Introduction

The orofacial region is the site of some of the most common acute and chronic pain conditions. This region also has special psychological, social and emotional meaning and importance in eating, drinking, sexual behaviour, speech and expression of emotions. The orofacial tissues are densely innervated by nociceptive afferents and have an extensive somatosensory representation in the central nervous system (CNS). These features may also account for why many people find it unpleasant and painful to go for a routine dental examination.

This chapter first highlights the peripheral and central neurobiological mechanisms underlying orofacial pain and then outlines the clinical features of some of the most common or perplexing chronic orofacial pain conditions.

Orofacial nociceptive processes

Primary afferent mechanisms

The rich innervation of the orofacial region is almost exclusively by branches of the trigeminal nerve. Many trigeminal primary afferent fibers terminate in these tissues as free nerve endings and function as nociceptors. The nociceptive afferents are either small‐diameter, myelinated (A‐delta) afferents or even smaller (and slower conducting) unmyelinated (C) afferents. Their primary afferent cell bodies occur in the trigeminal ganglion.

Like analogous afferent endings and ganglion cell bodies of spinal nerves (see Chapter 3), trigeminal nociceptive afferents are subject to considerable modulation because a peripheral substrate exists for complex interactions between the neural, immune, cardiovascular and endocrine systems [1–7]. Tissue damage, and inflammation if present, cause the release of chemical mediators, some of which can enhance the excitability of the nociceptive endings (e.g. prostaglandins, interleukins, ATP, glutamate). The increased excitability can be expressed as outright activation or as so‐called nociceptor or peripheral sensitization. This sensitization can be reflected in a lowered activation threshold, increased responsiveness to subsequent noxious stimuli and spontaneous activity of the nociceptive endings that contribute, respectively, to the allodynia, hyperalgesia and spontaneous pain that are features of acute and many persistent orofacial pain conditions [1–7]. The chemical mediators may also spread through the tissues and act on the endings of adjacent nociceptive afferents and thus contribute to the spread of orofacial pain. Injury or inflammation of peripheral tissues, including nerves, may also lead to phenotypic changes, sprouting or abnormal discharges of the nociceptive afferents and be of pathophysiological significance in certain chronic pain conditions. It is also notable that some of the chemical mediators may reduce the excitability of the nociceptive afferent endings. Peripherally acting analgesic drugs may act by counteracting the effects of mediators that enhance afferent excitability; for example, aspirin affects the synthesis of prostaglandins. It is also noteworthy that some of these effects of orofacial injury or inflammation may also be expressed in the neuronal cell bodies of the primary afferents in the trigeminal ganglion and involve several mediators and non-neural cells in the ganglion (e.g. satellite glial cells) [3, 5]. Interestingly, the excitability changes induced in the ganglion neurons by these factors may occur not only in the neurons innervating the injured or inflamed tissues but also other ganglion neurons innervating non-injured or non-inflamed tissues. Many of these neuronal excitability changes are excitatory and, as a result, abnormal ectopically evoked afferent inputs may project into the brainstem and contribute to the spread, poor localization and ectopic sensations that occur in some orofacial pain conditions.

Facial skin, oral mucosa, temporomandibular joint (TMJ), craniofacial muscle and periodontal tissues are supplied by nociceptive afferents with properties generally analogous to those of spinal nociceptive afferents although corneal and cerebrovascular nociceptive afferents do have some special properties as do those supplying the tooth pulp [2, 5, 7]. The tooth pulp is a highly vascular and richly innervated tissue which is exceptionally sensitive to stimulation and a frequent source of dental pain. The dentine encasing the pulp is also very sensitive despite its sparse innervation and it appears that activation of intradentinal afferents is brought about by a hydrodynamic mechanism; non-neural cells in the pulp (e.g. odontoblasts) are also involved. Injury to the tooth and pulpal inflammation (e.g. as a result of dental caries) can induce peripheral sensitization of intradental afferents, which may result in extremely intense toothache, because inflammation of the pulp occurs in a non-compliant environment (it is encased by dentine) with a high extracellular tissue pressure. This is thought to be an important factor accounting for the great sensitivity of pulp afferents when the pulp is inflamed [2].

Brainstem mechanisms

From the trigeminal ganglion, trigeminal afferents project into the brainstem and terminate on neurons especially in the trigeminal brainstem sensory nuclear complex. Here they release neurochemicals (e.g. glutamate, neuropeptides) that can activate the neurons. The trigeminal brainstem sensory nuclear complex consists of the trigeminal main sensory and the trigeminal spinal tract nucleus. The latter is subdivided into three subnuclei: oralis, interpolaris and caudalis (Figure 33.1). The subnucleus caudalis is a laminated structure with many morphological and functional similarities to the dorsal horn of the spinal cord; indeed, it is often termed the medullary dorsal horn. Based on its anatomic, neurochemical and physiological features and the effects of brainstem lesions, caudalis is now considered the principal although not exclusive brainstem relay site of trigeminal nociceptive information. Indeed, the other subnuclei (oralis, interpolaris), the so‐called transition zone between subnuclei caudalis and interpolaris, and even the upper cervical spinal dorsal horn (which itself receives some trigeminal afferent inputs), may contribute to the brainstem mechanisms of orofacial pain [3–7].

Some caudalis nociceptive neurons respond only to stimulation of a cutaneous or mucosal mechanoreceptive field and can do so in a graded manner as stimulus intensity is increased. As a consequence, they are thought to have an important role in our ability to localize, detect and discriminate superficial noxious stimuli and their intensity. However, most neurons can also be activated by peripheral afferent inputs from other tissues (e.g. tooth pulp, TMJ, jaw muscle or cerebrovasculature) innervated by trigeminal nerve branches and some by afferent inputs from tissues supplied by non‐trigeminal nerves (e.g. upper cervical nerves). Such features are thought to contribute to the very common clinical findings of poor localization and referral of pain from deep tissues or from one tooth to another.

Neurons in caudalis and other components of the trigeminal brainstem complex project to the thalamus either directly or indirectly by polysynaptic pathways (e.g. via the reticular formation) (Figure 33.1). Some of the latter projections, as well as those to the cranial nerve motor nuclei and brainstem autonomic nuclei, provide part of the central substrate underlying autonomic, endocrine and muscle reflex responses to orofacial stimuli. Some neurons have only intrinsic projections such that their axons do not leave the trigeminal brainstem complex but instead terminate within it (e.g. interneurons in lamina II of caudalis, the so‐called substantia gelatinosa).

Thalamocortical mechanisms

Orofacial somatosensory information is relayed from the brainstem to the lateral thalamus (e.g. ventrobasal complex; the ventroposterior nucleus in humans) and medial thalamus (e.g. medial nuclei) which contain nociceptive neurons with properties generally similar to those described for nociceptive neurons in the subthalamic relays such as subnucleus caudalis [4–7]. Those in ventrobasal thalamus have properties and connections with the overlying somatosensory cerebral cortex which point to a role in localization and discrimination of orofacial noxious stimuli, whereas those in the more medial thalamic nuclei project to other higher brain areas (e.g. hypothalamus, anterior cingulate cortex) which are involved more in the affective or motivational dimensions of pain, by analogy with the spinothalamic system and its presumed functional aspects.

Modulatory influences

Pain is modulated by a variety of influences that regulate perceptual, emotional, autonomic and neuroendocrine responses to noxious stimuli by utilizing several excitatory and inhibitory neuro‐chemicals. Some of these modulatory influences may be expressed at thalamic and cortical levels, but the intricate organization of each subdivision of the trigeminal brainstem complex, coupled with the variety of inputs to each of them from peripheral tissues or descending from some parts of the brain (e.g. in the thalamus, reticular formation, limbic system and cerebral cortex), provides a rich substrate for numerous and complex interactions between the various inputs that can result in the modulation of orofacial nociceptive transmission [3–7]. This means that the neural circuitry underlying nociceptive transmission, including that in the trigeminal system, is “plastic” and not “hard‐wired” which may be a significant feature in the chronification of orofacial pain.

The descending influences are activated by a variety of behavioral and environmental events and can modify pain. Orofacial nociceptive transmission is also subject to modulation by so‐called segmental or afferent influences, which can be evoked by peripheral stimulation and involve the interneuronal circuitry existing within subnucleus caudalis and adjacent brainstem areas. Segmental or descending inhibitory substrates are thought to contribute to the efficacy of several analgesic approaches (e.g. deep brain stimulation; drugs such as morphine, carbamazepine, tricyclic antidepressants [TCAs]).

As in the spinal system, nociceptive transmission in the trigeminal system can also be enhanced by alterations to the peripheral afferent inputs to the CNS as a result of trauma or inflammation to peripheral tissues or nerves. Trauma or inflammation produces a barrage of nociceptive primary afferent inputs into the CNS that may lead to neuroplastic alterations in subnucleus caudalis (and spinal dorsal horn) and/or higher‐order neurons; processes which collectively have been termed central sensitization. Trigeminal central sensitization is reflected in an increased excitability of caudalis nociceptive neurons, manifested as an increase in spontaneous activity, mechanoreceptive field expansion, lowering of activation threshold and enhancement of peripherally evoked nociceptive responses of the neurons [3–7]. These neuroplastic changes can be prolonged and contribute to the development and maintenance of persistent and chronic orofacial pain and its common characteristics of spontaneous pain, pain spread and referral, allodynia and hyperalgesia. Several membrane receptor mechanisms, ion channels and intracellular signaling processes are involved in trigeminal central sensitization and include purinergic and neurokinin as well as N‐methyl‐D‐aspartate (NMDA) and non‐NMDA (e.g. metabotropic) glutamatergic receptor processes. Non‐neural cells (especially astroglia and microglia) in subnucleus caudalis have been shown to be key players in the development and maintenance of trigeminal central sensitization Trigeminal central sensitization occurs not only in subnucleus caudalis but also in subnucleus oralis and higher brain regions such as ventrobasal thalamus; nonetheless, caudalis has been shown to be responsible for the expression of central sensitization in these structures by way of its projections to both. Several currently used analgesic approaches (e.g., opioids, pregabalin) have been shown to act by counteracting the processes underlying central sensitization [4, 5, 7] and the standard approach in dentistry of using local anesthesia to minimize pain before, during and after an operative procedure is effective because it blocks the nociceptive afferent inputs from the operative site that otherwise would induce trigeminal central sensitization. This brings us to consider other clinical aspects bearing on orofacial pain and in particular its more chronic manifestations.

Clinical aspects

Orofacial pain covers a wide range of conditions with different clinical manifestations. Recently, a comprehensive classification of all types of orofacial pain was published based on an international multidisciplinary collaboration, the International Classification of Orofacial Pain (ICOP) [8]. The following sections focus on some of the most common and most perplexing of these conditions. Because of their complexity, plus the special emotional and psychosocial meaning of the orofacial region, the diagnostic work‐up and management strategy will often require a substantial interdisciplinary approach between the medical profession, dentists, psychologists and specialists in orofacial pain.

Temporomandibular disorders

Temporomandibular disorders (TMD) cover an umbrella of common and related pain conditions in the jaw muscles, TMJ and associated structures. A milestone paper in the field suggested that these conditions could be divided into three main categories [9]: 1). Myofascial pain; 2). Disc displacements; and 3). TMJ arthralgia, osteoarthrosis and osteoarthritis. Perhaps more important than this physical axis (axis I) was the introduction of an axis II to cover the disability and pain‐related distress of the patient [9]. A follow‐up on this classification ‐ the so‐called Diagnostic Criteria for TMD (DC/TMD) [10] proposed a reorganization into 1). Muscle disorders (myalgia and myofascial pain) 2). TMJ disorders (arthralgia, disc displacements, degenerative joint diseases and dislocation and 3). Headache attributed to TMD. The recent release of the ICOP mentioned above integrates the DC/TMD with the International Association for the Study of Pain and International Classification of Diseases (ICD11) [11] and the International Classification of Headache Disorders (ICHD‐3) [12]. An important aspect of these classifications are the introduction of primary and secondary pains. Chronic primary pain is pain that persists greater than 3 months and cannot be explained by another chronic pain condition ‐ pain as a disease in its own right. Secondary chronic pain is pain linked to other diseases as the underlying cause and may initially be regarded as a symptom. Thus, for all TMD pain conditions, there are now operationalized and specific criteria to help in phenotyping the specific subtype of TMD pain on two axes.

TMD pain is very common in the population (3–15%) and is 1.5–2 times more prevalent in women than in men, with a peak around 20–45 years [13]. Degenerative TMJ conditions generally increase over the lifespan. The incidence of TMD pain is 2–4%, with the incidence of persistent types being 0.1%. Generalized pain conditions such as fibromyalgia, whiplash‐associated disorders, tension‐type headache/migraine, low‐back pain, irritable bowel syndrome and general joint laxity, as well as sleep disturbances, depression and anxiety, have all been found to be often comorbid with TMD pain conditions [13].

Overall, there are three cardinal symptoms of TMD:

1. Pain in the jaw muscles and/or TMJ.
   
2. Sounds from the TMJ (clicks, crepitation).
   
3. Limitation in range of jaw motion [14].

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