Clinical manifestations

Presentation and course

	• Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures generally corresponds to the site of an underlying lesion, disease, or trauma.
	• Myofascial orofacial pain is typically localized to the temporalis and/or masseter muscle and contributes to headache.
	• Painful clicking, popping or grating sounds in the temporomandibular joint when opening and closing the mouth are frequent presenting symptoms of temporomandibular joint disorders.
	• Neuralgias involving the trigeminal nerve, glossopharyngeal nerve, and nervus intermedius nerves are characterized by severe, brief, sharp, shooting, or stabbing paroxysmal face pain in the territory of the nerve branches. Neuropathies typically present as continuous pain and can be associated with paresthesias, dysesthesias, and/or allodynia.
	• Orofacial pains can resemble presentations of primary headaches including migraine, cluster headache, paroxysmal hemicrania, SUNCT, and SUNA.
	• Pain resulting from idiopathic facial pain syndromes is typically persistent and poorly localized.
	• Contact point headache results in pain secondary to mucosal contact points in the sinonasal cavities.

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. Orofacial pain is often a result of disease or injury to the dental structures such as the tooth pulp, the periodontium, which includes supporting structures of the teeth such as the periodontal ligament and/or adjacent alveolar bone tissue, or gingival tissues. It can also be a result of disease or injury to non-dental structures, such as the oral mucosal, salivary glands, and jawbone tissues.

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures is generally superficial somatic pain, or localizable pain. Typically, the location of pain corresponds to the site of an underlying lesion, disease, or trauma, and is exacerbated or provoked by a physical stimulus applied to the structure (84). In most cases, the pain is acute, lasting less than 3 months, and is reversed by adequate treatment of its underlying etiology. Rarely, this pain is chronic or present for more than 3 months and on at least 15 days/month.

Chronic dental pain is more likely to be associated with headache. Resolution or treatment of dental disease may improve long-standing refractory headache (65).

Myofascial orofacial pain. Myofascial orofacial pain is an overarching label that describes pain originating from the masticatory muscles. Pain is typically localized to the temporalis and/or masseter muscle. Pain of this type can be provoked through palpation or jaw opening. It is often acute but can be chronic. Chronic myofascial orofacial pain is typically accompanied by psychosocial distress. Interestingly, myofascial pain of the muscles of mastication may be more contributory to headache than myofascial pain of the neck and shoulder muscles.

Temporomandibular joint disorders. Temporomandibular joint pain is often localized to the temporomandibular joint and in or in front of the ear. However, it can also be referred beyond the temporomandibular joint and can radiate to the neck, face, and head. The pain can be unilateral, if the temporomandibular complex is the primary cause of pain, or bilateral, if muscular involvement is predominant (36). Temporomandibular joint pain can occur with jaw movement, palpation, and/or spontaneously at rest. Temporomandibular joint pain may be accompanied by modification of jaw movement or abnormal jaw functions, such as clenching, limited or asymmetric jaw movements, and locking on jaw opening.

There is a clear link between head pain and temporomandibular disorders; headache disorders increase the risk of temporomandibular joint disorders, and temporomandibular joint disorders increase the risk of headache disability and migraine chronification (12; 33; 34; 04). Headache is typically reported alongside temporomandibular disorders (75). In people with episodic and chronic daily headache, both temporomandibular joint and masticatory muscle pain are more common and more severe (24). In addition, patients with migraine who have comorbid temporomandibular disorders have increased cutaneous allodynia (12).

Orofacial pain attributed to lesion or disease of the cranial nerves. There are several causes of cranial and facial pain (36; 84). Among these, the most relevant to orofacial pain include:

• Pain attributed to a lesion or disease of the trigeminal nerve • Pain attributed to a lesion or disease of the glossopharyngeal nerve • Pain attributed to a lesion or disease of nervus intermedius • Neck-tongue syndrome

Trigeminal neuralgia and painful trigeminal neuropathy. Pain attributed to a lesion or disease of the trigeminal nerve is characterized by recurrent unilateral brief, severe electric shock-like pains (36; 84). The pain is abrupt in onset and termination, typically lasting for seconds to 2 minutes, although the duration can lengthen over the course of the disease. The location of the pain is limited to the distribution of one or more divisions of the trigeminal nerve (ophthalmic, maxillary, or mandibular). In classical trigeminal neuralgia, the pain is most often present in the maxillary (V2) or mandibular (V3) branches (36). In trigeminal neuralgia, the pain is triggered by innocuous stimuli but can also present with a concomitant constant pain (36). After a painful paroxysm, there is typically a refractory period during which pain cannot be triggered.

Associated symptoms include tic douloureux, which occurs when severe pain evokes contraction of the muscles of the face on the affected side (84). Additionally, a patient may have mild autonomic symptoms (lacrimation, conjunctival injection) involving the ipsilateral eye. Sensory abnormalities are typically only detected using advanced testing, such as quantitative sensory testing; sensory deficits on clinical exam should prompt neurodiagnostic testing to investigate for a secondary etiology.

Painful trigeminal neuropathy is another condition that presents with facial pain in the territory of the trigeminal nerve(s). Unlike trigeminal neuralgia, painful trigeminal neuropathy is continuous or near continuous; although there may be brief paroxysms of pain, this is not a predominant characteristic. Patients with painful trigeminal neuropathy describe a burning or squeezing pain, or a pins and needles sensation.

Glossopharyngeal neuralgia. Glossopharyngeal neuralgia is characterized by a unilateral, brief, stabbing pain in the territory of the glossopharyngeal nerve and auricular and pharyngeal branch of the vagus nerve (36). Pain is localized in the base of the tongue, tonsillar fossa, beneath the angle of the jaw, or ear. It can occur concurrently with trigeminal neuralgia. Rarely, vagal symptoms can occur with glossopharyngeal neuralgia; these include cough, hoarseness, syncope, and/or bradycardia (84). Sensory changes are not common on exam; however, mild deficits may be evident. A reduced or absent gag reflex should prompt further neurodiagnostic testing for a secondary etiology.

Painful glossopharyngeal neuropathy is another condition that presents with facial pain in the territory of the glossopharyngeal nerve, and typically in the ipsilateral ear (36). Painful glossopharyngeal neuropathy, unlike glossopharyngeal neuralgia, is continuous or near continuous; although there may be brief paroxysms of pain, this is not a predominant characteristic. Patients with painful glossopharyngeal neuropathy describe a burning or squeezing pain, or a pins and needles sensation. This condition may be accompanied by sensory deficits in the ipsilateral posterior tongue, tonsillar fossa, or weakened or absent gag reflex.

Pain attributed to a lesion or disease of nervus intermedius. Nervus intermedius, or geniculate, neuralgia is characterized by severe, brief, sharp, shooting, or stabbing paroxysmal pain. The pain is characteristically felt deep in the auditory canal; however, it can also be felt in the auricle, around the mastoid processes, the soft palate, or in the temporal region or the angel of the mandible (36). Associated symptoms can include disorders of lacrimation, salivation and/or taste (36). Pain can be triggered by stimulation of the posterior auditory canal and/or periauricular region.

Painful nervus intermedius neuropathy is another condition that presents with facial pain in the territory of the intermedius nerves. Unlike nervus intermedius neuralgia, the pain is continuous or near continuous; although there may be brief paroxysms of pain, this is not a predominant characteristic (36). Mild sensory deficits in the region of the pain can accompany this disorder.

Neck tongue syndrome. Neck tongue syndrome is characterized by immediate-onset, unilateral, sharp or stabbing, and usually severe occipital and/or upper neck pain (36). The pain is brought on by sudden rotatory head movement and is accompanied by abnormal sensation and/or posture of the ipsilateral tongue. It can be accompanied by dysesthesia.

Orofacial pains resembling presentations of primary headaches. The International Classification of Orofacial Pain describes three types of populations with both head and face pain (Table 2).

Table 2. Types of Populations with Head and Face Pain

Type 1	Patients with primary headache disorders who report additional facial pain during, and usually ipsilateral to, headache exacerbation.
Type 2	Patients with primary headache disorders whose headache disorder is well controlled but who develop new facial pain attacks of the same quality, length and intensity, including occurrence of the associated symptoms of the former headache.
Type 3	Patients without a known history of a primary headache disorder who develop new onset attacks of orofacial pain that resemble one of the primary headache types in pain character, duration and intensity, with or without the associated symptoms of these headache types.
Adapted from (84)

Orofacial migraine. It is important to recognize migraine as a cause of dental pain to avoid unnecessary dental procedures (57). Lovshin was the first to describe migraine as facial pain that could occur in the absence of headache (48; 84). Sometimes called “facial migraine” or “lower-half migraine,” orofacial migraine causes pain in the second and third divisions of the trigeminal nerve but not headache pain, and is accompanied by often under-recognized migrainous features. These migrainous features include unilateral location, pulsing quality, moderate or severity intensity, exacerbation with physical activity, sensitivity to light and sound, nausea, or vomiting. Notably, bilateral orofacial migraine and orofacial migraine with aura have not been described (84). Chronic orofacial migraine is an entity that occurs on 15 or more days/month for more than 3 months, with migrainous features on at least 8 days/month (84).

Tension-type orofacial pain. Tension-type orofacial pain is episodic or chronic pain in the orofacial region reminiscent of features of tension-type headache, but without headache (84). These characteristics include bilateral, pressing, or tightening pain, without aggravation by physical activity or nausea. This type of pain overlaps with myofascial orofacial pain (84).

Trigeminal autonomic orofacial pain and cephalalgias. Cluster headache, which, along with paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks (SUNCT and SUNA), and hemicrania continua, make up the trigeminal autonomic cephalalgias. All trigeminal autonomic cephalalgias and orofacial attacks are characterized by unilateral head pain and have either one or both of the following: conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid edema, forehead and facial sweating, miosis and/or ptosis, and/or a sense of restlessness or agitation (36). The International Classification of Orofacial Pain describes orofacial counterparts, which consist of attacks of severe, strictly unilateral facial and/or oral pain, without head pain (84).

Cluster headache. Cluster headache typically has features of severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes, ipsilateral autonomic symptoms involving the conjunctiva, pupil, eyelid, nose, ear, or forehead, and restlessness or agitation (36). Sixty-five percent of 42 patients observed with cluster headache received unnecessary dental treatments because of the facial presentation of the pain (14). Others reported three patients with episodes of orofacial pain compatible with cluster headache (59).

Paroxysmal hemicrania. Paroxysmal hemicrania is characterized by at least 20 attacks over at least 1 year of severe unilateral orbital, supraorbital, and/or temporal pain lasting 2 to 30 minutes accompanied by ipsilateral autonomic symptoms involving the conjunctiva, pupil, eyelid, nose, ear, or forehead (36). This disorder can also present as orofacial pain. Delchano and Graff-Radford described two patients with chronic paroxysmal hemicrania who complained, primarily, of tooth pain that radiated to the maxillo-temporal regions (23). Both patients were well controlled with indomethacin. Multiple cases of paroxysmal hemicrania within the orofacial area have been reported in the dental literature (10).

The orofacial counterparts of cluster headache, paroxysmal hemicrania, SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing), and SUNA (short-lasting unilateral neuralgiform headache with cranial autonomic symptoms), are listed in the International Classification of Orofacial Pain as orofacial cluster attacks, paroxysmal hemifacial pain, and short-lasting unilateral neuralgiform facial pain attacks with cranial autonomic symptoms (SUNFA), respectively (84). Orofacial cluster attacks resemble cluster headache attacks. However, importantly, autonomic symptoms in orofacial cluster attacks may be less prominent than or different from those occurring as features of cluster headache as defined by the ICHD-3. Recognition of cluster headache and orofacial cluster attacks is important to avoid mistreatment. Attacks of paroxysmal hemifacial pain are characterized by severe, strictly hemifacial pain, without head pain, lasting 2 to 30 minutes and occurring several or many times a day and may occur without prominent autonomic signs. SUNFA is characterized by attacks of moderate or severe, strictly unilateral oral and/or facial pain, without head pain. Like SUNA and SUNCT, these attacks only last seconds to minutes. SUNFA attacks occur at least once a day and are usually associated with prominent lacrimation and redness of the ipsilateral eye and/or other local autonomic symptoms and/or signs.

Chronic orofacial cluster attacks, paroxysmal hemifacial pain, and SUNFA are disease states that occur for more than 1 year without remission, or with remission periods lasting less than 3 months (84).

Neurovascular orofacial pain. The International Classification of Orofacial Pain describes neurovascular orofacial pain as a distinct primary pain disorder of the face, which presents with pulsing, toothache-like symptoms. Neurovascular orofacial pain can be accompanied by mild autonomic (ipsilateral lacrimation and/or conjunctival injection, rhinorrhea and/or nasal congestion, ipsilateral cheek swelling) and/or migrainous symptoms (nausea and/or vomiting, photophobia and/or phonophobia) (84). Other associated symptoms could include abnormal sensitivity to cold, both ictally and interictally. The syndrome can be short lasting (1 to 4 hours) or long lasting (greater than 4 hours).

Idiopathic orofacial pain. The category of idiopathic orofacial pain contains some of the most challenging pain syndromes to diagnose and manage, as the pain is typically persistent and poorly localized. These syndromes include burning mouth syndrome, persistent idiopathic facial pain, persistent idiopathic dentoalveolar pain, and constant unilateral facial pain with additional attacks.

Burning mouth syndrome. Burning mouth syndrome describes oromucosal pain (tongue, mouth, or entire oral cavity) without identifiable cause. The pain is typically bilateral and is described as tender, burning, tingling, hot, or numb, mainly involving the anterior two thirds of the tongue (45; 54; 36; 84). The pain typically occurs daily and lasts for more than 2 hours/day for more than 3 months.

Pain can present with allodynia with tooth brushing (15). It can also be described as a tingling, pricking, pins and needles, numbness, itching, and electrical sensations (15). Associated symptoms can include dysgeusia, dysesthesia, and xerostomia (36; 84).

A clinical sensory exam typically does not reveal sensory deficits; however, quantitative sensory testing is often abnormal (84).

Persistent idiopathic facial pain. Persistent idiopathic facial pain, or atypical face pain, is a term for medically unexplained face or dental pain (79; 36; 84). The onset of persistent idiopathic facial pain may be linked to a minor operation or injury to the face, maxilla(e), teeth, or gingiva(e), but clinical and neurodiagnostic testing do not reveal an underlying etiology. Persistent idiopathic facial pain typically poorly localized, with a dull, nagging, aching, deep or superficial quality. There may be superimposed exacerbations, typically provoked by stress. Although typically localized in the face, it can spread to the craniocervical area as well. The pain typically occurs daily and lasts for more than 2 hours/day for more than 3 months.

The pain is often comorbid with other pain conditions, irritable bowel syndrome, psychiatric diseases, and psychosocial disability. A clinical sensory exam rarely reveals sensory deficits to light touch or pinprick perception; however, quantitative sensory testing may reveal deficits (84).

Persistent idiopathic dentoalveolar pain. Persistent idiopathic dentoalveolar pain, or atypical odontalgia, represents a subgroup of persistent idiopathic facial pain that often presents as continuous pain in one or more teeth/tooth socket after dental extraction (36; 84). The pain is typically described as deep, dull, or pressure-like. There may be superimposed exacerbations, typically provoked by stress. Although typically localized to a dentoalveloar site, it can spread to the craniocervical area as well. A clinical sensory exam rarely reveals sensory deficits to light touch or pinprick perception; however, quantitative sensory testing may reveal deficits (84).

Constant unilateral facial pain with additional attacks. Constant unilateral facial pain with additional attacks is an entity described as an unremitting unilateral facial pain. Although this type of pain is typically mild or moderate, there are distinct superimposed attacks of moderate to severe pain lasting 10 to 30 minutes (84). There are no accompanying migrainous or autonomic features (84).

Contact point headache. Contact point headache or “Sluder neuropathy” can result in new daily persistent headache, which can be described as a unilateral or bifrontal headache or facial pain localized to the upper teeth or mouth (07; 70). The cause is believed to be irritation of the anterior ethmoid nerve or sphenopalatine ganglion from mucosal contact points within the sinonasal cavity. Pain has been noted to start after an infection. Septal abnormalities may also contribute to pain.

Prognosis and complications

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. The prognosis of dental disease-causing face pain is excellent. Dental problems seldom produce long-term or significant disability. Infection is usually local and does not produce systemic complications. However, chronic pain may result from inadequate treatment of the underlying etiology, systemic disease, or central sensitization.

Myofascial orofacial pain. Acute myofascial pain can be successfully managed with treatment of the underlying cause (40). However, acute pain can transition to chronic pain if the underlying etiology remains untreated or if coexisting factors, such as psychological influences, stress, or environmental factors, have a dominant role in pain activation and remain unaddressed (40).

Temporomandibular joint disorders. Temporomandibular disorders are usually self-limiting and resolve with or without treatment (30). It is reassuring for patients with temporomandibular disorders to know that these problems rarely persist beyond the fourth decade. Patients who are not responsive to physical medicine approaches should not be considered surgical candidates automatically; rather, behavioral factors that perpetuate the disorder should be considered.

Orofacial pain attributed to lesion or disease of the cranial nerves. The prognosis of cranial neuralgias varies widely and typically depends on if they are primary or secondary. Secondary, for example, include neuralgias due to a space occupying lesion, or a vascular compression. There are generally both episodic forms of the neuralgias and pain syndromes, with refractory periods in between attacks, but they can also transition to chronic forms with concomitant chronic pain in between attacks.

Orofacial pains resembling presentations of primary headaches.

Orofacial migraine. There are a variety of preventive and episodic treatments available for migraine. Risk factors of transitioning from episodic (attacks occurring less than 15 days/month) to chronic migraine include obesity, medication overuse, stressful life events, and sleep disorders (13; 78). Early treatment may be able to reduce the risk of transformation from episodic to chronic migraine (13).

Trigeminal autonomic orofacial pain and cephalalgias. Of the trigeminal autonomic cephalalgias, cluster headache is the most prevalent, and its prognosis is better studied. About 80% to 90% of patients with cluster headache have episodic cluster headache, whereas 10% to 15% of patients with cluster headache have chronic cluster headache (90). Ten percent of patients with episodic cluster headache transform to chronic cluster headache (90). On the other hand, about a third of patients with chronic cluster headache can revert to episodic cluster headache (90). The length of time between cycles can increase as a patient ages, and a patient may note that their cluster headache is “improving” (90).

Idiopathic orofacial pain. Syndromes of idiopathic orofacial pain are typically chronic and require multimodal management (32).

Contact point headache. Contact point headache can be surgically or medically managed, with outcomes varying with management modality (44).

Biological basis

Etiology and pathogenesis

	• Pain referred from extradental structures (as in primary headache disorders or cranial neuralgias) typically results from activation of the trigeminovascular system; this overarching pathway of trigeminovascular activation helps explain why orofacial pain and primary headache disorders have overlapping features and can be difficult to distinguish.
	• The trigeminovascular system receives sensory information from and can sensitize nerve branches that innervate parts of the mouth, parts of the ear, extracranial skin, and parts of the meninges. This sensory information is carried by cranial nerves VII (the facial nerve), IX (the glossopharyngeal nerve), and X (the vagus nerve) (25; 56). The trigeminal nucleus caudalis converges with the dorsal horn cells of the upper cervical cord. Sensitization of the trigeminal nucleus caudalis results in dysfunction in central neural processing and pain modulation. Because of the relationship of the trigeminal nucleus caudalis to many other cranial and cervical nerves, the pain referral pattern may be confusing and can include face, periorbital, and upper neck pain. Therefore, one must always keep in mind that when local dental pathology cannot be found, referral from other sources may explain the pain
	• Calcitonin gene-related peptide (CGRP) is integral in migraine pain pathways but also has a significant presence in orofacial and myofascial facial pain.

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. Dental pain is most commonly a result of pulpitis, typically due to dental caries, fractures, or abrasions (42). Sensory output from dental pulp is carried by the trigeminal system (42). Interestingly, calcitonin gene-related peptide (CGRP), which is integral in migraine pain pathways, also facilitates pulpar repair and is released from the apical foramen or surrounding blood vessel supply into the pulp to induce neurogenic inflammation (38; 18). In dental pulp associated with irreversible pulpitis, the expression of CGRP is significantly increased as compared to normal pulp (17). Increased levels of CGRP have also been associated with periodontal inflammation. Moreover, individuals with both chronic migraine and periodontal disease have higher serum levels of IL-6, a proinflammatory cytokine, compared to individuals with chronic migraine without periodontal disease (46). The presence of CGRP suggests a pathogenesis link between dental disease and head pain.

Chronic dentoalveolar pain may result from inadequate treatment of the underlying etiology, systemic disease, or central sensitization. Systemic disease should always be considered in cases of chronic dentoalveolar pain, and several dermatological autoimmune diseases may result in orofacial pain of this type (84). These diseases include pemphigus vulgaris, mucous membrane pemphigoid, recurrent aphthous stomatitis, oral lichen planus, erythema multiforme, Sjogren syndrome, Behcet disease, systemic lupus erythematosus, graft versus host disease, erythema migrans, Chron disease, ulcerative colitis, celiac disease, and others. Endocrinological/hormonal changes, nutritional deficiencies, and hematological and gastrointestinal disorders may also contribute. Infections and neoplasms must be excluded.

Myofascial orofacial pain. Myofascial orofacial pain may be primary in origin or could be a result of secondary causes such as inflammation, infection, or muscle spasm. Pain from myofascial trigger points can generate and maintain both episodic and chronic headache (22).

The underlying basis of myofascial orofacial pain is a result of trigger points, or hyperirritable regions within taut bands of muscle fiber (40). These hyperirritable regions form as a result of the inhibited activity of acetylcholinesterase, which leads to a buildup of acetylcholine in the region of the synaptic cleft and in turn causes prolonged contraction of the sarcomere and endplate dysfunction. CGRP again may play a role here; CGRP may inhibit acetylcholinesterase or upregulate acetylcholine receptors, contributing to dysfunctional end plates. Prolonged contraction results in muscle damage and the subsequent release of inflammatory mediators and the perception of pain, hyperalgesia, and allodynia (40).

Temporomandibular disorders. The temporomandibular disorders are classified into joint-related problems (arthralgia), intra-articular disorders, and muscle disorders (myalgia). Most problems that occur are a result of a combination of these etiologies but may also present as isolated problems. In cases of chronic temporomandibular disorders, secondary causes such as arthritis, infection, or an autoimmune disorder should be considered (84). Other etiologic factors for temporomandibular disorders include bruxism, trauma, occlusal interferences, and emotional stressors (11; 02; 49; 28; 29; 76; 74; 77).

Joint inflammation is usually associated with degenerative changes (seen on bony imaging). Rheumatoid arthritis and psoriatic arthritis do affect the temporomandibular joint; standard serology for these conditions will confirm the diagnosis.

Commonly, inflammation within the temporomandibular joint is complicated by dysfunctions of the intra-articular and intracapsular portions (ligaments and disc). Inflammation of the temporomandibular joint may occur in conjunction with internal derangements or incoordination of the disc condyle and temporal bone. Joint noise present on movement may be due to anatomical changes of any of the articulating surfaces or to remodeling from micro- or macrotraumas. Noise may also be present when the disc is displaced (usually anteriorly and medially). Mandibular manipulation or movement results in a clicking or popping noise as the condyle moves under the disc during translation of the disc condyle complex along the articular eminence. As the teeth come back together, noise can again be noted. This condition is called an anterior displaced disc with reduction. These situations can be painful when they are accompanied by associated intracapsular inflammation. Local anesthetic or a steroid injection decreases the pain and aids in localizing the pathology. When the mandible cannot move beyond the displaced disc, the condition is called a closed lock or anterior displaced disc without reduction. A closed lock may require manual manipulation with local anesthetic or arthroscopic intervention.

Again, CGRP is suggested to be the common link between temporomandibular disorders and headache (69). One study showed that behavioral nociceptive responses secondary to masseteric inflammation were decreased by blocking the CGRP pathway with a CGRP receptor antagonist. Similarly, another study showed that migraine-like episodes secondary to massenteric inflammation were diminished by selective CGRP receptor antagonists (04).

Orofacial pain attributed to lesion or disease of the cranial nerves. Classical cranial neuralgias and facial pain syndromes are due to neurovascular compression (36; 84). Secondary cranial neuralgias are due to structural/demyelinating lesions from multiple sclerosis, space occupying lesions, or other causes such as skull base bone deformities, radiation and chemotherapy, barotrauma, connective tissue disease, arteriovenous malformations, and dural arteriovenous fistulas (36; 84; 43; 08). Idiopathic cranial neuralgias, in which neither electrophysiological testing nor neuroimaging shows significant abnormalities, may be a result of genetic neuronal hyperexcitability.

In primary headache disorders, pain is thought to originate from sensitization of the trigeminovascular system (25; 56). Activation of trigeminal nociceptors (sensory receptors that perceive pain or harm), which innervate specific intracranial vascular and meningeal structures, results in sensitization of the trigeminal ganglia. Trigeminal ganglia activation results in the release of inflammatory neuropeptides, including CGRP, neurokinin A, and substance P into perivascular nerve endings. This release triggers neurogenic inflammation, which consists of vasodilation, plasma protein extravasation, degranulation of mast cells, and platelet aggregation. Neurogenic inflammation results in the sensation of pain that is unilateral and throbbing and aggravated by movement. Importantly, the trigeminal ganglion also receives input from all branches of the trigeminal nerve, which includes ophthalmic, maxillary branches, and mandibular branches innervating the face and mouth. Heightened activation of the trigeminal ganglia can sensitize these branches of the trigeminal nerves, resulting in orofacial pain. In addition, the mandibular nerve (a branch of the trigeminal nerve) supplies motor function to the masseter muscle as well as sensory functions and could account for the “jaw tightness” seen in many patients with migraine.

If signals to the trigeminal ganglia continue, the trigeminal nucleus caudalis is activated (25; 56). Activation of the trigeminal nucleus caudalis results in dysfunction in central neural processing and pain modulation and can present with orofacial pain. The resulting head pain from central sensitization is persistent and more refractory to treatment. Because the trigeminal nucleus caudalis also receives input from the extracranial skin, it is also often superimposed with pain of the extracranial skin, which results in scalp tenderness and cutaneous (skin) allodynia. In addition, the trigeminal nucleus caudalis receives input from deep tissues around the eye. Activation of the trigeminal nucleus caudalis, which occurs in central sensitization, is also thought to produce the referred pain of migraine around the eye.

Trigeminal autonomic cephalalgias. Dysregulation of the hypothalamus, the trigeminal nerve, and the parasympathetic system combine to produce orofacial pain and autonomic symptoms (91; 53). Signals from various structures, including the hypothalamus, activate the thalamus, which then activates the superior salivatory nucleus and results in activation of the trigeminal-autonomic reflex (91; 53; 81). The reflex results in pain from trigeminal nerve (mostly the ophthalmic branch, V1) activation and autonomic symptoms (lacrimation, rhinorrhea, and conjunctival injection) from the parasympathetic activation. The parasympathetic reaction is facilitated by a sympathetic deficit (miosis, ptosis), which is inherent to trigeminal nucleus caudalis.

Idiopathic orofacial pain.

Burning mouth syndrome. Tongue biopsy results suggest an etiology of trigeminal small-fiber sensory neuropathy as a cause of burning mouth syndrome (45). Secondary burning mouth syndrome can occur from candidiasis, lichen planus, hyposalivation, medications, anemia, vitamin B12 or folic acid deficiencies, Sjögren syndrome, or diabetes (36).

Persistent idiopathic face pain. The causes of persistent idiopathic face pain is unknown; however, myofascial trigger points and/or a small fiber pathology, akin to complex regional pain syndrome, have been hypothesized as potential contributors (09; 32).

Contact point headache. Contact point headache is a result of mucosal contact points in the sinonasal cavities. Common contributing anatomical factors include septal deviation, septal spurs, concha bullosa, and middle turbinate pneumatization (44). Other anatomical abnormalities found in patients with contact point headache include a hypertrophied inferior turbinate, medialized middle turbinate, an uncinate bulla, a medialized or lateralized uncinate process, a paradoxical middle turbinate, or large ethmoidal bulla (44). The pathophysiology of pain is thought to be secondary to the release of CGRP and other peptides at the peripheral endings of the trigeminal nerves innervating the mucous membranes of the nasal cavity (07).

Epidemiology

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. The prevalence of pericoronitis is reported to be 81% and occurs primarily in the third decade (64). The frequency and epidemiology of headache and tooth pain is unknown. Headache is usually a secondary phenomenon, and it does not pose a significant diagnostic dilemma.

Myofascial orofacial pain. Myofascial pain and myofascial pain with limited jaw opening was shown to be present in 9.7% of the general population (40).

Temporomandibular joint disorders. Temporomandibular disorders affect approximately 5% to 12% of the population (75). However, epidemiologic studies of temporomandibular disorders typically have not differentiated headache from facial pain specifically, and there is still overlap between headache attributed to temporomandibular disorder due to muscular tension and tension-type headache (36). This should not deter clinicians from managing headaches using proven treatments aimed at the temporomandibular structures, but it should caution against drawing the conclusion that if treatment is effective, the cause is temporomandibular disorder (11; 02).

Orofacial pain attributed to lesion or disease of the cranial nerves. Trigeminal neuralgia is the best studied of all the cranial neuralgias. It has an annual incidence around 5.9 per 100,000 person-year (female) and 3.4 per 100,000 person-year (male) (41). It is different to characterize the prevalence of many cranial neuralgias and facial pain syndromes due to nonspecific diagnosis or characterization of these rarer disorders.

Orofacial pains resembling presentations of primary headaches.

Migraine and orofacial migraine. Migraine affects 38 million people in the United States (12% of the overall population); an estimated 4 million people in the United States have chronic migraine. Global estimates are generally higher (16). Chronic migraine affects 1% to 2% of the global population; 2.5% of persons with episodic migraine progress to chronic migraine each year (16). Although not uncommon, orofacial migraine is often unrecognized, which leads patients to seek treatment from a variety of physicians specializing in fields other than headache including otolaryngologists, dentists, ophthalmologists, and oral maxillofacial surgeons. Approximately 12% of patients evaluated for facial pain in a London rhinology clinic were diagnosed as having migraine (21). More interesting is that 47% of these patients with migraine had migraine isolated to the second division of the trigeminal nerve (21). A larger German study found that about 9% of 517 migraine patients experienced pain in the lower half of the face in addition to migraine (89).

Cluster headache and orofacial cluster attacks. Cluster headache has a low prevalence with a lifetime prevalence of 124 per 100,000 and a 1-year prevalence of 53 per 100,000 (27). The overall sex ratio was 4.3 (male to female) (27). Recognition of cluster headache and orofacial cluster attacks is important to avoid mistreatment. Sixty-five percent of 42 patients with cluster headache received unnecessary dental treatments because of the facial presentation of the pain (14). Others reported three patients with episodes of orofacial pain compatible with cluster headache (59).

Idiopathic orofacial pain. Per reports, prevalence of burning mouth syndrome has a wide range in general populations from 1% to 15% (50). Interpretation of epidemiologic data on persistent idiopathic face pain is difficult as its criteria are loosely defined. The estimated lifetime prevalence of persistent idiopathic face pain is around 0.03% with the incidence 4.4 per 100,000 person years (09).

In orofacial pain clinics, persistent idiopathic face pain may account for around 10% to 21% of the patient population. In a neurologic tertiary care center that studied patients referred for facial pain, about 21% to 27% had persistent idiopathic facial pain, whereas only 3% of patients with side-locked unilateral headache and facial pain presenting to a neurology outpatient clinic were diagnosed with persistent idiopathic face pain. Most patients seen are female, and mean age of onset is in the mid 40s. Atypical odontalgia occurs in 3% to 6% of patients following endodontic treatment. There is a female predominance, and it occurs primarily in the fifth decade (52).

Contact point headache. The prevalence and incidence of contact point headache is unknown.

Prevention

Prevention of dental disease is achieved through comprehensive oral hygiene programs. Education and the use of fluorides have dramatically curtailed the problems of dental decay. However, once disease is present, removal or infection control is essential (26).

Prevention of primary pain disorders is difficult as there is often an underlying genetic basis or predisposition for trigeminal neurovascular sensitivity. However, evaluation and treatment for underlying etiologies, such as autoimmune disorders or infection, prompt medical management, and management of co-existing psychiatric and psychological factors may help prevent or delay transition from the acute to chronic pain states (40).

Differential diagnosis

Associated or underlying disorders

The majority of dental pain is acute and caused by dentoalveolar or anatomically related etiology. However, a clinician should consider other causes of pain arising from a shared pathway of trigeminovascular activation. The differential diagnosis for orofacial pain includes evaluation for both dental and extra-dental etiologies.

Specific clinical symptoms may be “red flags” for secondary intracranial causes of pain that require urgent evaluation. Examples of secondary causes requiring urgent evaluation include tumors, vascular abnormalities (aneurysm, AVM, intracranial bleeding), intracranial edema, or severe infection (abscess).

Table 3. Red Flags

Acute onset of pain with rapid progression of severity Pain exacerbation with changes in position Evidence of papilledema or other signs of increased intracranial pressure Neurologic deficits (speech, motor, sensory, visual, mental status, gait, or balance changes) New onset seizures Severe sleep disturbances from pain

Table 4. Differential Diagnosis of Toothache

Pain arising in the tooth
	• Pulpitis
		- Reversible - Irreversible
	• Periodontal disorders
Pain arising outside of the tooth
	• Myofascial orofacial pain • Temporomandibular disorders • Trigeminal neuralgia • Painful trigeminal neuropathy • Glossopharyngeal neuralgia • Painful glossopharyngeal neuropathy • Nervus intermedius neuralgia • Painful nervus intermedius neuropathy • Neck-tongue syndrome • Orofacial migraine • Tension-type orofacial pain • Orofacial cluster headache • Paroxysmal hemifacial pain • Short-lasting unilateral neuralgiform facial pain attacks with cranial autonomic symptoms (SUNFA) • Neurovascular orofacial pain • Burning mouth syndrome • Persistent idiopathic facial pain • Constant unilateral facial pain with additional attacks • Contact point headache

Diagnostic workup

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. Diagnostic workup of local dental pathology includes inspecting the tooth for carious lesions, testing sensitivity to percussion, and examining vitality. X-ray imaging is useful in diagnosing caries and periapical pathology. The majority of atypical odontalgia patients do not have radiologic evidence of bone destruction, but the use of cone-beam CT may detect more abnormalities than plain radiographs (61). MRI imaging studies do not appear to improve diagnostic accuracy or demonstrate significant inflammation (60).

A more extensive workup may be required when chronic dental pain is present. The common tests to exclude dental disease must be performed, but cranial nerve screening, temporomandibular examination, and myofascial examination should also be done. Cervical spine evaluation can be performed if needed. These tests will rule out additional pathological processes. Differential blockade may be useful for those pains that are not musculoskeletal in origin (86). This can be a diagnostic neural blockade and diagnostic pharmacologic blockade. Diagnostic neural blockade is best achieved with a double-blind, placebo-controlled format. If this is not possible, repeated procedures are required. The basic purpose of the diagnostic block is to differentiate sensory from sympathetic pain mechanisms. Phentolamine infusions are useful in diagnosing sympathetically maintained pain.

Myofascial orofacial pain. Myofascial orofacial pain can be diagnosed with clinical exam, which can show provoked pain on palpation or jaw opening or trigger points.

Temporomandibular joint disorders. The diagnosis of temporomandibular joint disorder is primarily clinical and is confirmed by physical examination. Ultrasound and MRI exams may increase diagnostic yield (05). Biomarkers for disease activity, including cytokine-like gland-derived vascular endothelial growth factor from the joint, may be emerging (37).

Orofacial pain attributed to lesion or disease of the cranial nerves. Neuropathic orofacial pain is classified based on distinct clinical characteristics and etiology. Secondary causes such as demyelinating disease, space-occupying lesions, vessel abnormalities, and local or systemic disorders should be ruled out with neurodiagnostic testing (36). Quantitative sensory testing may reveal sensory abnormalities in some subtypes.

Orofacial pains resembling presentations of primary headaches. Primary headache disorders are clinically diagnosed with a thorough history on the temporal pattern, location, and quality of pain. A physical and neurologic exam shows an absence of neurologic deficits.

Idiopathic orofacial pain. Idiopathic orofacial pain syndrome is clinically diagnosed, after careful consideration and exclusion of secondary etiologies. Patients with idiopathic orofacial pain should be assessed for psychosocial disorders (32).

Contact point headache. Diagnosis of contact point headache involves evidence of a contact point through nasal endoscopy and/or CT imaging after the exclusion of secondary etiologies, such as acute rhinosinusitis (07).

Management

Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures. Dental problems are best managed with conventional dental therapies and rarely produce any long-term or significant disability.

Myofascial orofacial pain. OnabotulinumtoxinA injections and low-dose tricyclic antidepressants have been found to be helpful for myofascial orofacial pain (80).

Temporomandibular joint disorders. Temporomandibular disorders are usually self-limiting and resolve with or without treatment (30). For this reason, most patients do not require aggressive, irreversible, and expensive treatments. The patient who has failed all conventional treatments should be managed in the same manner as any patient with chronic pain. Further invasive and irreversible treatments should be avoided. These patients often require a multidisciplinary pain management approach.

Temporomandibular disorders usually require several management modalities, discussed below:

(1) Patient education and home care form the backbone of treatment for temporomandibular disorders. This program requires a detailed explanation of the problems the patient faces and the effects of perpetuating factors; this clarification enables the patient to play a part in his or her therapy. The home program requires instruction on what can be chewed without provoking pain.

(2) Behavior modification and psychosocial interventions may add to the treatment of temporomandibular disorders (03; 67). Such interventions could address poor postural and oral habits. Stress can be reduced through biofeedback, self-hypnosis, or other relaxation techniques.

(3) Pharmacotherapy is helpful in the treatment of temporomandibular disorders (31). Analgesics or anti-inflammatory agents should be prescribed on a time-contingent and non-pain-contingent basis. Anti-inflammatory, analgesic, muscle relaxant, and serotonergic (antidepressant) medications may be effective in the management of temporomandibular disorders.

(4) There is weak evidence for the use of physical therapy. Numerous devices and modalities are available, all of which must be used with care. Posture education helps to alter jaw position and minimizes diurnal clenching or excess strain on other muscles. Stretching exercises help maintain range of motion and aid in neuromuscular re-education. Splinting and resultant muscular hyperactivity can be reduced with stretching along with cold vapocoolant sprays for distraction. Iontophoresis, therapeutic ultrasound, moist heat, and ice may be useful.

(5) Noninvasive nerve stimulation therapies may help with pain. Transcutaneous electrical nerve stimulation (TENS) relieves pain and reduces muscle hyperactivity. High-frequency, high-intensity transcutaneous electrical nerve stimulation reduced myofascial pain significantly better than placebo or low-frequency transcutaneous electrical nerve stimulation in one study (35), and transcutaneous electrical nerve stimulation can be useful in combination with other treatment modalities (68). A small study showed equal efficacy of microcurrent nerve stimulation (MENS) as compared to transcutaneous electrical nerve stimulation for the treatment of masticatory muscle discomfort, although pain relief was quicker with MENs (39). A small-sample study showed some mild improvement with extracorporeal low-intensity, high-frequency shock wave therapy (83).

(6) Appliance therapy is a physical medicine technique used to manage temporomandibular disorders. Appliances are hypothetically meant to eliminate occlusal disharmony, prevent attrition, reduce bruxism and parafunction, prevent pain associated with masticatory muscle dysfunction, and correct internal derangement. The reduction of painful symptoms is well documented (19). These appliances are usually worn at night and occasionally during the day. Many different appliances are described in the literature, but two types are used most often. The first is the stabilization appliance, which has a flat surface of hard acrylic that covers all surfaces of either the maxillary or mandibular teeth. It appears to distribute the forces evenly and relax the elevator muscles (19). The second type is the repositioning appliance, which has been used in disc displacement. By producing translation of the condyle without rotation (protrusion), one can continually reduce the anterior displacement. It was thought that holding the jaw in this position with the aid of a repositioning appliance would allow remodeling and permanent reduction of the anterior displacement. Although there was initial enthusiasm for this technique, long-term effectiveness was achieved in only 36% of patients. A drawback of repositioning therapy is a resultant posterior open bite that sometimes requires extensive orthodontic or prosthodontic treatment to reestablish posterior tooth contact. Prior to performing this treatment on carefully selected patients, informed consent regarding the possible treatment side effects must be obtained.

(7) Occlusal therapy is based primarily on anecdotal study. There is no research supporting a direct relationship between occlusal interferences and temporomandibular disorders. A metaanalysis found very low-quality evidence for the use of noninvasive splints or bruxism to reduce pain in temporomandibular disorders (66). Therefore, occlusal therapy should not be undertaken when acute symptomatology is present but kept in the context of dental maintenance (31).

(8) Surgery, including arthroscopy and joint replacement, is used in the treatment of temporomandibular disorders. The best indication for surgical treatment is the anterior displaced disc without reduction (closed lock). Arthroscopic treatment has been reported to be effective for other intracapsular problems, including synovitis, deviation in form, osteoarthritis, and hypo- and hypermobility (72; 73). Further long-term studies are required. Open surgery is performed for bony ankylosis and neoplasia but remains controversial in disc displacement. Surgery is not indicated for treating inflammation. Provided that the goals of surgery are not overestimated, there is scope for improvement in certain areas. Surgery does not restore diseased tissue to normal, and patients should be made aware of this prior to surgery.

(8) OnabotulinumtoxinA has been studied for a myriad of conditions causing orofacial pain, including temporomandibular disorders, atypical odontalgia, and trigeminal neuralgia. Although the complete mechanisms of action of onabotulinumtoxinA are not understood, the evidence suggests that it prevents release of local nociceptive neuropeptides and excitatory neurotransmitters, including CGRP (82; 20; 62). OnabotulinumtoxinA also may act to decrease pain sensitivity and lower peripheral sensitization by decreasing the translocation of the transient receptor potential vanilloid 1 to neuron cell membranes (20). In temporomandibular disorders, onabotulinumtoxinA can be used prior to surgery and if conservative approaches were ineffective (82). Administration of onabotulinumtoxinA into the muscles of mastication, primarily the masseter, temporalis, and lateral pterygoids muscles, can help relieve pain (82). OnabotulinumtoxinA was also shown to reduce both attack frequency and pain severity in a randomized, double-blind, placebo-controlled trial (87). A study on using onabotulinumtoxinA for atypical odontalgia showed that patients had significant pain relief ranging from pain freedom to intermit mild pain (20). Complications from onabotuliumtoxinA arise from weakness or paralysis in the muscles injected (82; 20).

Orofacial pain attributed to lesion or disease of the cranial nerves. The treatment for cranial neuralgias and neuropathies is discussed extensively in other articles in MedLink Neurology.

Orofacial pains resembling presentations of primary headaches. The treatment for migraine and TACs is discussed extensively in other articles in MedLink Neurology.

Idiopathic orofacial pain. The lack of a clear pathophysiological basis makes the treatment of persistent idiopathic face pain difficult. Nonrandomized medication trials have suggested the use of tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and anticonvulsants. A study using diode laser therapy showed some benefits for pain reduction in persistent idiopathic face pain (88). High-frequency repetitive transcranial magnetic stimulation (rTMS) on the right secondary somatosensory (S2) cortex has shown some pain improvement (47). An open trial in a small number of patients showed possible benefit of pulsed radiofrequency treatment of the sphenopalatine ganglion, although a prospective, randomized, controlled study is needed to confirm results (06). Atypical odontalgia may respond to multiple treatments, such as tricyclic antidepressants with or without phenothiazines (51). Medication used for other types of pain may be effective, as demonstrated by a clinical trial in which duloxetine 60 mg produced significant clinical improvements in 2 weeks (55). OnabotulinumtoxinA has been shown to be helpful in treating atypical odontalgia as well (20).

Contact point headache. Patients with contact point headache may be medically managed with nasal corticosteroid sprays and decongestants. In patients with radiologic evidence of contact point headache, surgical treatment may be effective in reducing pain severity or frequency (01). Surgical options, including nasal-paranasal surgery, septal and/or turbinate surgery, and/or ethmoid–sphenoid surgery may be superior to medical management for symptom relief (44). Unilateral pain or a good response to topical lidocaine may predict good outcomes with endoscopic management (71). Radiofrequency thermocoagulation may be effective in some cases (58).

Special considerations

Anesthesia

Anesthesia carries little risk, but intubation may result in loss of teeth or augmentation of the temporomandibular disorders in patients with loose teeth or temporomandibular disorders. Specific informed consent should be obtained prior to anesthesia. Appropriate screening of patients with temporomandibular disorders should include the following:

(1) Measurement of mouth opening (2) Palpation for tenderness over lateral and dorsal capsules (3) Auscultation for joint noise (4) Questioning regarding pain caused by temporomandibular joint function.