Journal of Oral & Facial Pain and Headache, 04/2004

Neuropathic pain in the orofacial region poses a difficult challenge to the treating physician. In some cases diagnosis is far from easy. Common causes of orofacial neuropathic pain are reviewed here, with a focus on the 2 most common: postherpetic neuralgia and posttraumatic painful peripheral neuropathy. In addition, the discussion includes idiopathic trigeminal neuralgia (tic douloureux), a neuropathic pain syndrome that is nearly unique to the trigeminal distribution (very rarely, it has also been reported in the glossopharyngeal region). Brief summaries of major research problems and successes are also provided. Keywords: postherpetic neuralgia, trigeminal neuralgia

Injury to a branch of the trigeminal nerve may lead to the development of chronic pain in the affected area. The etiology of this condition is not clear, but there is strong evidence to suggest that spontaneous and mechanically induced neural discharge from the injury site plays a crucial role. In laboratory studies, we have characterized this discharge following injury to the inferior alveolar or lingual nerves and have shown a temporal association with the accumulation of neuropeptides in the damaged axons. Substance P, calcitonin gene-related peptide, and vasoactive intestinal polypeptide were all found to be capable of increasing the discharge when applied systemically, and enkephalin caused a decrease. There were also changes in the expression of specific sodium channels and nitric oxide synthase, both at the injury site and in the trigeminal ganglion. Studies on lingual nerve neuromas taken from patients undergoing nerve repair also revealed accumulation of peptides, as well as inflammatory and structural changes, but the presence of these features did not correlate directly with the reported symptoms. The application of corticosteroids to an experimental injury site decreased the mechanically induced discharge, and the anticonvulsant carbamazepine reduced the spontaneous discharge in some axons. Some of the responses that result from damage to a branch of the trigeminal nerve appear to differ from those that follow damage to other peripheral nerves. These differences will need to be taken into account when developing new therapeutic approaches for the management of injury-induced trigeminal pain. Keywords: ectopic discharge, nerve injury, neuropeptides, sodium channels, trigeminal nerve

Peripheral nerve injury produces a hyperexcitability of primary afferents and neurons in the spinal cord that is considered important in the development of nerve injury-induced pain. The authors recently developed a nerve injury model in the trigeminal region of the rat to study the neuronal mechanism of neuropathic pain in the trigeminal system. The escape thresholds to mechanical stimulation applied to the whisker pad area were significantly lower in rats with an inferior alveolar nerve (IAN) transection than those evoked from the contralateral, sham-operated whisker pad. Also, background activity and mechanically evoked responses in infraorbital nerve (ION) afferents and hyperpolarization-activated current (Ih) in trigeminal ganglion ION neurons were increased following IAN transection. Background activity and mechanically evoked responses of wide dynamic range (WDR) neurons in trigeminal subnucleus caudalis on the ipsilateral side relative to the transection were also significantly increased after the operation. A large number of cells expressed c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following non-noxious mechanical stimulation of the faces of rats with IAN transection. The effect of aging on spinal dorsal horn neurons and the involvement of nerve injury in producing abnormal pain sensation in rats with advancing age were also studied. The incidence of licking behavior in response to noxious radiant heat stimulation of the hind paw was lower in the aged rats than in younger adults, but paw withdrawal latency was shorter and the activities of spinal dorsal horn neurons were higher in the aged rats. Furthermore, the descending inhibitory systems were impaired in the aged rats. These observations suggest that the changes in neuronal activity in the aged rats likely corresponded to the changes observed in the rat model of peripheral nerve injury. Keywords: aging, dorsal horn, medulla, neuropathic pain, trigeminal nerve

Nerve signals arising from sites of tissue or nerve injury lead to long-term changes in the central nervous system and contribute to hyperalgesia and the amplification and persistence of pain. These nociceptor activity-dependent changes are referred to as central sensitization. Central sensitization involves an increase in the excitability of medullary dorsal horn (subnucleus caudalis) and spinal dorsal horn neurons brought about by a series of events including neuronal depolarization; removal of the voltage-dependent magnesium block of the N-methyl-D-aspartate (NMDA) receptor; release of calcium from intracellular stores; phosphorylation of the NMDA, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and neurokinin (NK) 1 receptors via activation of protein kineses; a change in the neuron's excitability; and an increase in synaptic strength. Central sensitization occurs in trigeminal nociceptive pathways, and more robust neuronal hyperexcitability occurs following deep tissue stimulation than cutaneous stimulation. Utilizing Fos protein immunocytochemistry, it has been found that 2 distinct regions are activated in the trigeminal brainstem sensory nuclei, the subnuclei interpolaris/caudalis transition zone (Vi/Vc) and the caudal part of the subnucleus caudalis. The latter is very similar to the spinal dorsal horn and is involved in the sensory discriminative aspects of pain. In contrast, the ventral pole of the Vi/Vc is unique. In addition to its role in the nociceptive sensory processing of deep tissues, it is involved bilaterally in somatovisceral and somatoautonomic processing, activation of the pituitary-adrenal axis, and descending modulatory control. The findings support our overall hypothesis that the ventral pole of Vi/Vc is involved in the coordination of bilateral sensorimotor functions of the trigeminal system associated with the response to deep tissue injury. Keywords: caudal subnucleus caudalis, central sensitization, immunocytochemistry, orofacial pain, subnuclei interpolaris

The aim of this article is to outline mechanisms underlying generation and maintenance of pain arising from trauma to peripheral nerve fibers and to present an overview of our recent studies of animal models of peripheral neuropathic pain and pain of temporomandibular disorders (TMD). The former model was induced by placing a polyethylene cuff around the sciatic nerve of the Sprague-Dawley rat and the TMD model was induced by injection of complete Freund's adjuvant into the rat's temporomandibular joint. In cuff-implanted rats, ongoing activity of dorsal horn neurons was greater than in controls, the cutaneous receptive field size of the neurons was greater, and both noxious and innocuous mechanical stimuli to the receptive field elicited an excitatory response during stimulation but also a marked afterdischarge that lasted up to 30 minutes; this afterdischarge was never observed in control rats in response to innocuous stimulation. The model of TMD was characterized by joint space narrowing, bone remodeling, infiltration of immune cells, loss in the range of jaw opening, and signs of nociception. Alterations in the neural substrate of nociception in animal models, and therefore also possibly in humans, appear to include changes in peripheral as well as central neurons. In the periphery, changes include alterations in the phenotype and central projections of large-diameter sensory nerve fibers. At the level of the trigeminal brainstem and spinal cord, there appear to be several types of change. One type is an increased efficacy of synaptic transmission onto second-order neurons. Another type of change is a reduction in inhibitory mechanisms, including a shift of gamma-amino butyric acid (GABAA) receptor activation to excitation. There is a need for further studies to focus on mechanisms for either the generation or the maintenance, or both, of neuropathic pain. Keywords: animal models, neuropathic pain, temporomandibular disorders, trigeminal pain

Chronic orofacial pain syndromes are produced by nerve injury, diseases, and toxins. They constitute an unsolved medical problem because they affect a considerable number of adults and are difficult to treat. There is a remarkable variability among adults in terms of susceptibility to chronic orofacial pain and its characteristics, which suggests that these syndromes are complex heritable traits controlled by alleles of certain polymorphic genes that interact with the environment. Each syndrome is assumed to be determined by a unique set of genes. In the present report, a practical study design is proposed to identify the genes responsible for interindividual variability in orofacial pain levels. This design is based on research strategies that have been used for studying other human diseases as well as pain syndromes outside the orofacial region. Specifically, this design has been used successfully by the authors and others over the past 8 years to study chronic pain syndromes such as migraines, radiculopathy, amputation pain, and postmastectomy pain. The strategies used to study these topics have been adapted to address the unique problems of orofacial pain. The authors believe that the study of genetics provides a novel research approach from which to identify targets for the development of individually tailored approaches in orofacial pain medicine, such as diagnostic and prognostic kits and novel drugs that would prevent pain chronicity in susceptible individuals or alleviate it once it had developed. This report focuses on human models. A follow-up report is intended to extend this design into animal models of orofacial pain syndromes. Keywords: genetic susceptibility, orofacial pain, polymorphic genes

Transmission of noxious-stimulus-evoked inputs in the spinal and trigeminal systems is mediated primarily through excitatory glutamatergic synapses using alpha amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors. Glutamatergic synapses exhibit multiple forms of short-lasting and long-lasting synaptic plasticity. Persistent enhancement of nociceptive transmission, known as "central sensitization", is a form of lasting plasticity that is similar mechanistically to long-term potentiation of glutamatergic transmission in other regions of the central nervous system. This potentiation of AMPA/kainate transmission is dependent upon the activity of NMDA receptors, which become enhanced following noxious peripheral stimulation as a result of several convergent mechanisms. Central sensitization is thus an expression of increased synaptic gain at glutamatergic synapses in central nociceptive- transmission neurons and thereby contributes importantly to pain hypersensitivity. In addition, recent evidence has revealed a new player in the mechanisms underlying pain hypersensitivity following nerve injury-microglia. Understanding of the roles of microglia may lead to new strategies for the diagnosis and management of neuropathic pain. Keywords: glutamate receptors, microglia, pain, spinal dorsal horn, synaptic plasticity, tyrosine kinases

The goal of a classification system of medical conditions is to facilitate accurate communication, to ensure that each condition is described uniformly and universally and that all data banks for the storage and retrieval of research and clinical data related to the conditions are consistent. Classification entails deciding which kinds of diagnostic entities should be recognized and how to order them in a meaningful way. Currently there are 3 major pain classification systems of relevance to orofacial pain: The International Association for the Study of Pain classification system, the International Headache Society classification system, and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). All use different methodologies, and only the RDC/TMD take into account social and psychologic factors in the classification of conditions. Classification systems need to be reliable, valid, comprehensive, generalizable, and flexible, and they need to be tested using consensus views of experts as well as the available literature. There is an urgent need for a robust classification system for neuropathic trigeminal pain. Keywords: classification, pain

This article provides a brief overview of the tools and methods that may be useful to assess neuropathic trigeminal pain. Pain is a complex multidimensional and biopsychosocial experience. While the assessment of neuropathic trigeminal pain is complex, there are several meaningful ways available for the systematic assessment of neuropathic pain and its effects and manifestations. The key to such an analysis is a standardized pain history and examination and a good knowledge of pain mechanisms. Patients can be asked to provide detailed information about their spontaneous pain (ie, stimulus-independent pain), eg, quality, intensity, localization, time course, and modifying factors. Stimulus-dependent pain components can be characterized with clinical examination procedures and quantitative psychophysical techniques such as application of mechanical, thermal, chemical, and electrical stimuli. The description of the stimulus-dependent pain is important to reveal the function of the somatosensory system and to map the extent of hyperalgesia, hyperesthesia and allodynia, because the normal relationship between stimulus intensity and perceived intensity is distorted in many neuropathic pain conditions. In addition to the psychophysical techniques, a number of laboratory tests for assessment of trigeminal pain have been developed and tested, although critical information on sensitivity, specificity, and predictive values is still scarce. There is also a need for common guidelines on classification, diagnostic procedures, and management. This will require concerted international, interdisciplinary action. Keywords: neuropathic pain, pain assessment

Evaluating sensory nerve damage is a challenging and often frustrating process. Diagnosis and follow-up is usually based on the patient's history and gross physical evaluation in addition to simple sensory tests such as brushing or pin prick. Based on evidence accumulated from clinical and animal experiments, quantitative sensory testing (QST) has emerged as a useful tool in the assessment of sensory nerve damage. QST has demonstrated diagnostic capabilities in temporomandibular disorders, burning mouth syndrome, oral malignancies, numb chin syndrome, posttraumatic pain, and whiplash injuries, and in elucidating mechanisms of central sensitization. In this article specific clinical uses of QST are described and its clinical applicability is demonstrated. Future studies should be directed at exploring the use of QST in the diagnosis and classification of further nerve pathologies. Keywords: burning mouth syndrome, neuritis, neuropathic pain, oral malignancy, quantitative sensory testing

This article reviews the utility of psychophysical approaches in the assessment of posttraumatic neuropathic trigeminal pain. Methods of quantitative sensory testing are derived from psychophysical principles and provide a widely accepted means for characterizing sensory dysfunction in patients who experience injury to the trigeminal nerve. No published study, however, has sought to compare sensory findings from trigeminal nerve-injured patients who develop neuropathic pain with those from trigeminal nerve-injured patients who remain pain-free. Moreover, sensory testing data from trigeminal nerve-injured patients with pain have been published in only a few reports. As a result, remarkably little is known about sensory factors associated with the development of posttraumatic trigeminal neuralgia. Review of the separate literatures suggests that both trigeminal nerve-injured patients with pain and pain-free trigeminal nerve-injured patients exhibit grossly similar impairments in sensory function. In addition, trigeminal nerve-injured patients with pain may be more likely to report cold allodynia than patients without pain and to exhibit signs of central sensitization such as allodynia to light brushing tactile stimuli and abnormal temporal summation of pain. New studies using state-of-the-art psychophysical methods are needed to search for sensory markers that bear on the development of pain. Moreover, the relationship between psychophysical indices of central sensitization and measures of clinical pain should be addressed to obtain a better understanding of the underlying pathophysiology. Keywords: allodynia, neuropathic pain, sensitization, sensory testing, trigeminal nerve injury

This article reviews the utility of neurophysiological recordings and quantitative sensory testing (QST) in providing sensitive, quantitative, and objective tests for the diagnosis and localization of damage to the trigeminal nerve. Electromyography and recordings of the masseter reflex and compound muscle action potential evoked by transcranial magnetic stimulation or direct electrical stimulation of the masseteric nerve can be of value in evaluating the function of α motor neurons supplying the muscles of mastication. Orthodromic recording of the sensory action potential and trigeminal somatosensory-evoked potential recording with the near-nerve stimulation technique are sensitive tools for the investigation of trigeminal sensory Aß afferents, whereas recordings of polysynaptic trigeminal brainstem reflexes and tactile QST are less sensitive. At late stages of recovery, the blink reflex and masseter inhibitory reflex are often normal, but at earlier stages, the blink reflex recording has good prognostic value, and the presence of a reflex response may confirm continuity of the nerve trunk after partial laceration. Trigeminal small-fiber function (Aδ and C) can be studied with thermal QST of the cool, warm, heat pain, and cold pain detection thresholds or with laser-evoked potential recording. Thermal QST may remain abnormal years after axonal damage and aids in the diagnosis of late sequelae of trigeminal nerve injury. In a study of the diagnostic value of neurography, blink reflex and thermal QST, and various commonly used clinical sensory tests, neurophysiologic tests and thermal QST had better sensitivity (50% to 88% vs 40% to 59%) and negative predictive values (78% to 100% vs 70% to 74%) compared to clinical examination, whereas the specificity (55% to 100%) and positive predictive values (48% to 73%) were similar. At 1 year after trigeminal nerve injury, the risk of a false negative finding with clinical sensory testing was 94%, whereas the combination of nerve conduction recordings and thermal QST increased the diagnostic yield to 100% in patients with long-standing postsurgical sensory alteration. In conclusion, clinical neurophysiological recordings and QST improve the diagnostic accuracy for trigeminal neuropathy. Keywords: neuropathy, neurophysiologic examination, quantitative sensory testing, trigeminal nerve

This article reviews current models of neuropathic pain and relates recent research in the neurobiology of pain to improved understanding of psychiatric and psychological aspects and treatment of chronic aspects of pain. Some of the anomalies associated with beliefs about chronic pain are also outlined. In particular, the notion that pain is either verifiable or due to psychiatric disturbance is laid to rest; the onus is on the clinician to understand and treat the patient with sensitivity, rather than on the patient to provide proof of pain. Keywords: neuropathic pain, psychiatric and psychological management guidelines

The purpose of this article is to review the pharmacological treatment of neuropathic trigeminal pain by means of a systematic review. A number of randomized controlled trials and important historical and uncontrolled studies in trigeminal neuralgia and postherpetic neuralgia were identified. Trigeminal neuralgia is a unique neuropathic pain disorder with a specific therapy. It does not respond to the usual drugs used for other neuropathic pains. The drug therapy of trigeminal postherpetic neuralgia is similar to that of other neuropathic trigeminal pain conditions. Keywords: trigeminal neuralgia, neuropathic trigeminal pain, treatment

Neuropathic trigeminal pain conditions are more common than is generally appreciated. Sites inside the mouth as well as involvement of extraoral tissues are common manifestations of these disorders. There is a general lack of recognition of the complex characteristics of neuropathic trigeminal pain that frequently lead to mischaracterization of the nature of the complaint. Dentists are in an excellent position to detect the presence of neuropathic trigeminal pain and help to provide a rational diagnosis. The high prevalence of orofacial pain of dental origin and the dramatic similarities between neuropathic orofacial pain and odontogenic and other pathologic pains in the region frequently lead to incorrect diagnoses and, more importantly, inappropriate treatments that are frequently invasive and irreversible. The records of patients presenting with neuropathic pain at our university pain clinic were reviewed to gain insight into dental factors as they related to the etiology, presentation, diagnosis, and management of neuropathic pain of the trigeminal system. Relative to etiology, the records review revealed that most onsets were associated with a specific dental treatment or odontogenic symptom that resulted in a dental diagnosis or treatment. Initial treatment modalities that either caused the pain or were used to address painful symptoms commonly included replacement of restorations, endodontic therapy, apicectomy, extraction, splint therapy, and occlusal equilibration. Correct diagnosis, and particularly early definitive diagnosis, of neuropathic trigeminal pain is crucial to avoid invasive and potentially more damaging forms of treatment. Keywords: diagnosis, orofacial pain

Neuropathic pain therapy remains enormously challenging despite the increases in knowledge of pain etiology and mechanisms drawn from animal studies. Mechanism-based discovery underlies key approaches toward reduction of peripheral and central hyperexcitability. These include a number of poorly validated molecular targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, as well as downstream regulators of protein phosphorylation. Improvement in translating these approaches into the development of drugs for use in the pain clinic remains a significant but surmountable challenge. Keywords: adenosine triphosphate, fructalkine, G-protein coupled receptors, ion channels, kinase