Orofacial pain and female gender - Pathos

Orofacial pain is characterised by a heterogeneous set of pathologies, wherein pain manifests as a symptom, an expression of musculo-articular dysfunction, a pain disease, or a sign of partly idiopathic syndromes. The prevalence of this condition is high, affecting 26 per cent of the adult population. The female sex is predominant in the vast majority of cases, with only a small number of exceptions, and this represents a significant risk factor. The burning mouth syndrome (BMS) paradigm is posited as an exemplar of a painful condition that is almost exclusively a female prerogative.

The term 'orofacial pain' (OFP) is defined as a heterogeneous group of painful pathologies that occur in the anatomical region of the mouth and face. The numerous pathologies in question are distinguished by a multifaceted pathogenesis, which engenders a complex differential diagnosis. This variety and complexity is well expressed by the numerous international classifications that attempt to impose order on the subject in order to facilitate understanding. The International Association for the Study of Pain (IASP) and the International Classification of Diseases (ICD) are two examples of classifications systems that group other pain conditions in addition to DOF. Conversely, the International Classification of Headache Disorders (ICHD-3)1 is a system that lists orofacial pain and headaches together. In this classification, orofacial pain is assessed to facilitate differential diagnosis with primary and secondary headaches. In addition, DOF is categorised alone in other classifications. The most recent of these is the ICOP (International Classification of Orofacial Pain),2 which was published in February 2020. The present document will be referred to since, in addition to being both comprehensive and recent, it was produced through the collaboration of odontostomatologists, neurologists and algologists.

The International Classification of Pain (ICOP) is a taxonomy which categorises all painful pathologies into six groups:

Pain associated with dental pathologies (e.g. pulp, periodontium, gums) and anatomical structures in the vicinity. In this group, pain is the primary symptom.

Myofascial and temporomandibular pain is characterised by pain arising from dysfunction of the muscles and joints.3 Despite its classification within two distinct categories, it is a single disorder that is designated temporomandibular musculature disorder (TMD). This disorder can be characterised by the presence of pain of various origins, which can be further categorised into subgroups. These subgroups include myofascial dysfunctional pain, affecting the muscles involved in mastication; pain and dysfunction resulting from disc displacement; and arthralgia of the temporomandibular joint (TMJ). When considered as a whole, TMD is three times more prevalent in women than in men, particularly in the subgroup of muscle pain.

The complexity of the clinical picture, which invariably involves the psychic sphere and alters interpersonal relationships, has led to the classification of TMD as a bio-psycho-social disorder. In the multifaceted picture, patients suffering from a form of headache that is indistinguishable from tension headaches are also recognised.

The term "cranial nerve diseases and injuries" is used to denote a range of conditions affecting the nerves of the head and face. These include neuralgic diseases, such as trigeminal neuralgia4 and glossopharyngeal neuralgia, and neuropathic diseases, such as post-herpetic neuropathy or post-traumatic painful trigeminal neuropathies (PTTN).5

The most well-known of these conditions is trigeminal neuralgia, which is considered to be the most prevalent orofacial neuropathic pain condition among individuals over the age of 50. The incidence of the condition ranges from 4.3 to 27 cases per 100,000 inhabitants per year. The female population is disproportionately affected, exhibiting a ratio of 1.6:1 compared to the male population. The underlying cause of neuralgia is demyelination of the A beta and A delta fibres. This, in turn, results in paroxysmal electric shock pain lasting a few seconds to a few minutes through a complex series of peripheral and central interferences, the full extent of which is not yet fully elucidated. Post-traumatic neuropathies, conversely, are the consequence of peripheral axonal damage of various origins (surgical, actinic, iatrogenic from neurolysis, post-traumatic, following numerous dental procedures, etc.). Damage may be sustained in either the intra- or extra-oral cavity. In the former instance, the assessment of neurological deficits is particularly challenging. In this particular instance, the patients are predominantly female.

Pain has been observed to bear a resemblance to the presentation of primary headaches, including migraine, tension-type headache and trigeminal autonomic headache.6

A prime example of how these factors can interfere with each other, causing a very high prevalence of the female sex in determining susceptibility to develop a chronic orofacial pain condition, is provided by the burning mouth syndrome.

BMS14,15 is an intraoral burning or dysesthetic sensation that occurs daily for more than two hours a day for more than three months without any detectable lesion causing it. A distinction must be made between the primary form, which is relatively infrequent (1% to 3.7% according to the most reliable estimates), and the secondary form. The latter can be caused by a systemic or local pathology such as diabetes, candida, thyroid disorders, gastro-oesophageal reflux, lichen planus, Sjögren's syndrome, but also nutritional deficiencies (iron, ferritin, zinc, vitamin B12, folic acid) or allergies to denture materials, foods or additives or drugs (ACE inhibitors, ADT, lithium) or parafunctions such as ‘tongue-pushing’.

The prognosis in secondary forms is much better than in primary when the cause is identified and eliminated or otherwise controlled. The prevalence of primary BMS increases with age (fifth to seventh decade) and is higher in post-menopausal women and women with systemic diseases. Frequent accompanying symptoms are xerostomia and dysgeusia. It is very rare in men.16

The natural history of the condition is not well understood, and spontaneous remission or remission following treatment occurs in less than 5 per cent of cases.

Patients diagnosed with primary BMS have been found to experience a higher prevalence of gastrointestinal diseases (irritable bowel syndrome), chronic fatigue, anxiety and depression when compared with the general population. Furthermore, it may manifest in a concomitant or consecutive manner with other orofacial pain or more widespread chronic pain.

The presence of anxiety and depression, as well as personality disorders, in conjunction with comorbidity for chronic pain conditions, should be understood in the context of a shared vulnerability that is mediated by dysfunctional brain dopamine activity, frequently characterised by a reduced presence. In the majority of patients diagnosed with BMS, there appears to be evidence of neuropathic damage involving a lesion of the nervous system along the trigeminal axis (peripheral damage).17 As demonstrated in Pain 2002; 99:41-47, and in accordance with the work of Jääskeläinen (SK.), the presence of a low dopamine tone within the nigro-striatal system is indicative of central damage.18 This is a key feature of primary burning mouth syndrome (PBS). As demonstrated in the 2012 publication of the Clin Neurophysiol, 123. 71-77). The potential for achieving substantial pain relief in approximately 50% of patients following anaesthetic blockade of the lingual nerve facilitates the identification of patients with peripheral damage who respond positively to this treatment modality. This is in contrast to those with central damage, who demonstrate an absence of pain relief. The capacity to accurately identify patients facilitates the personalisation of therapeutic interventions.

However, it is imperative to explore the underlying mechanisms that precipitate these alterations in both the central and peripheral nervous systems. It is important to consider why these occur so frequently in the female sex and so rarely in the male.

One of the most compelling pathogenetic hypotheses considers the most prevalent characteristics of patients with BMS: namely, the menopause, the high prevalence of anxiety and depression, the intra-oral localisation of symptoms, and signs of peripheral and central neuropathic damage. The persistent presence of anxiety has been demonstrated to result in alterations within the adrenal gland, manifesting as an increase in the production of corticosteroids (basal hypercorticosolism). Simultaneously, the menopause is distinguished by a precipitous decline in oestradiol, progesterone, and ovarian androgens (bibliographical note 10). Within the same age group, a significant and progressive decline in adrenal androgens is also observed. These changes in steroid hormones have been shown to disrupt the synthesis of neurosteroids (allopregnanolone and DHEA). These devices serve multiple purposes, including:

1) Short-acting receptor membranes are activated.

2) The chlorine conductivity of GABA A receptors is modified through their interaction with benzodiazepine receptors.

3) As they are synthesised in the skin, mucous membranes, central and peripheral nervous systems, and have a paracrine and autocrine mode of action, their action is exerted in restricted somatic and brain areas.

In support of their role in the protection of pain sensitivity in localised areas of the face, there is evidence of reduced morning salivary concentrations of DHEA in patients with BMS. This finding is corroborated by data from some experimental studies on animal samples.

It is widely acknowledged that the onset of the menopause can precipitate a decline in the hypothalamic-pituitary-adrenal axis, which in turn has the potential to modify the protective functions of the nervous system. Neurosteroids have been demonstrated to offer protection against injuries and diseases of the nervous system, and to facilitate nerve regeneration.

In addition to the hormonal and neuroprotective steroid changes induced by the menopause and chronic anxiety, internal and external (environmental/pharmacological/disease-related) neurotoxic agents are also present. Nigro-striatal dopaminergic neurons exhibit heightened vulnerability to environmental toxic agents, a factor that may contribute to the elevated incidence of Parkinson's disease, which frequently manifests with small peripheral fibre neuropathy. Finally, given that the occurrence of neuropathic pain is limited to a subset of patients with a pathological involvement of the nervous system, it can be deduced that a genetic susceptibility for the development of BMS must also be present.

To summarise, the aetiology of the condition under investigation is hypothesised to be multifactorial, involving chronic anxiety, menopause, exposure to neurotoxic agents and genetic susceptibility. The proposed pathophysiology, through alterations in gonadal and adrenal hormone production and reduced production of neuroprotective steroids, is believed to result in small-fibre neuropathy in the periphery and nigro-striatal dopaminergic hypofunction. Conversely, the symptom triad consisting of burning pain, dysgeusia and xerostomia can be attributed to trigeminal neuropathy and reduced tone of endogenous dopaminergic inhibitory pain control.

The present article does not deal with considerations of the therapeutic treatment of BMS.

The author declares that the clinical case was written in the absence of conflict of interest