FormalPara Key Points

Orofacial pain disorders are complex and can be quite challenging to diagnose and manage. The orofacial pain specialist is trained to diagnose and manage these conditions.

The management plan is individualized and may include different pharmacological and non-pharmacological modalities.

Orofacial pain disorders are within the realms of dentistry and medicine. Multidisciplinary management is key for optimal care.

Novel and safer therapeutic targets exclusively for the management of trigeminal mediated pain and the development of evidence-based guidelines and protocols for the management of the different orofacial pain disorders are greatly needed, to offer better care and reassurance to this patient population.

1 Introduction

Orofacial pain is the dental specialty that involves the evaluation, diagnosis, and management of pain disorders of the head, face, jaw, mouth, and neck [1]. Perhaps for the reader, the first thing that comes to mind when dentistry and orofacial pain is mentioned, is dental pain. Pains of odontogenic origin can be the most excruciating pain experiences, and fortunately they are relieved once the dental or periodontal pathology is resolved. However, there are other types of pains in this region that are of non-odontogenic origin and can become chronic. The focus of this narrative review is to discuss these orofacial pain disorders and their pharmacological management. Our search, within PubMed, focused on the last 10 years of orofacial pain and headache literature and included international classifications, guidelines, consensus, systematic and meta-analysis reviews, narrative reviews, prospective and retrospective studies, basic science studies and, when available, clinical trials. Some older references were also included because they were considered of key importance to our topic.

Orofacial pain (OFP) disorders are complex conditions that impact dramatically the quality of life of the patient [2]. Their prevalence varies between studies, but it has been reported that up to a quarter of the population may report orofacial pain and 11% may be chronic [2,3,4,5]. OFP comprises disorders of different etiology and pathophysiology, from musculoskeletal to neuropathic and neurovascular in nature, including the temporomandibular disorders (TMDs), neuropathic pains such as trigeminal neuralgia, as well as headache disorders [1, 6]. The interrelated anatomy and physiology of the region adds to the complexity of these disorders, presenting to the clinician a diagnostic and a management challenge. In persistent pain disorders of idiopathic etiology such as burning mouth syndrome and persistent idiopathic facial and dentoalveolar pains, diagnosis is further challenging as it has to be made by exclusion of other pain disorders [7, 8]. Moreover, another layer of complexity is the psychological burden that these disorders inflict on the individual, which impact greatly on management [2, 9, 10].

The heterogeneous nature of these disorders requires a management plan tailored exclusively to the patient following the biopsychosocial framework and diagnosis. Management may include different pharmacological and non-pharmacological approaches, as well as trial of different medications and modalities. An orofacial pain specialist is key for the evaluation, diagnosis, and management of these disorders, but management is multidisciplinary, and it is necessary that a team of health professionals from different fields, including but not limited to neurology, pain medicine, psychiatry, psychology, otolaryngology, and physical therapy are involved for effective management.

The intent of this review is to examine the most common orofacial pain disorders and their management. The focus is on pharmacological approaches; however, non-pharmacological approaches are key in the management plan of this patient population, so they will be briefly discussed.

2 Temporomandibular Disorders

Temporomandibular disorders (TMDs) are a number of disorders affecting the muscles of mastication, the temporomandibular joint (TMJ), and contiguous structures [1]. After chronic lower back pain, these disorders are the most common musculoskeletal disorders that cause pain and disability [11]. According to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), the most common pain-related TMDs are myalgia, local myalgia, myofascial pain, myofascial pain with referral, arthralgia and headache attributed to TMDs; and the most common intraarticular disorders are disc displacement with reduction, disc displacement with reduction and intermittent locking, disc displacement without reduction with or without limitation at opening, degenerative joint disease, and subluxation [12]. The etiology of TMDs is still ambiguous but diverse factors including history of trauma to the masticatory structures, parafunctional habits, and genetic and psychosocial factors may contribute to the onset, perpetuation, and predisposition of TMDs [1, 13]. The presence of behaviors known as parafunctional habits, such as clenching and grinding included in the broad term of bruxism do not usually result in TMD symptoms but in some individuals may be contributing factors [14,15,16]. However, further research is still necessary to clarify this relationship [17]. The International Classification of Orofacial Pain (ICOP) distinguishes two main diagnostic categories of TMD that include myofascial orofacial pain and TMJ pain [18]. Primary myofascial orofacial pain and TMJ pain could be acute (<3 months) or chronic (≥3 months). Secondary myofascial orofacial pain is caused by myositis, muscle spasm, or tendonitis. Secondary TMJ pain is caused by arthritis, degenerative joint disease, disc displacement, or subluxation [1, 18]. Overall, the most prevalent painful TMD is of muscular origin. Myofascial pain is estimated to be the most prevalent with 45% or higher prevalence [19,20,21]. TMJ disorders such as TMJ disc displacements are highly prevalent in the population. A systematic review and meta-analysis reported their prevalence to be high, at 25.9% for adults and elderly [22]. The main indicator of this alteration in condyle-disc function is clicking or popping sounds, which are usually non-painful (non-painful TMD) but sometimes can be accompanied by pain (arthralgia) and with limited mouth opening during condylar movement, such as in the cases of disc displacement without reduction [23].

Migraine, lower back pain, fibromyalgia, irritable bowel syndrome, anxiety and depression, sleep disorders, vulvodynia, and chronic fatigue are more prevalent among TMD patients and are considered comorbid disorders [24,25,26]. In addition, anxiety and depression have been reported to affect about 40–65% of patients with TMD [27] and is noted in particular in patients with myofascial orofacial pain [28].

Accurate diagnosis of TMD conditions is essential for effective management. Signs and symptoms include pain located in the preauricular area or muscles of mastication, difficulty in mouth opening, TMJ noises such as clicking, popping, crepitus, intensified by jaw activities such as chewing, eating, talking, yawning, and smiling, among others [29]. Complexity in diagnosing specific TMDs lies in the fact that referred pain from associated muscles of mastication, as in the case of myofascial pain, may be present at a different site, such as a toothache or a headache, masking the actual source of pain. Palpation of the TMJ and muscles of mastication to verify pattern of referral, and diagnostic tests, such as trigger point injections in the suspected muscle source of pain are essential to confirm the diagnosis.

2.1 Management

TMD symptomatology tends to improve over time [10, 30] and therefore management should be conservative and reversible and based on evidence-based therapeutics [31]. Management is within the biopsychosocial framework whereby behavioral approaches are included in the management plan [1, 32]. When a TMD is chronic, for some patients, management can be quite challenging, greatly affecting their quality of life [33].

Several modalities are currently used for the management of TMDs and a management plan including different modalities is tailored to diagnosis and patient needs. These modalities include conservative and non-invasive approaches (patient education and self-management, physical therapy, pharmacological management, and oral appliances), minimally invasive approaches (intra-articular injections), and surgical interventions (e.g., arthrocentesis) [34]. The clinical outcomes expected with these therapies include pain relief and improvement of function. The medications used in the management of TMDs include non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, anticonvulsants, antidepressants, and corticosteroids. While high quality evidence such as randomized controlled trials are lacking for most drugs in specific TMD diagnoses, observational studies, preclinical and clinical studies have documented their efficacy.

2.1.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Oral NSAIDs are supported to be used as first line to alleviate acute muscle and joint pain [35]. NSAIDs such as ibuprofen, naproxen, celecoxib, and diclofenac sodium have been shown to reduce TMD-related pain and improve mouth opening. Both systemic intake and topical formulations of NSAIDs have been shown to be helpful in the management of TMDs. However, high quality evidence is lacking on specific NSAIDs and the dosage and duration of treatment for different TMDs [36, 37]. NSAIDs are usually prescribed short term and should be avoided in patients with active gastrointestinal disorders and kidney disease. Caution should also be exercised in cardiovascular disease with risk of endothelial injury [38].

2.1.2 Muscle Relaxants

Muscle relaxants such as cyclobenzaprine, baclofen, and tizanidine are helpful in the management of myofascial orofacial pain [39]. Cyclobenzaprine is the most studied drug in this category with supporting evidence [40]. Side effects include sedation, so it is usually prescribed short term at lower doses of 5–10 mg at bedtime for the management of myofascial orofacial pain [6, 29, 41].

2.1.3 Antidepressants

Tricyclic antidepressants (TCAs) and selective norepinephrine and serotonin reuptake inhibitors (SNRIs) have been effective in pain management. Examples of these drugs include amitriptyline, nortriptyline, duloxetine, and venlafaxine [1]. Amitriptyline has been reported to provide a reduction of pain and discomfort in patients with chronic TMD [42], in addition to being useful in patients with headache attributed to TMD and tension-type headache [6].

2.1.4 Anticonvulsants

Gabapentin and pregabalin are two commonly prescribed medications for neuropathic pain and there have been reports of use for the management of myofascial orofacial pain as well [43]. However, these are not first-line management approaches, and there is limited data to support their use, and so they are not normally used in TMD management. Gabapentin may be considered as an alternative for patients who do not respond to TCAs [44].

2.1.5 Trigger-Point Injections—Local Anesthetics, Botulinum Toxin

Myofascial trigger points are hypersensitive spots located within taut bands of the skeletal muscles, which can cause pain locally or at distant sites when compressed or stretched [45]. Intramuscular injections have been used for the management of myofascial orofacial pain, usually with local anesthetics, corticosteroids (tendinitis), or botulinum toxin, as well as dry needling without any injection drugs. Limited evidence has shown the beneficial effects of trigger-point injections with local anesthetics [46, 47] and dry needling [48]. The use of botulinum toxin A (BTX) is approved for the management of chronic migraine [49]. BTX has shown superiority over placebo in reducing TMD symptomatology, although data are still unclear [50, 51], and it currently does not have FDA approval for use in TMD management. However, BTX is useful in patients with myogenous TMD refractory to conventional therapy and in patients with significant parafunctional behaviors, such as bruxism [51,52,53]. More randomized controlled trials (RCT) are necessary to support standardized protocols of care and it should not be used as a first line of management.

2.1.6 Temporomandibular Joint (TMJ) Injections

Intra-articular injections are indicated for joint pain, limited mouth opening, and inflammatory and degenerative joint diseases. There are several advantages for the use of TMJ injections in addition to being a conservative therapy with very low risk of complications. These advantages are direct local drug delivery into the TMJ, increased bioavailability of the drug in the joint, and lower systemic effects and toxicity. All of these ultimately result in a lower dose of medication needed to achieve a therapeutic effect [54]. TMJ injections appear to be a good choice for cases where conservative measures have failed, in cases that are not yet in need of surgical intervention, or for patients that do not wish to undergo surgery as a supportive therapy.

2.1.6.1 TMJ Injections—Corticosteroids

Systemic corticosteroids are only prescribed short term for acute episodes of painful arthralgia and inflammation, and when NSAIDs have been not effective. Oral methylprednisolone is commonly used at a starting dosage of 4 mg in a 6-days course for acute management [6, 55]. Corticosteroid injections are indicated for inflammatory conditions affecting the TMJ to decrease pain and improve function. They are also helpful for patients that are not responding to usual self-management strategies and/or oral anti-inflammatory medications, or for those patients with gastro-esophageal reflux (GERD) or gastritis. Several steroids can be used for injections in the TMJ, namely, tenoxicam [56], betamethasone [57], and methylprednisolone [58, 59]. Triamcinolone is a steroid that is commonly used, and which is usually injected in the superior joint space in a 10–20 mg dose and mixed with an equal amount of local anesthetic, such as lidocaine or bupivacaine [55]. Although corticosteroid injections are considered a safe treatment modality with low risk of morbidity, some complications are reported with its use [60, 61]. Major limitations of intra-articular corticosteroids include a short duration of effect and limited frequency of use due to safety reasons [54]. The general guideline for steroid use recommends injecting the TMJ no more than three times in a 12-months period [55].

2.1.6.2 TMJ Injections—Hyaluronic Acid

Hyaluronic acid (HA), a natural glycosaminoglycan that is found in the synovial fluid and is produced by synovial cells [62], aids in joint stabilization, nutrition, elasticity, and viscosity of the synovial fluid. HA has been used as a viscosupplementation of TMJ to help in the management of internal derangement and osteoarthritis. HA injections are usually indicated for patients who only responded temporarily or partially to intra-articular corticosteroid injections. These injections have been shown to improve TMJ pain and jaw motion by decreasing inflammation, and to have a moderate success rate in patients with new-onset osteoarthritis with crepitation [63, 64]. Additionally, HA has been shown to be effective in treating patients with anterior disc displacement with or without reduction [65, 66]. HA injections appear to improve jaw function and induce condylar reparative remodeling in patients with ADD associated with osteoarthritis [67]. The usual practice for HA is a series of three injections once a month [55]. In osteoarthritis and anterior disk displacement with or without reduction, HA treatment when used alone has been shown to be effective in pain reduction compared with placebo or other therapies in many studies. However, HA, when combined with arthrocentesis, has not been shown to be effective compared with arthrocentesis alone. There is no single universal clinical protocol with a specific molecular weight, dose and concentration of HA, and number of applications, and this has created a heterogenous and equivocal body of evidence [68].

2.1.6.3 TMJ Injections—Platelet-Rich Plasma

Platelet-rich plasma is an orthobiological agent comprising a concentrate of platelets derived from the patients’ own blood. Due to its high concentration of growth factors, it possesses anti-inflammatory and analgesic properties and hence aids in the healing of bones, muscles, tendons, and cartilage [69]. PRP is produced by centrifuging whole autologous blood with an anticoagulant and separating the platelets from the other contents of the blood and diluting them to the ideal concentration [70]. The duration of this process varies by system used. There is increasing evidence that intra-articular injection of PRP is a promising treatment modality for degenerative conditions of the joints such as osteoarthritis and disc displacement with osteoarthritic lesions [71]. The benefits of PRP in degenerative TMDs may result from its capacity to restore HA in the joint, trigger the synthesis of glycosaminoglycans from chondrocytes, and provide a scaffold for the stem cells [72]. Clinical studies for the treatment of osteoarthritis of the TMJ have shown PRP to be beneficial in preventing the recurrence of pain and joint sounds and improvement of mandibular opening in comparison with HA and corticosteroids in long-term follow-ups [73]. Similarly, PRP may be more effective long term in decreasing pain and increasing mandibular function in comparison with HA for patients with osteoarthritis of the TMJ [71]. Moreover, PRP effectiveness has been studied for the treatment of internal derangements. Intra-articular injection of PRP in patients with anterior disc displacement with reduction resulted in decreased pain levels and joint sounds and increases in mandibular opening in comparison with arthrocentesis [74]. A systematic review compiled nine studies (443 patients) that investigated HA, corticosteroids, and/or autologous blood products in patients with temporomandibular joint osteoarthritis. They concluded that all of these injectables along with arthrocentesis were effective in reducing pain and improving maximum mouth opening [75].

2.1.6.4 Prolotherapy

Prolotherapy involves injection of hypertonic dextrose into the joint space and has been shown to be helpful in the management of TMD pain as well as subluxation and hypermobility [76]. The mechanism of action is unclear and has been attributed to a transient inflammatory response and tissue proliferation. A systematic review compiled ten randomized control trials, of which five trials were combined in a meta-analysis. Hypertonic dextrose prolotherapy was found to be better than placebo injections in improving TMJ pain symptoms at 12 weeks. However, dextrose prolotherapy did not provide additional benefits in maximum inter-incisal mouth opening and disability scores [77].

2.1.7 Surgical Therapy

The decision to perform a surgical intervention is made carefully and for very specific cases and depends on the degree of intraarticular pathology and adaptation. From the surgical interventions available, arthrocentesis and arthroscopy reduce pain and improve joint function by reducing the inflammatory mediators in the joint space. These are minimally invasive surgical procedures. Surgical interventions, according to the American Association of Oral and Maxillofacial Surgeons, should be reserved to intractable cases after non-invasive options have been tried and failed [78].

3 Neuropathic Orofacial Pain

Neuropathic pains are caused by a lesion or disease of the somatosensory system [79]. In the orofacial region, neuropathic pains can occur as a consequence of sensitization from nerve injury secondary to dental procedures, facial trauma, injury associated with inflammation, infection or neoplasia, and due to some metabolic disorders [80,81,82]. Pre-clinical and clinical evidence support that this maladaptive response to peripheral and central sensitization is associated with multiple mechanisms involved in neuroplastic changes in the nervous system, leading to a dysregulation in descending pain modulation, favoring pain facilitation and maintenance [83,84,85,86,87].

Trigeminal neuralgia is the most common neuropathy in the orofacial region. Less common conditions include disorders affecting the glossopharyngeal nerve such as glossopharyngeal neuralgia, and the facial nerve in the case of nervus intermedius neuralgia. As with any other neuropathic pain in other body regions, allodynia and hyperalgesia are present as well as other signs that accompany nerve injury such as paresthesia and dysesthesia. The pain can be continuous or episodic, spontaneous, and triggered by touch. These types of pain are accompanied by significant psychosocial burden affecting the quality of life of the patients, impairing activities such as eating, talking, kissing, smiling, and social interactions [88,89,90].

It is very important to highlight that these pains, in the trigeminal distribution and their branches, can be reported by the patient as a toothache, and therefore they have the potential risk of being misdiagnosed as being of dental origin. Unfortunately, misdiagnosis is not uncommon, leading to unnecessary dental procedures in an attempt to alleviate the symptomatology, with the potential to exacerbate the pain and cause more suffering [90, 91]. Therefore, a careful differential diagnosis performed by an orofacial pain specialist to differentiate between odontogenic and non-odontogenic pain is necessary.

Thanks to the International Classification of Headache Disorders (ICHD-3) [92] and, more recently, the International Classification of Orofacial Pain (ICOP) [18], a diagnostic criteria for the different neuropathic orofacial pain disorders is now available. The use of opioids in orofacial pain management is not supported by the literature and the risks for the development of hyperalgesia, tolerance, and physical dependence outweigh any benefit [93, 94]. The management of orofacial neuropathic pain is based on the guidelines and recommendations for the management of other neuropathic pain disorders of other areas of the body [95]. However, evidence-based sources and guidelines with the focus on trigeminal and other orofacial neuropathic pains are becoming more available [1, 96]. Research focusing exclusively on craniofacial neuralgias and trigeminal neuropathic pains is greatly needed.

We have divided the following sections of neuropathic orofacial pains into episodic and continuous disorders according to their temporal features [1]. Episodic disorders are characterized by their intermittent patterns of pain and their characteristic presence of painful paroxysms (neuralgic pain), while continuous disorders are characterized by unremitting, constant patterns of pain and occasionally they may also present episodes of painful paroxysms. Information about common oral medications used for trigeminal neuralgia and other trigeminal neuropathic pains including dosages and side effects are summarized in Table 1. Topical agents commonly used in neuropathic orofacial pains are summarized in Table 2.

Table 1 Medications used for trigeminal neuropathic pains [1, 94, 96, 102,103,104,105]
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Table 2 Topical agents used in neuropathic orofacial pains [138,139,140,141,142, 207]
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3.1 Episodic Disorders

3.1.1 Trigeminal Neuralgia

Trigeminal neuralgia (TN) (ICOP 4.1.1; ICHD 13.1.1) is the most characteristic episodic neuropathic pain disorder and the most common neuralgia in the orofacial region [97]. The average onset is in the sixth decade of life; it is more prevalent in women and has an incidence of 12.6–27.0 per 100,000 person-years [96]. It is characterized by episodic unilateral and severe sharp, shooting, electrical-like paroxysmal pain localized in the distribution of one or more of the divisions of the trigeminal nerve, usually the maxillary (V2) and the mandibular (V3) divisions, where trigger areas can be localized intraorally and extraorally. Therefore, it is important to highlight that in the case of an intraoral trigger zone, a differential diagnosis to rule out dental pathology is necessary. The paroxysmal pain can be triggered but it can also present spontaneously. When it is triggered it can be elicited by innocuous stimuli and daily life activities, such as teeth brushing, washing the face, shaving, applying makeup, a cool breeze touching the face, eating, and talking [1, 98]. The duration of the pain can usually be from seconds to 2 min and can present periods of remission lasting days, to months to years in which minimal or no pain is appreciated. A distinctive characteristic of TN is that when the pain subsides, it presents a refractory period between attacks in which the pain is not elicited [1]. Pathophysiology may involve axonal demyelination and possible gain of function mutations of voltage-gated sodium channels (NaV) [96].

During the differential diagnosis of TN, it is critical to explore the cause further; therefore, imaging of the brain is necessary (e.g., magnetic resonance imaging/MRI). The ICHD-3 and the ICOP categorize TN into classical, where the cause is a neurovascular compression; secondary, where it is caused by an underlying disease including multiple sclerosis, an occupying lesion (e.g., cerebellum-angle tumor), or arteriovenous malformation; and lastly idiopathic, where no abnormalities in brain imaging or electrophysiological tests have been found [18, 92]. TN can present purely paroxysmal or also with concomitant continuous pain. Moreover, in some cases TN may present mild autonomic features and therefore the possibility of a trigeminal autonomic cephalgia or trigeminal autonomic orofacial pain should be explored during interview and examination. Short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA), or short-lasting unilateral neuralgiform facial pain attacks with cranial autonomic symptoms (SUNFA) [18, 99] should be considered in the differential diagnosis when autonomic symptomatology is more profound. As in TN, SUNFA can be localized in V2 and V3, but SUNCT and SUNA are localized in the ophthalmic division (V1). Another distinction is that unlike TN, these disorders do not have a refractory period [99, 100].

3.1.1.1 Management

The medication class used for the management of TN is antiepileptics and the only medication that is approved by the FDA for both TN and glossopharyngeal neuralgia is carbamazepine (see Table 1). Other medications such as oxcarbazepine, gabapentin, pregabalin, lamotrigine, baclofen, duloxetine, and topiramate are used too, but their use is off label [101]. Carbamazepine and oxcarbazepine are generally used as first line of management with specific recommendations [94, 96, 102,103,104]. When carbamazepine and oxcarbazepine are ineffective or patients present poor tolerability, other options such as gabapentin, pregabalin, baclofen, lamotrigine, anesthetic blocks, and botulinum toxin should be considered as an addition or monotherapy [94, 105, 106]. Other medications such as topiramate and duloxetine, an SNRI, have been reported in the use of TN but with unclear effectiveness and a lack of controlled studies to confirm their efficacy [101, 107, 108]. The use of carbamazepine needs to be monitored with complete blood count (CBC) and differential and liver function tests since there is a risk of hepatotoxicity and myelosuppression [109]. Screening of human leucocyte antigen (HLA) allele HLA-B*15:02 and HLA-A*31:01 is recommended when prescribing carbamazepine to avoid the risk for toxic epidermal necrolysis/Steven-Johnson syndrome (SJS), which even though rare, has been shown to be a greater risk in populations of Southeast Asian and Japanese descent [110, 111]. Serum sodium levels need to be monitored while using oxcarbazepine to avoid hyponatremia, and genetic testing for HLA-B*15:02 is recommended since it can also cause SJS [112].

It is not uncommon that TN symptomatology may present sudden exacerbations while a medication regimen has provided stability. Steroid administration is effective in the acute management of flare ups, and it may also potentially reduce the likelihood of surgical intervention [113]. Type of steroid, rescue dosages and length of treatment may vary (e.g., IV dexamethasone 20–40 mg to higher) in the emergency room setting [113, 114]. TN secondary to multiple sclerosis may also benefit from the use of steroid therapy; in addition, the use of prostaglandin-E1-analogue misoprostol (600 μg/day) has been shown to be effective in refractory cases [115, 116].

As described above, pharmacotherapy is the first line of management for TN. However, neurosurgical options need to be discussed when pain is refractory to management or side effects arise causing poor tolerability [105]. Unfortunately, there is no protocol that indicates how many medications the patient should try before surgery is discussed, but carbamazepine and oxcarbazepine should be tried in combination as well as the other options discussed above before surgery is offered [96, 117].

3.2 Continuous Disorders

3.2.1 Trigeminal Postherpetic Neuralgia

Post-herpetic neuralgia (PHN) (ICOP 4.1.2.2; ICHD-3 13.1.2.2) is a persistent and refractory pain condition present for 3 months or more following an outbreak of acute herpes zoster, known as shingles. PHN is more common in the elderly and immunocompromised populations and is associated with the reactivation of the dormant varicella zoster virus. The herpes zoster infection induces changes in the peripheral nervous system impairing all sensory fiber groups as well as changes in the central nervous system somatosensory processing. The pain experience is variable and described as a constant deep, aching, burning pain, and can present episodes of lancinating pain [118, 119].

3.2.1.1 Management

PHN is an extremely complex drug-resistant neuropathic pain. Medications including anticonvulsants, tricyclic antidepressants, opiates, topical capsaicin and lidocaine, botulinum toxin injections, and nerve blocks are used for its management [120, 121]. The use of opioids for orofacial pain is not supported by the literature and the risks for the development of hyperalgesia, tolerance, and physical dependence outweigh any benefit. See Tables 1 and 2 for summary.

3.2.2 Post-Traumatic Trigeminal Neuropathic Pain/Painful Post-Traumatic Trigeminal Neuropathy

Post-traumatic trigeminal neuropathic pain (PTTN) (ICOP 4.1.2.3)/painful post-traumatic trigeminal neuropathy (ICHD 13.1.2.3) can arise after injury to the trigeminal nerve and its branches and cause severe dysfunction. PTTN can occur after third molar extraction, local anesthetic blocks, root canal therapy, dental implant surgery, orthognathic surgery, as well as after ablation procedures for trigeminal neuralgia [92, 122, 123]. The prevalence in development can range from 3 to 5% [89, 124]. Pain is reported as continuous and variable in intensity, and can be described as burning, pricking, tingling, and accompanied by electric-like paroxysms of pain. In addition, positive somatosensory symptoms such as allodynia, and negative symptoms such as hypoesthesia and hypoalgesia may be present [125].

3.2.2.1 Management

Management of PTTN is based on evidence and guidelines associated with neuropathic pain management in other parts of the body and of different etiologies [94, 102]. Pharmacological therapy is the first line of management and comprises antidepressants and anticonvulsants [126]. These include tricyclic antidepressants such as amitriptyline and nortriptyline, which are often used as first-choice management, SNRIs such as venlafaxine and duloxetine, or anticonvulsants such as gabapentin or pregabalin [1, 127,128,129]. For summary, see Tables 1 and 2. Microsurgery can be recommended for PTTN when the injury involves the inferior alveolar nerve and/or the lingual nerve and when non-surgical options have been ineffective. However, these procedures carry their risks and challenges. Different variables (location, severity of injury, and pain characteristics and duration) need to be taken into account to select the right candidate for these procedures [89, 123].

3.3 Idiopathic Orofacial Pains

Idiopathic orofacial pains are a group of disorders where there is absence of any other obvious etiology. They may present somatosensory changes or not, as determined by qualitative and quantitative sensory testing [18, 130], and they may possibly be of nociplastic nature. Persistent idiopathic facial pain (PIFP), persistent idiopathic dentoalveolar pain (PIDAP) and burning mouth syndrome (BMS) will be briefly discussed. Diagnosis of these conditions is by exclusion where clinical and radiological exams are normal. A more comprehensive definition and criteria are listed in the ICOP [18].

PIFP (ICOP 6.2; ICHD-3 13.1.2.5 idiopathic painful trigeminal neuropathy), previously known as atypical facial pain, has an incidence estimated at 4.4 per 100,000 person-years and is more prevalent in women [131, 132]. It is characterized by a dull, aching, deep or superficial diffuse pain, is poorly localized, may not follow neuroanatomical distributions, and sometimes may present sensory abnormalities with considerable overlap with trigeminal neuropathic pain [18, 130, 133]. PIDAP (ICOP 6.3), previously known as atypical odontalgia, phantom tooth pain and primary dentoalveolar pain disorder (PDAP) [18], is presented as persistent tooth or teeth pain or pain over a dentoalveolar site in the absence of any detectable pathology during a radiological and clinical exam, and with no history of precipitating event/dental procedure for the last 6 months or more. PIDAP/PDAP can be comorbid with TMD and may be considered a chronic overlapping pain condition (COPC) [134]. BMS (ICOP 6.1; ICHD-3 13.11) may have some elements of neuropathic pain but it is still poorly understood. It is more prevalent in menopausal women and is characterized by an intraoral burning with fluctuating intensity that usually is bilateral with a common site such as the tongue. In BMS it is necessary to rule out any other secondary cause including candida infection, oral mucosa lesions, tobacco chewing, autoimmune and endocrine disorders, nutritional deficiencies, medication side effects, and chemotherapy [1, 8, 18].

3.3.1 Management

There are few RCTs for the pharmacological management of these disorders and there is not a standardized protocol. Management is multidisciplinary and should include pharmacological and non-pharmacological modalities, such as cognitive behavioral therapy and psychological support [128, 135]. See Tables 1 and 2 for more details. Pharmacological modalities include TCAs, SSNRIs (duloxetine), anticonvulsants (gabapentin, pregabalin), and for BMS, management options are even more limited—not only due to the incomplete understanding of its etiology and pathophysiology, but also for the appearance of side effects such as dry mouth with the use of some medications like TCAs that may exacerbate symptoms in some individuals. In addition to cognitive behavioral therapy, topical clonazepam, topical capsaicin, alpha-lipoic acid, and laser therapy appear to be beneficial in some patients [8, 127, 135]. Moreover, a couple of case reports show potential promise with the use of low-dose naltrexone (LDN) with a positive response decreasing BMS symptomatology as well as pain associated with other comorbidities present in these patients [136, 137].

3.4 Topical Medications, Botulinum Toxin and Nerve Blocks in the Management of Neuropathic Orofacial Pains

In addition to management with oral systemic medications (Table 1), other pharmacological modalities can be implemented as adjunct topical therapy and in specific cases as monotherapy if there is a contraindication to systemic medications.

3.4.1 Topical Agents

Topical agents offer safety, lower side effect profile, and rapid onset of action [138,139,140]. They are very useful in the case of peripheral neuropathies where during neurosensory testing complete pain relief is reported using a topical anesthetic or local anesthetic block, as well as in cases of centralized neuropathies where during neurosensory testing there is significant decrease in allodynia. Different compound formulations can be tailored for the patient and depending on the preparation and pain localization, they can be applied intraorally in the oral mucosa and extraorally in the skin as creams or patches. When they are indicated to be applied in the oral mucosa, a stent (neurosensory stent) is fabricated to help retain the topical agent in place covering the affected area [6]. Anesthetics such as lidocaine 5% and benzocaine 20% are commonly used intraorally as well as vanilloid agents such as capsaicin in a concentration of 0.025%–0.075%. When capsaicin is used, it needs to be used with caution as it can cause burning. Therefore, it is recommended that it is mixed with lidocaine or benzocaine to avoid this. Other preparations may include anticonvulsants (carbamazepine), tricyclic antidepressants (amitriptyline), antispasmodics (baclofen), NSAIDs (ketoprofen), N-methyl-D-aspartate (NMDA) antagonists (ketamine), and sympathomimetic agents (clonidine) [138, 139]. For BMS specifically, a clonazepam rinse, 0.5-mg/mL solution (5 mL) has been found beneficial [141, 142] (see Table 2).

3.4.2 Botulinum Toxin Type A Injection, Nerve and Sphenopalatine Ganglion Blocks

Evidence is growing supporting the use of botulinum toxin type A as an effective therapy approach for the management of TN and other trigeminal neuropathic pains [96, 143,144,145]. There is no current standardized protocol, but this approach could be used as adjunct therapy or monotherapy in some cases when oral systemic medications have not been effective or present poor tolerability. The injection approach could be extraoral as well as intraoral, localized in the area of trigger or pain. Approach, dosage units, and volumes vary [143, 146]. See Table 1.

3.4.3 Peripheral Nerve Blocks and Sphenopalatine Ganglion (SPG) Block

Peripheral nerve blocks are valuable as adjunct therapy in orofacial pain such as in the case of cranial neuralgias, and headache disorders. The most common anesthetic agents are lidocaine and bupivacaine in a variety of concentrations and volumes. Usually in clinical practice, nerve blocks are provided in infiltration series and based on the response of the first block. They include supratrochlear, supraorbital, infraorbital, auriculotemporal and greater occipital and lesser occipital injections [147,148,149]. In a retrospective study, occipital blocks were reported to be useful for trigeminal neuralgia and trigeminal neuropathic pain but not for persistent idiopathic facial pain [150]. This functional inhibition provided by the occipital nerve block on trigeminal nociceptive responses may be explained due to the converging of C2 and trigeminal inputs in the trigeminocervical complex before being processed in higher centers [151]. See Table 3 for summary.

Table 3 Common targets for peripheral nerve blocks in the management of orofacial pain
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Sphenopalatine ganglion (SPG) anesthetic block is useful in migraine and cluster headache and in some cases of facial pain such as trigeminal neuralgia [152,153,154]. Anesthesia of the SPG can be performed with a transnasal approach with topical application of local anesthesia to the mucosa of the lateral wall of the nasal cavity. This can be done with the use of an intranasal catheter or a long cotton-tipped applicator saturated with 4% lidocaine that is inserted intranasally [155].

3.5 Considerations for the Management of Neuropathic Orofacial Pains

Due to the different presentations and etiologies of neuropathic orofacial pain disorders, a careful diagnosis is critical. In addition, a combination of different management approaches may be implemented for the same individual in an effort to provide adequate pain relief. Some considerations for patients with trigeminal neuralgia and continuous trigeminal neuropathic pains are provided. These provide guidance and do not pretend to be exhaustive. Protocols may vary in different care provider settings.

3.5.1 Considerations for the Management of Trigeminal Neuralgia (TN)

Step 1

  • TN may mimic dental pain; therefore, during differential diagnosis and more so if pain is localized intraorally, it is important to consider a dental examination and imaging to rule out possible odontogenic causes.

  • Do not confuse TN with TMD. The symptomatology is different, however, patients with TN may also present myofascial pain as a secondary muscle co-contraction or protective muscle co-contraction in response to the paroxysm of TN pain.

  • When odontogenic causes and TMD are ruled out, conduct brain imaging to identify if TN is classical, secondary, or idiopathic.

  • Prepare a plan that includes pharmacological and non-pharmacological modalities. Consider consultation/referral with other health providers.

    Step 2

  • Start with carbamazepine or oxcarbazepine as first line. Screen for HLA-B*15:02 and HLA-A*31:01. Order laboratory tests: liver function test; complete (full) blood count (CBC) as baseline and to monitor during therapy with carbamazepine.

  • Gabapentin (or pregabalin) may be chosen as an alternative in case of side effects as well as to prevent possible medication interactions that may exclude the use of carbamazepine.

  • Alternatives to carbamazepine are to switch to oxcarbazepine or the addition of baclofen in cases when it is being effective but side effects arise.

  • Trigger areas may benefit from adjunct therapy with the use of anesthetic blocks or botulinum toxin type A.

    Step 3

  • If no or inadequate pain relief, lamotrigine can be tried.

  • Gabapentin, pregabalin, baclofen, lamotrigine and botulinum toxin should be considered as an addition or monotherapy.

    Step 4

  • If pain is refractory or side effects are intolerable after different trials of combination therapy, surgical options should be discussed.

3.5.2 Considerations for the Management of Continuous Trigeminal Neuropathic Pains

Step 1

  • Establish the diagnosis. In the case of idiopathic or ‘atypical’ facial pains, diagnosis could be even more challenging. Include in your differential diagnosis possible musculoskeletal sources of pain such as TMD, inflammation of the stylohyoid ligament (eagle syndrome) and neurovascular sources, either orofacial pain resembling primary headache disorders or secondary headaches. In the case of possible BMS, carry out a thorough examination and medical history to rule out possible secondary sources.

  • Prepare a plan that includes pharmacological and non-pharmacological modalities. Consider consultation/referral with other health providers.

    Step 2

  • Management can be initiated with first-line medications using TCA (e.g., amitriptyline, nortriptyline) or an SNRI (duloxetine, venlafaxine). Anticonvulsants such as gabapentin and pregabalin can also be used.

  • In cases of BMS, initiate treatment with clonazepam rinse, TCA, or gabapentin. Symptomatology may require the use of more than one of these medications. If dry mouth due to the use of TCA is present, consider the use of venlafaxine.

  • In cases of post-traumatic trigeminal neuropathy, if the patient reports continuous pain accompanied by paroxysms of sharp, shooting electrical pain, similar to TN, consider the use of anticonvulsants starting with calcium channel blockers.

  • In cases of peripheral neuropathic pain/intraoral pain, consider the use of topical medication, anesthetic blocks and/or botulinum toxin A injection.

  • During neurosensory testing, if the anesthetic block does not completely relieve the chief pain complaint (centralized) but a pain reduction is reported, the use of topical medications should be considered in the treatment plan as an adjunct therapy to oral pharmacology.

  • The addition of more than one oral medication may be necessary for optimal management. Consider including anesthetic blocks and botulinum toxin A injections if side effects arise to provide substantial pain relief.

    Step 3

  • If pain relief is not optimal, consider the use anticonvulsants including carbamazepine, oxcarbazepine, or lamotrigine.

    Step 4

  • If trials of first-line medication, combination treatment, and adjunct therapy is still not optimal, consider referral to a multidisciplinary pain center for other management options.

4 Headache and Orofacial Pain

Patients with TMD can also report headache symptomatology, with dull, aching, sore, or tension-type pain in the head region. This pain is aggravated by TMJ biomechanics and/or parafunctional habits such as clenching or grinding. The ICHD-3 categorizes this type of head pain as headache secondary to TMD [92]. This headache may be ipsilateral to the area of TMD symptomatology or bilateral and may also refer to the temple area. TMD and primary headache disorders, particularly migraine and chronic daily headache, can be comorbid [156, 157], in that they are more likely than chance to occur together. The shared anatomical and physiological relationship of the craniofacial structures are likely a factor in this comorbidity; both are mediated by the trigeminal nociceptive system. However, calcitonin gene-related peptide (CGRP), a neuropeptide thought to be integral to migraine mechanisms and an established therapeutic target, is also involved in TMD pathogenesis and may be a potential therapeutic target [158,159,160]. Lastly, the presence of TMD, particularly chronic TMD, in migraine patients is a significant risk factor to accelerate progression to chronic migraine [161]. A further concern is that the presence of TMD in migraine patients significantly impacts migraine therapeutic management, making it much more challenging [157, 162,163,164,165,166]. Current recommendations are for each disorder to be managed simultaneously [25, 159, 167]. However, perhaps in the future for certain cases, protocols targeting an overlapping mechanism, such as CGRP as a monotherapy, when this comorbidity is present, may offer an effective avenue for management [159].

Primary headache disorders are most commonly localized in the frontal, temporal, parietal, and occipital areas, behind the eye (V1 distribution) or the neck (C1–C2 distribution) [17, 92]. However, they can also be localized in the mid-facial region, classified as ‘orofacial pains resembling presentations of primary headaches’ [18]. It is known that stimulation of the dura mater can induce pain that resembles a migraine phenotype, not only in the ophthalmic division [168, 169], but through all three divisions of the trigeminal nerve [170, 171]. Moreover, the convergence of inputs in the trigeminocervical complex from all three trigeminal divisions, the upper cervical regions [172], as well as the trigeminal autonomic reflex and the interactions with higher centers, may explain this clinical presentation [173]. Orofacial pains that resemble characteristics and features of primary headache disorders may present a challenge during diagnosis and therefore management. This is especially the case when the clinician is not aware of this presentation. It is imperative during differential diagnosis, in addition to ruling out odontogenic and other types of musculoskeletal or neuropathic orofacial pains, that there is screening for red flags and potential sources of secondary headache disorders. Consultation and collaboration with neurology and headache medicine is essential.

Within the ICHD-3 there is mention of ‘facial migraine’ under the subcategory of migraine without aura [92]. However, the ICOP provides a more thorough diagnostic criteria of ‘orofacial pains resembling presentations of primary headache’, including orofacial migraine, tension type orofacial pain, trigeminal autonomic orofacial pain, and neurovascular orofacial pain [18]. For example, in the case of an orofacial migraine, the use of migraine therapeutics will be indicated, and in the case of paroxysmal hemifacial pain (trigeminal autonomic orofacial pain), a response with therapeutic doses of indomethacin is indicated to confirm diagnosis and for management.

Migraine management involves pharmacotherapy including medications, nerve blocks, and the onabotulinum toxin A protocol for chronic migraine, as well as non-pharmacological approaches that include neuromodulatory devices and behavioral approaches. More comprehensive discussions about headache therapeutics can be found elsewhere, including consensus updates for integrating newer migraine treatments provided by the American Headache Society [174,175,176], and summarized in Table 4 (acute treatments) and Table 5 (preventive treatments).

Table 4 Commonly used acute migraine treatments [208,209,210,211]
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Table 5 Preventive migraine treatments [208,209,210,211,212]
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It is worth noting that this is an exciting new era in headache management with new specific medications that target CGRP and its receptor, as well as non-pharmacological approaches such as non-invasive neuromodulation [174]. Alongside established acute treatment approaches, including NSAIDs, over-the-counter analgesics, and triptans, there are the newer small molecule CGRP receptor antagonists, gepants, including rimegepant, ubrogepant [177], and the newly approved nasal spray, zavegepant [178]. Lasmiditan, a 5HT-1F receptor agonist, is also approved for the acute management of migraine [177]. There are four approved monoclonal antibodies for migraine prevention that directly target CGRP (fremanezumab, eptinezumab, and galcanezumb) or the CGRP receptor complex (erenumab) [179]. Two gepants (atogepant and rimegepant) are also now approved for the prevention of episodic migraine [180]. For treatment options for tension-type headache and trigeminal autonomic cephalalgias, readers are referred to these detailed review papers [181, 182].

5 General Pearls in Orofacial Pain Management

5.1 Comprehensive Medical History

Obtaining a complete description of the pain (onset, frequency, duration, quality, and intensity) is necessary in the diagnostic process in order to determine etiology and subsequently in the treatment planning process. Pain associated with function and TMJ biomechanics may indicate the possibility of a TMD, pain associated with migrainous symptoms or autonomic phenomena may indicate the possibility of an orofacial migraine or trigeminal autonomic orofacial pain. A history of persistent dental pain, history of trauma, vesicles indicating probable viral origin (PHN), and systemic symptoms indicating possible rheumatologic disease or a neurologic demyelinating process will be crucial in directing the provider to the appropriate diagnostic tests to order, and to determine which tests are not necessary.

5.2 Performing a Thorough Clinical Exam

The clinical exam serves to help the provider rule out secondary pathology as well as to identify the source of pain, pattern of referral, location of the symptoms and trigger zones. With the identification of trigger zones, incorporating topical management strategies can improve pain symptoms with minimal adverse effects. Diagnostic testing with trigger point injections, in cases of suspicious dental pains when dental pathology has been ruled out, is a great resource to identify possible myofascial pain and muscular source. In addition, for neuropathic pains, diagnostic testing with peripheral nerve blocks from topical anesthetics, local infiltration, and regional blocks will be invaluable in determining whether the symptoms are able to be modulated through peripheral versus systemic treatment modalities, or whether both should be considered.

5.3 Medication Interactions, Dosages, Titrating, and Tapering

Oral medications are considered first-line management. Review medical history for possible contraindications and interactions. Antidepressants or anticonvulsants are typically used for the management of primary neuropathic pain. However, these can also cause adverse effects and synergistic effects with other medications including serotonin syndrome. Medications may interact with current medications that can have an additive effect in terms of side effects. With tricyclic antidepressants, cardiac toxicity is a concern, and should be used with caution in patients with ischemic cardiac disease or ventricular conduction abnormalities. With the gabapentinoids, dosage reduction is recommended in patients with renal insufficiency, and dosage adjustments can be made in relation to creatinine clearance. It is recommended to titrate slowly to avoid the abrupt appearance of side effects. Increase dose until sufficient pain relief is attained, or intolerable side effects appear. While tapering dose, decrease the dosage to the lowest effective dose where the patient experiences pain relief or where intolerable side effects disappear, or tolerable side effects are present [105].

5.4 Pregnancy

Our knowledge about the impact of medications for the management of orofacial pain and headache during pregnancy is limited, and the use of topical medications and local anesthetic blocks should be considered. When a CNS-acting drug is used during pregnancy, careful follow-up during pregnancy and after childbirth is required. It is important to have a conversation with the patient about pregnancy plans and to establish a plan with the patient and other care providers. Regarding TMD, the use of acetaminophen as an analgesic is safe but non-pharmacological approaches in the management plan may be the focus to optimize care. For neuropathic pains, folic acid supplements are recommended from the prenatal stage for mothers using some antiepileptics to diminish the risk of neural tube defects [183]. The first trimester should be a period with minimum drug exposure if possible. Medications should be used at the minimum effective dose and monotherapy is preferable [184]. For headache management, triptans are considered safe, and the use of magnesium as well as neuromodulation devices can be added to the toolbox care of the patient [185, 186].

5.5 Team-Based Approach to Management

Patients seeking OFP care often have multiple comorbid health conditions that impact their prognosis. These include, but are not limited to, depression and anxiety, sleep disorders, and chronic overlapping pain conditions [10, 16, 33, 187,188,189]. In addition, in case of headache disorders or the possibility of red flags and secondary headache sources, it is essential to consult with neurology/headache medicine specialists. Therefore, optimal care necessitates a multidisciplinary management approach tailored to the individual patient [190] with a team of healthcare professionals. Modalities used in the management of neuropathic pain involve medications, interventions including somatic nerve blocks, autonomic nerve blocks (sphenopalatine and stellate ganglion), neuroablative procedures, surgical options (neurectomy), injection of botulinum toxin, and psychological management. When a multimodal approach is necessary, referral for evaluation and treatment to other providers should be made for optimal patient outcomes and improvement in quality of life.

6 Discussion

Orofacial pain disorders comprise a vast array of disorders with different etiologies and pathophysiological mechanisms supporting their complexity. These together with the interrelated anatomy and physiology of the craniofacial and cervical structures, may pose a challenge in diagnosis. In particular, when pain mimics dental pain or is localized intraorally, there is a risk of misdiagnosis followed by unnecessary dental procedures in efforts to relieve symptomatology. In order to diagnose and manage these disorders, specialty care by an orofacial pain specialist is required. In the United States, orofacial pain is a newly recognized dental specialty that focuses on the evaluation, diagnosis, and evidence-based management of these complex disorders bridging the domains of dentistry and medicine.

Furthermore, after a correct diagnosis, these complex conditions may still be challenging to manage. It has been reported that pharmacological management may require different trials of medication protocols until a plan is built depending on the diagnosis and may include systemic and topical medications, trigger point injections, and nerve blocks. In addition to pharmacological management, the focus of this review, non-pharmacological approaches and a multidisciplinary team of care is essential, underscoring the importance of the biopsychosocial model of care [2].

The biopsychosocial framework assesses the multilayered interplay between a person’s biological, psychological, and social health and how this may influence both the perception of, and response to, pain [191]. In the context of a biopsychosocial stratified care approach, a variety of therapeutic categories should be considered to target modifiable contributory factors. This approach may be chosen if a patient’s pain is high impact and causes severe functional limitations, as it has been shown to produce better clinical outcomes and reduced disability [192].

Self-management approaches are particularly useful in TMD, and may include patient education, jaw relaxation and habit reversal, sleep optimization, healthy nutrition intake, physical activity, and breathing techniques [193, 194]. Oral parafunctional activities such as clenching or grinding the teeth, protruding or pressing the tongue to the palate, mandibular posturing, or other masticatory overuse activities, such as chewing gum, pose a physiologic risk to the trigeminal system and may increase the risk of head or face pain in a vulnerable individual [13, 195]. Therefore, modifying these habits and teaching jaw posture relaxation may play an essential role in recovery [196]. The use of oral appliances such as stabilization appliances can be utilized as part of the management plan even though RTC and systematic reviews have brought into question their efficacy, but other studies have shown favorable results improving myogenous and arthrogenous symptomatology [197].

Cognitive behavioral therapy (CBT) has been shown to be effective for several OFP conditions and should be strongly considered as part of the management strategy [198]. In addition, complementary modalities, such as acupuncture therapy, has demonstrated benefit for chronic pain in a large meta-analysis assessing over 20,000 patients [199], including showing benefit for some OFP patients [200,201,202]. As many studies question whether acupuncture benefit is derived from the procedure itself or a non-specific effect, further well-designed studies should explore the value of acupuncture in orofacial pain patients, but its safe and conservative nature warrant consideration as part of a management strategy.

New pharmacological and non-pharmacological approaches in the field of orofacial pain are greatly needed. Often, reaching the effective therapeutic dosage of pain control may originate the appearance of side effects, presenting the dilemma of relieving the pain that is affecting the quality of life of the patient with medications that also may greatly impact this quality. Efforts in understanding pain modulation and neuroplasticity in orofacial pain disorders in addition to identifying new and safer targets for management are essential. In particular, research that focuses exclusively on trigeminal neuropathic pains is needed since current therapeutic options are not optimal. CGRP is a neuropeptide involved in peripheral and central sensitization in the nervous system and a current therapeutic target for migraine that has shown not only efficacy, but safety [203]. Promising clinical research efforts are being geared towards exploring targeting CGRP as a management approach for OFP since evidence suggests that CGRP also has a role in TMD pathophysiology [158], as well as in trigeminal neuropathic pains [204]. Moreover, the use of LDN, a semisynthetic opioid that in higher dosages functions as an opioid antagonist, but in very low dosages (0.1–5 mg) acts as a glial modulator through the Toll-like receptor 4 (TLR4), has shown to induce antinociceptive and anti-inflammatory actions with a relatively low side effect profile [205, 206]. LDN may also be a promising new therapeutic approach for the management of chronic orofacial pain as is indicated by a couple of case reports supporting its use in BMS [136, 137, 206]. Further exploration of LDN, CGRP therapeutics, and the discovery of new potential targets in addition to other modalities of management for orofacial pain disorders, is greatly needed.

7 Conclusion

Orofacial pain disorders can be challenging to diagnose and manage. The orofacial pain specialist is trained to diagnose and manage these conditions. Pharmacological and non-pharmacological management in a multidisciplinary manner is the best approach to care for patients with these conditions. Research efforts on novel and safer pharmacotherapeutic targets for OFP management are essential to offer better care of this patient population.