in Primary Care: Prevalence, Associated Factors, and Importance in Diagnosing Migraine. Headache 2015, 55, 840–845.
    92. Silva-Néto, R.P.; Rodrigues, Â.B.; Cavalcante, D.C.; Ferreira, P.H.; Nasi, E.P.; Sousa, K.M.; Peres, M.F.; Valença, M.M. May headache triggered by odors be regarded as a differentiating factor between migraine and other primary headaches? Cephalalgia 2017, 37, 20–28.
    93. Chalmer, M.A.; Hansen, T.F.; Olesen, J. Nosographic analysis of osmophobia and field testing of diagnostic criteria including osmophobia. Cephalalgia 2019, 39, 38–43.
    94. Terrin, A.; Mainardi, F.; Lisotto, C.; Mampreso, E.; Fuccaro, M.; Maggioni, F.; Zanchin, G. A prospective study on osmophobia in migraine versus tension-type headache in a large series of attacks. Cephalalgia 2020, 40, 337–346.
    95. Blau, J.N.; Solomon, F. Smell and other sensory disturbances in migraine. J. Neurol. 1985, 232, 275–276.
    96. Porta-Etessam, J.; Casanova, I.; García-Cobos, R.; Lapeña, T.; Fernández, M.J.; García-Ramos, R.; Serna, C. Osmophobia analysis in primary headache. Neurologia 2009, 24, 315–317.
    97. Kayabaşoglu, G.; Altundag, A.; Kotan, D.; Dizdar, D.; Kaymaz, R. Osmophobia and olfactory functions in patients with migraine. Eur. Arch. Otorhinolaryngol. 2017, 274, 817–821.
    98. Kandemir, S.; Pamuk, A.E.; 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 2021, 49, 613–617.
    99. Marmura, M.J.; Monteith, T.S.; Anjum, W.; Doty, R.L.; Hegarty, S.E.; Keith, S.W. Olfactory function in migraine both during and between attacks. Cephalalgia 2014, 34, 977–985.
    100. Hirsch, A.R. Osmophobia and taste abnormality in migraineurs: A tertiary care study. Headache 2005, 45, 763–764.
    101. Doğan, A.; Bayar Muluk, N.; Şahan, M.H.; Asal, N.; Inal, M.; Ergün, U. Olfactory bulbus volume and olfactory sulcus depth in migraine patients: An MRI evaluation. Eur. Arch. Otorhinolaryngol. 2018, 275, 2005–2011.
    102. Aktürk, T.; Tanık, N.; Serin, H.; Saçmacı, H.; İnan, L.E. Olfactory bulb atrophy in migraine patients. Neurol. Sci. 2019, 40, 127–132.
    103. Demarquay, G.; Royet, J.P.; Mick, G.; Ryvlin, P. Olfactory hypersensitivity in migraineurs: A H(2)(15)O-PET study. Cephalalgia 2008, 28, 1069–1080.
    104. Stankewitz, A.; May, A. Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology 2011, 77, 476–482.
    105. Anderson, A.K.; Christoff, K.; Stappen, I.; Panitz, D.; Ghahremani, D.G.; Glover, G.; Gabrieli, J.D.; Sobel, N. Dissociated neural representations of intensity and valence in human olfaction. Nat. Neurosci. 2003, 6, 196–202.
    106. Hillert, L.; Jovanovic, H.; Ahs, F.; Savic, I. Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A) receptor binding potential in the anterior cingulate and amygdala. PLoS ONE 2013, 8, e54781.
    107. Hillert, L.; Musabasic, V.; Berglund, H.; Ciumas, C.; Savic, I. Odor processing in multiple chemical sensitivity. Hum. Brain Mapp. 2007, 28, 172–182.
    108. Del Casale, A.; Ferracuti, S.; Mosca, A.; Pomes, L.M.; Fiaschè, F.; Bonanni, L.; Borro, M.; Gentile, G.; Martelletti, P.; Simmaco, M. Multiple Chemical Sensitivity Syndrome: A Principal Component Analysis of Symptoms. Int. J. Environ. Res. Public Health 2020, 17, 6551.
    109. Suzuki, K.; Okamura, M.; Haruyama, Y.; Suzuki, S.; Shiina, T.; Kobashi, G.; Hirata, K. Exploring the contributing factors to multiple chemical sensitivity in patients with migraine. J. Occup. Health 2022, 64, 1348–9585.
    110. Coleman, E.R.; Grosberg, B.M.; Robbins, M.S. Olfactory hallucinations in primary headache disorders: Case series and literature review. Cephalalgia 2011, 31, 1477–1489.
    111. Mainardi, F.; Rapoport, A.; Zanchin, G.; Maggioni, F. Scent of aura? Clinical features of olfactory hallucinations during a migraine attack (OHM). Cephalalgia 2017, 37, 154–160.
    112. Henkin, R.I.; Levy, L.M.; Lin, C.S. Taste and smell phantoms revealed by brain functional MRI (fMRI). J. Comput. Assist. Tomogr. 2000, 24, 106–123.
    113. Henkin, R.I.; Potolicchio, S.J.; Levy, L.M. Olfactory Hallucinations without Clinical Motor Activity: A Comparison of Unirhinal with Birhinal Phantosmia. Brain Sci. 2013, 3, 1483–1553.
    114. Kayan, A.; Hood, J.D. Neuro-otological manifestations of migraine. Brain 1984, 107 Pt 4, 1123–1142.
    115. Saberi, A.; Nemati, S.; Amlashi, T.T.; Tohidi, S.; Bakhshi, F. Phonophobia and migraine features in patients with definite meniere’s disease: Pentad or triad/tetrad? Acta Otolaryngol. 2020, 140, 548–552.
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      Villar-Martinez, M.D.; Goadsby, P.J. Pathophysiology and Therapy of Associated Features of Migraine. Encyclopedia. Available online: (accessed on 30 January 2023).
      Villar-Martinez MD, Goadsby PJ. Pathophysiology and Therapy of Associated Features of Migraine. Encyclopedia. Available at: Accessed January 30, 2023.
      Villar-Martinez, Maria Dolores, Peter J. Goadsby. "Pathophysiology and Therapy of Associated Features of Migraine," Encyclopedia, (accessed January 30, 2023).
      Villar-Martinez, M.D., & Goadsby, P.J. (2022, September 24). Pathophysiology and Therapy of Associated Features of Migraine. In Encyclopedia.
      Villar-Martinez, Maria Dolores and Peter J. Goadsby. ''Pathophysiology and Therapy of Associated Features of Migraine.'' Encyclopedia. Web. 24 September, 2022.