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Acute and Chronic Orofacial and Dental Pain


SUMMARY

The constellation of orofacial pain disorders is a major health care issue with high prevalence, intensity, and immeasurable impact on quality of life. Although there are many common aspects of pain transduction and processing between the trigeminal and spinal systems, there are also numerous examples of unique features in the peripheral and central components of the trigeminal pain system. Accordingly, ongoing basic and clinical research in the area of orofacial pain is required to understand the unique features of this pain system and to develop and evaluate better ways to treat patients with orofacial pain. This chapter provides an overview of key distinguishing features between the trigeminal and spinal pain system and summarizes mechanisms and management of selected common orofacial and dental pain disorders.

Introduction

Orofacial pain disorders are a major and expensive component of health care and collectively have a high prevalence rate with a large range in pain intensity and a commensurate, often devastating impact on quality of life ( ). In summarizing this issue, the U.S. Surgeon General concluded that “… oral health means much more than healthy teeth. It means being free of chronic oral-facial pain conditions …” ( ). Community-based surveys indicate that many subjects commonly report pain in the orofacial region, with estimates of more than 39 million, or 22% of the adult population, in the United States alone (Lipton et al 1994). Other population-based surveys conducted in the United Kingdom ( ), Germany ( ), or regional pain care centers in the United States ( ) report similar occurrence rates ( ). Importantly, chronic widespread body pain, patient sex and age, and psychosocial factors appear to be risk factors for chronic orofacial pain ( ; ; ; ). In addition to their high degree of prevalence, the reported intensity of various orofacial pain conditions is similar to that observed with many spinal pain disorders ( Fig. 57-1 ). Moreover, orofacial pain is derived from many unique target tissues, such as the meninges, cornea, tooth pulp, oral and nasal mucosa, and temporomandibular joint ( Fig. 57-2 ), and thus has several unique physiological characteristics with respect to the spinal nociceptive system ( ). Given these considerations, it is not surprising that accurate diagnosis and effective management of orofacial pain conditions represent a significant health care problem.

Figure 57-1, Comparison of pain intensity in spinal and orofacial pain disorders with the McGill Total Pain Rank Index (PRI [T]).

Figure 57-2, Unique target tissues innervated by the trigeminal sensory system.

In this chapter we focus on the pathophysiology and treatment of several common forms of acute and chronic orofacial pain, including oral and dental pain conditions, as well as musculoskeletal-based disorders and neuropathic pain disorders. This review focuses more on intraoral forms of orofacial pain since extensive reviews of many other important orofacial pain disorders, such as trigeminal neuralgia and headache, are available in other chapters in this text and others ( ).

Neurobiology Of Orofacial Pain

Extensive overviews of basic research on the trigeminal nociceptive system have been published ( ), including recent studies on the electrophysiological ( ), anatomical ( ), and pharmacological ( ) properties of trigeminal afferents innervating distinct target tissues. One important emerging concept is that the target tissue is not merely a passive location for the termination of afferent fibers. Instead, target tissues dynamically interact with neuron terminals either via soluble factors such as neurotrophins ( ) or by binding of extracellular matrix molecules to cellular integrins ( ), thereby regulating the expression or trafficking of neuronal proteins, including ion channels and receptors ( ) or second-messenger signaling pathways ( ). Thus, the presence of multiple and unique target tissues innervated by trigeminal afferent fibers (see Fig. 57-2 ) probably contributes to differences in the responsiveness of these neurons. From this perspective it should be appreciated that notable differences have been reported among trigeminal afferents innervating different orofacial tissues, as well as between trigeminal and spinal afferent neurons. Differences between these afferent systems under basal conditions have recently been reviewed ( ). Table 57-1 illustrates differences between the trigeminal and spinal systems after various forms of injury. Collectively, these studies indicate that the trigeminal system has many unique features that may contribute to distinct response patterns under basal conditions and after tissue injury.

Table 57-1
Comparison of the Trigeminal and Spinal Afferent Systems after Injury
MARKER INJURY MODEL COMPARISON REFERENCES
Galanin Axotomy TG ~ DRG for up-regulation Arvidsson et al 1994, Zhang et al 1996
NPY Axotomy TG ~ DRG for up-regulation Arvidsson et al 1994, Zhang et al 1996
Sympathetic fiber sprouting into ganglia and basket formation Axotomy or CCI TG: no; DRG: yes Bongenhielm et al 1999, Benoliel et al 2001
Sympathetic fiber sprouting into ganglia NGF infusion ICV × 14 days DRG > TG Nauta et al 1999
SNS/PN3 = Na v 1.xx Axotomy TG: down-regulation followed by normalization
DRG: persistent down-regulation		 Bongenhielm et al 2000
Ankyrin (G) Axotomy TG: persistent down-regulation Bongenhielm et al 2000
Ectopic firing of afferents Axotomy TG < DRG Tal et al 1992
Augmented excitability Axotomy TG ~ DRG Tal and Devor 1992, Zhang et al 2002, Cherkas et al 2004
Frequency and rhythmicity of spontaneous discharges Tight ligation of the infraorbital versus sciatic nerves DRG had a significantly greater spontaneous discharge rate than TG neurons did for both myelinated and unmyelinated fibers. DRG afferents had rhythmic discharge rates (not seen with TG) Tal and Devor 1992
Satellite glial cells Axotomy TG ~ DRG for up-regulation of GFPA, proliferation Woodham et al 1989, Stephenson et al 1995
NOS Axotomy TG ~ DRG for up-regulation Hokfelt et al 1994
P2X 3 and ATF3 expression Partial axotomy TG ~ DRG Tsuzuki et al 2001
GM 3 ganglioside Knockout of the GM 2 /GD 2 and GD 3 synthase gene Facial wounding > the rest of the body with peripheral nerve degeneration Inoue et al 2002
Peripheral chromatolysis LiCl TG ~ DRG Levine et al 2004
Sensory neuropathy with neuronal degeneration Sjögren’s syndrome TG ~ DRG Malinow et al 1986
Infectivity of contralateral ganglia HSV-1 infection 70% of TG contralateral to the side of HSV injection produced infections after inoculation, whereas only 10% of contralateral DRG produced infections Thackray et al 1996
HSV polypeptide ICP4 (VP175) expression in ganglia HSV-1 infection TG ~ DRG Pepose et al 1986
Viral replication and degradation of host cells, mRNA HSV-1 infection TG ~ DRG, with wild-type HSV more virulent in both ganglia than HSV mutants lacking virion host shutoff (vhs) protein Smith et al 2002
Infectivity of ganglia Simian varicella virus TG ~ DRG White et al 2001
Substance P in ganglia Streptozotocin-induced diabetes TG had 26% reduction ( P < 0.01), but DRG had an 11% non-significant reduction Robinson et al 1987
Substance P in ganglia mf rat ( mutilated foot ; an autosomal recessive sensory neuropathy with reduced pain responsiveness DRG < TG Scaravilli 1983
Caspase-3–mediated neuronal apoptosis Knockout of Rb (retinoblastoma tumor suppressor protein) TG ~ DRG for protection from apoptosis in double knockout of Rb and caspase-3 compared with single Rb knockout Simpson et al 2001
Number of neurons in ganglia TrkA knockout TG ~ DRG for extensive neuronal loss Smeyne et al 1994
Reactivation of virus HSV mutant with gamma 34.5 gene deletion TG more resistant than DRG to reactivation Spivack et al 1995
Widespread numbness and pain 4–12 days after antibiotic treatment Acute sensory neuronopathy syndrome in humans TG ~ DRG Sterman et al 1980
Pain Trigeminal neuralgia in humans TG: yes (maxillary and mandibular divisions > ophthalmic)
DRG: no equivalent		 Jannetta 1980, Sweet 1984, Wilkins 1985, Goya et al 1990, Hamlyn 1997, Hamlyn 1997, Tacconi et al 2000
Spontaneous behavior Formalin OVX females exhibited a significantly greater increase in formalin hyperalgesia after orofacial injection (upper lip) than after hindpaw injection. Result consistent with hypothesis of a difference in sex steroid regulation of nociception between the TG and DRG systems Pajot et al 2003
ATF3, activated transcription factor 3; CCI, chronic constriction injury; DRG, dorsal root ganglion; HSV, herpes simplex virus; GFPA, glycine site functional partial agonists; NGF, nerve growth factor; NOS, nitric oxide synthase; NPY, neuropeptide Y; OVX, ovariectomized; TG, trigeminal; Trk, tyrosine kinase.

The hypothesis of peripheral target tissue regulation of neuronal phenotype has been expanded by the demonstration that estradiol selectively alters gene transcription in trigeminal neurons ( ), with increased expression of neuropeptides, such as prolactin ( Fig. 57-3 A), that are capable of sensitizing neuronal responses to capsaicin or noxious heat and significantly enhancing capsaicin-induced nocifensive behavior in the trigeminal system ( Fig. 57-3 B). Thus, the estradiol–prolactin system sensitizes peripheral nociceptors to an enhanced response to noxious stimuli. This estradiol-dependent trigeminal nocifensive system is consistent with the well-recognized contribution of patient sex as a risk factor for many chronic orofacial pain conditions ( ), although additional mechanisms are also likely to contribute to chronic pain disorders ( ). Further studies have demonstrated that trigeminal peptidergic neurons undergo morphological changes (“sprouting”) in response to injury-induced inflammation of target tissues such as dental pulp ( ). In contrast, there is a lack of sympathetic fiber sprouting in trigeminal ganglion cells, unlike the well-recognized occurrence in the spinal system ( ). Thus, an emerging body of evidence is revealing the dynamic and specific responsiveness of the trigeminal system to either injury to its various target tissues or the presence of certain gonadal steroids.

Figure 57-3, Estrogen regulates prolactin (PRL) expression in trigeminal (TG) neurons. A, Real-time reverse transcriptase polymerase chain reaction experiments were performed with TG RNA samples from proestrous female rats and ovariectomized (OVX) female rats pretreated with either vehicle or estradiol (E 2 ; 80 μg/kg/day for 10 days). Reactions were performed with primers specific for the PRL gene and the internal control (18S). Data were normalized to the relative amount of OVX (vehicle [Veh]) PRL mRNA/18S. Data are presented as means ± SEM ( n = 5 per group; ∗∗ P < 0.01 versus PRL mRNA of the OVX/vehicle group, one-way analysis of variance with Bonferroni’s post hoc test). B, Effect of pretreatment with PRL on capsaicin (cap)-induced eye wiping in proestrous female rats. PRL (1 μg/μL in saline) or vehicle (40 μL) was applied to the eye, followed immediately by the application of 0.01% capsaicin or vehicle (40 μL), and the total time spent grooming the injected eye per 5-minute bins was measured by observers blinded to treatment allocation.

Acute Orofacial Pain

Odontogenic Pain

The dental pulp is innervated by both myelinated and unmyelinated trigeminal afferent fibers. Activation of dental pulp afferents by temperature, chemical, or mechanical stimulation primarily results in perception of pain in humans, although pre-pain sensations have also been described ( ). Somewhat surprisingly given the dominant nociceptive nature of the sensory modalities conveyed by pulp, it is innervated by a significant proportion of large myelinated fibers, many of which would be classically characterized as non-nociceptive afferents, including Aβ fibers ( ). Unlike most target tissues, there are distinct differences in the innervation pattern of these two major classes of sensory neurons in dental pulp: myelinated afferents typically innervate dentinal tubules, whereas unmyelinated afferents terminate in the perivascular or stromal regions of the dental pulp ( ). This anatomical segregation has clinical implications since dentinal hypersensitivity is due to exposed dentinal tubules ( ), with the chief complaints being characteristic of myelinated nociceptor–like pain, namely, sharp, bright, and stabbing sensations. Conversely, inflammation of the dental pulp (e.g., pulpitis) involves unmyelinated nociceptors, with the chief complaints being dull, aching, and throbbing pain sensations.

Since dental pulp is restricted to a small compartment (≈0.2 mL of tissue in a molar), can be stimulated by agents that activate nociceptors such as capsaicin, and can be collected from patients, it is a useful model system for studying human trigeminal nociceptors ( ). One approach is to collect human dental pulp and evaluate release of neuropeptides under in vitro superfusion conditions ( ). As shown in Figure 57-4 , human dental pulp neurons express calcitonin gene–related peptide (CGRP) and transient receptor potential vanilloid 1 (TRPV1), and additional analyses have demonstrated expression of the μ-opioid receptor on these fibers. Moreover, capsaicin triggers the release of CGRP from this tissue ( Fig. 57-5 A), and this effect can be reduced by pretreatment with either a TRPV1 antagonist ( Fig. 57-5 A) or a μ-opioid agonist ( Fig. 57-5 B).

Figure 57-4, Representative confocal image evaluating the expression patterns of calcitonin gene–related peptide (CGRP) and transient receptor potential vanilloid 1 (TRPV1) in nerve fibers located in human coronal dental pulp.

Figure 57-5, A, Effect of calcium-free buffer and the capsaicin receptor antagonist capsazepine on basal and capsaicin-evoked release of immunoreactive calcitonin gene–related peptide (iCGRP) from superfused human dental pulp. B, Effects of prostaglandin E 2 (PGE 2 ) (10 lM) and DAMGO (1 uM) on basal and capsaicin-stimulated (30 lM) release of iCGRP. The white columns on the left represent basal release in the absence and presence of PGE 2 and DAMGO as indicated, whereas the black columns correspond to stimulated release in the absence or presence of the modulators. An asterisk indicates a statistically significant difference between vehicle and experimental release, whereas a cross indicates a statistically significant difference in release after DAMGO treatment in the absence and presence of PGE 2 (one-way analysis of variance with Tukey’s post-test: ∗ P < 0.05 and † P < 0.001; n = 14–29 as indicated in the basal release columns). Data are presented as the mean percentage of basal CGRP release ± SEM.

The primary cause of pulpal inflammation is a localized infection by microorganisms ( ) and a limited immune response caused in part by the lack of collateral blood supply. Bacterial infection may indirectly activate trigeminal nociceptors by triggering the release of host cell inflammatory mediators, which in turn bind and activate receptors expressed on nociceptors. For example, pulpal levels of prostaglandin E 2 (PGE 2 ) are associated with pain reports in patients ( ), and drugs such as steroids or non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce tissue levels of PGE 2 in patients with pulpitis ( ). Alternatively, bacteria may directly activate the terminals of nociceptors innervating dental pulp. Interestingly, the TRPV1 + subclass of human trigeminal neurons express toll-like receptor 4 (TLR4; Fig. 57-6 ), which is activated by bacterial-derived lipopolysaccharide (LPS), and local application of LPS sensitizes capsaicin-induced activation of trigeminal neurons ( ). Thus, bacteria may activate nociceptive neurons by both direct and indirect mechanisms. Future research is required to determine whether spinal nociceptors express TLRs and whether this is a general mechanism for the pain associated with infections.

Figure 57-6, A–C, Evaluation of the expression patterns of toll-like receptor 4 (TLR4) and transient receptor potential vanilloid 1 (TRPV1) in human trigeminal sensory neurons. White arrows depict examples of neurons expressing both markers for each row of three images, and yellow arrows depict examples of neurons that express one but not both markers. D, Pretreatment of trigeminal neurons with lipopolysaccharide (LPS) (2 μg/mL) led to the sensitization of a subsequent capsaicin-evoked inward current. CAP, capsaicin treatment; Veh, vehicle.

Both peripheral and central changes occur in response to pulpitis. In the periphery there is a dramatic increase in arborization (“sprouting”) of trigeminal afferents in both pulpal and periapical tissue with substantially increased innervation in regions adjacent to injured tissue ( ). In addition, blood flow and plasma extravasation are increased in inflamed pulp, and the resulting exudation of plasma proteins significantly increases the local delivery of protein-bound drugs such as NSAIDs into inflamed dental pulp ( ). Finally, there is altered expression of ion channels (e.g., increased Na v 1.7, Na v 1.8, Na v 1.9, and Ca v subunit α2δ1) and other receptors and dramatic changes in nodal architecture in inflamed dental pulp ( ; ; ; ). In addition to these peripheral changes, several changes occur in the central nervous system. In cats, the axotomy associated with physical removal of dental pulp tissue is accompanied by neuronal changes in the medullary trigeminal nuclei ( ). Acute activation of TRPA1 by the administration of mustard oil to exposed rat dental pulp triggers a dramatic increase in cutaneous receptive field sizes, a finding suggestive of central sensitization in response to activation of pulpal nociceptors ( ). Moreover, patients with pulpitis exhibit mechanical allodynia in both the inflamed tooth and a contralateral control tooth, a finding consistent with the hypothesis that pulpitis triggers central sensitization in dental pain patients ( ). Thus, the development of pulpitis pain is associated with considerable plasticity in both trigeminal afferents and medullary dorsal horn neurons.

Post-surgical Pain

Post-surgical dental pain is a well-recognized acute inflammatory condition that triggers time-related increases in pain, swelling, and hyperthermia ( ). In particular, surgical extraction of third molars impacted within the mandible or maxillary bone serves as the well-recognized dental impaction pain model for clinical research. Previous studies have demonstrated that surgical extraction of teeth in locally anesthetized but not sedated patients is a physiologically relevant stressor that results in activation of both the sympathoadrenal and pituitary–adrenal axes, as reflected by increased circulating levels of epinephrine, norepinephrine, β-endorphin, and cortisol ( ). Concomitant with the markers of stress is activation of an endogenous opioid analgesic system, as revealed by an approximately three-fold increase in intraoperative pain after the administration of naloxone ( Fig. 57-7 ) ( ). In other studies, microdialysis probes were implanted into surgical wounds to determine time- and drug-related changes in local tissue levels of inflammatory mediators after surgery. One study revealed a time-dependent increase in local tissue levels of PGE 2 ( Fig. 57-8 ) that was reduced by pretreatment with drugs such as NSAIDs or steroids ( ). In addition, the relative homogeneity of this patient population with respect to age, health, and minimal drug exposure permitted the performance of genetic association studies to evaluate the impact of selected gene polymorphisms on postoperative pain or the effects of acute inflammation on local gene expression ( ). Thus, the dental impaction pain model has proved to be of great utility for conducting translational clinical research on stress, activation of endogenous opioid systems, release of inflammatory mediators, and gene association studies.

Figure 57-7, Effect of naloxone administration versus placebo on intraoperative pain levels in dental patients undergoing surgical removal of impacted third molars.

Figure 57-8, Tissue levels of immunoreactive prostaglandin E 2 (iPGE 2 ) determined from microdialysis probes implanted into the tooth extraction socket in patients receiving either 200 mg flurbiprofen or placebo at the onset of postoperative pain.

In addition to its application in translational mechanistic research, this clinical model has been used in both pharmacological and non-pharmacological clinical trials. For example, numerous studies have demonstrated the dramatic analgesic effects of NSAIDs in this clinical model ( ). Other studies have evaluated the effects of sedating agents (e.g., benzodiazepines), opioid combination drugs, local anesthetics, nitrous oxide, and investigational drugs (e.g., neurokinin 1 antagonists, excitatory amino acid receptor antagonists) in the dental impaction pain model ( ). Additionally, non-pharmacological interventions such as acupuncture, hypnosis, biofeedback, and others have also been evaluated with this clinical model. Collectively, the dental impaction pain model has shed considerable light on mechanisms of acute inflammatory pain and its regulation in humans.

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