Differential diagnosis of orofacial pain

Orofacial pain, especially if the problem is chronic, presents a diagnostic and management challenge to all health practitioners. This paper suggests how clinicians might simplify the diagnosis of orofacial pain. First, the pain is classified into one of the three basic pain categories: somatic, neuropathic, or psychogenic pain. Somatic pain results from noxious stimulation of normal neural structures. Neuropathic pain is caused by a structural abnormality in the nervous system. Psychogenic pain arises from psychic causes; there is no apparent physiologic or organic basis for the pain. The next step is to determine the tissue system from which the pain arises: intracranial, extracranial, musculoskeletal, neurovascular, neurogenous, or psychological. Finally, some of the more common orofacial pain syndromes within each category are discussed.     

Ultrasound appearance of gas bubbles in hepatic veins after orthotopic liver transplantation: a phenomenon with consequences?

Neuropathic pain is not well understood. Although central dorsal horn remodelling is likely important in maintaining chronic neuropathic pain, afferent activity from injured nerves or ganglia may initiate these changes. It is suggested, in this review that the peripheral nerve trunk is capable of sustaining a "flare" response as observed in injured skin and other tissues. The injury response may be associated with local vasodilatation, plasma extravasation and the generation of painful local afferent activity sustained by locally originating peptidergic fibers (nervi nervorum). These fibers contain substance P, calcitonin gene-related peptide and other peptides that have been linked to nociceptive transmission. Manipulation of the local injury response of the nerve trunk by pharmacologic means may provide one strategy in the treatment of neuropathic pain.     

The effect of peripheral glycerol on trigeminal neuropathic pain examined by quantitative assessment of abnormal pain and sensory perception

In nine patients with trigeminal neuropathic pain after nerve injury, we examined prospectively the effect of peripheral glycerol neurolysis on abnormal pain and sensory perception. In the painful facial skin area of these patients, we found increased temperature and tactile thresholds and the presence of abnormal temporal summation of pain. In seven patients, neuropathic pain was peripheral and disappeared after application of local anaesthesia at or proximal to the site of nerve injury. Neuropathic pain was central in two patients, and unresponsive to local anaesthesia applied proximal to the site of nerve injury. Six weeks after injection of glycerol proximal to the site of nerve injury, no or marginal pain relief was found in 8 patients with peripheral or central trigeminal neuropathic pain. On the other hand, in one of the patients with peripheral trigeminal neuropathic pain, glycerol was given at the site of nerve injury, and produced total pain relief for the whole observation period of 7 months. In this patient, pain relief was associated with normalisation of abnormal temporal summation of pain, which was not observed in the 8 patients with no or marginal pain relief. No further changes in temperature or tactile thresholds were found in any of the 9 patients after a single injection of absolute glycerol. Total pain relief in one of the patients probably is related to the ability of glycerol to inhibit ongoing ectopic impulse generation at the site of nerve injury. We suggest that glycerol-induced reduction of primary afferent hyperactivity may secondarily result in down-regulation of central neuronal hyperexcitability. The efficacy of application of glycerol at the site of nerve injury in patients with peripheral trigeminal neuropathic pain may warrant further investigation. However, this prospective study does not provide evidence that application of glycerol proximal to the site of nerve injury has a place in the treatment of trigeminal neuropathic pain.     

Interactions between non-immune host cells and the immune system during periodontal disease: role of the gingival keratinocyte

OBJECTIVE: The role of sympathetic blocks in pain therapy is examined in the light of changing concepts of pain pathophysiology. A critical review of the literature also sought to develop an evidence-based analysis of outcome studies to provide recommendations for appropriate applications of sympathetic blocks, together with ideas for further clinically based research. METHODS: A focus on the pathophysiology of neuropathic and inflammatory pain disorders was used to help redefine what contribution, if any, was provided by the sympathetic system, to chronic pain states. Validation of nerve block therapies based on historical practices and these newer concepts and outcome determinations has then been used to present an overview of clinical nerve block therapies as applied to the sympathetic nervous system. RESULTS: 1. Pain Diagnosis: A reclassification of reflex sympathetic dystrophy (RSD) to the new taxonomy of complex regional pain syndromes (CRPS) is supported, with evidence that only a questionable sympathetic contribution at the dorsal root ganglion level can be ascribed etiologically to this group of disorders. Sympathetic blocks can establish whether pains may be nonresponsive or variably responsive to such blocks, but are considered inappropriate in determining a clinical diagnosis. 2. Neuropathic Pain Therapy: (a) A critical review of the literature regarding the use of sympathetic blocks in the treatment of acute herpes zoster pain and in the treatment of postherpetic neuralgia found little support for the widely held view that sympathetic blocks reduced either the incidence of long-term reduction of pain in these disorders. Further attempts to reduce PHN by the combination of blocks with aggressive drug therapies during acute herpes infection are suggested. (b) CRPS (RSD) treatments are seen as evolutionary at present, with the role of sympathetic blocks being only part of a balanced pain treatment strategy aimed at getting patients activated under cover of good analgesia and improved function. These proposals come as consensus recommendations but are not substantiated by outcome studies. 3. Ischemic Pain: Permanent sympathetic block with neurolytic or thermocoagulation techniques provides up to 50% long-term improved blood flow and reduction of pain and ulceration for patients with advanced peripheral vascular disease. This is particularly appropriate at lumbar levels in which percutaneous techniques are safe when conducted with real time imaging control. CONCLUSIONS: Changes in the understanding of CRPS disorders and the role of the sympathetic nervous system in neuropathic pain has changed both the diagnostic and management strategies for these pain states. The sensitivity and specificity of response to sympathetic blocks in establishing their value at diagnostic aids will not be fully established without further clinical study. Further use of intravenous regional blocks or diagnostic intravenous infusions remains questionable. Preventive and therapeutic use of sympathetic blocks in herpes zoster pain remains open to well-controlled study.     

Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain

Sympathetic postganglionic fibers sprout in the dorsal root ganglion (DRG) after peripheral nerve injury. Therefore, one possible contributing factor of sympathetic dependency of neuropathic pain is the extent of sympathetic sprouting in the DRG after peripheral nerve injury. The present study compared the extent of sympathetic sprouting in the DRG as well as in the injured peripheral nerve in three rat neuropathic pain models: (1) the chronic constriction injury model (CCI); (2) the partial sciatic nerve ligation injury model (PSI); and (3) the segmental spinal nerve ligation injury model (SSI). All three methods of peripheral nerve injury produced behavioral signs of ongoing and evoked pain with some differences in the magnitude of each pain component. The density of sympathetic fibers in the DRG was significantly higher at all examined postoperative times than controls in the SSI model, while it was somewhat higher than controls only at the last examined postoperative time (20 weeks) in the CCI and PSI models. Therefore, data suggest that, although sympathetic changes in the DRG may contribute to neuropathic pain syndromes in the SSI model, other mechanisms seem to be more important in the CCI and PSI models at early times following peripheral nerve injury.     

Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat

Neuropathic pain accompanies peripheral nerve injury after a wide variety of insults including metabolic disorders, traumatic nerve injury, and neurotoxic drugs. Chemotherapy-induced neuropathic pain, caused by drugs such as vincristine and taxol, occurs in cancer patients who receive these drugs as antineoplastic agents. Although a variety of remediations have been attempted, the absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of treatment strategies. Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy in humans and mechanical hyperalgesia in rats. To test the hypothesis that alterations in C-fiber nociceptor function occur during vincristine-induced painful peripheral neuropathy, we performed in vivo extracellular recordings of single neurons from the saphenous nerve of vincristine-treated rats. Forty-one percent of C-fiber nociceptors were significantly hyper-responsive to suprathreshold mechanical stimulation. As a population, these mechanically hyper-responsive nociceptors also had significantly greater responses to suprathreshold heat stimulation; however, heat hyper-responsiveness was found only in a subset of these nociceptors and was never detected in the absence of mechanical hyper-responsiveness. In addition, mean conduction velocities of A-fibers and C-fibers in vincristine-treated rats were significantly slowed. Mean heat and mechanical activation thresholds of C-fiber nociceptors, their distribution among subclasses, and the percentage of spontaneously active neurons in vincristine-treated rats were not statistically different from controls. Vincristine does not, therefore, cause generalized impairment of C-fiber nociceptor function but rather specifically interferes with mechanisms underlying responsiveness to suprathreshold stimuli. Furthermore, vincristine-induced nociceptor hyper-responsiveness may involve alterations specifically in mechanotransduction in some nociceptors and alterations in general cellular adaptation mechanisms in others.     

An animal model of neuropathic pain: a review

Recent work has succeeded in producing models of painful peripheral neuropathies in laboratory animals. There is evidence that the animals experience both abnormal spontaneous pain and abnormal evoked pains (allodynia and hyperalgesia). Experimental analyses of these models have demonstrated potential pathophysiologic mechanisms in both the peripheral and central nervous systems; it is likely that the model neuropathic pain syndromes are due to several different mechanisms. One line of evidence suggests that these pain states gradually become centralized due to an excitotoxic effect on spinal cord dorsal horn inhibitory interneurons. The role of the sympathetic nervous system appears to vary, depending on the type of nerve injury and the temporal evolution of the syndrome. There is evidence indicating that the abnormality of cutaneous temperature regulation that often accompanies painful peripheral neuropathy is not necessarily due to the activity of sympathetic vasomotor efferents.     

Sympathetic axons surround neuropeptide-negative axotomized sensory neurons

Nerve injury can lead to sympathetically dependent neuropathic pain. A possible site of sympathetic-sensory interaction is the dorsal root ganglion (DRG), where sympathetic axons form pericellular 'baskets' around a subpopulation of DRG neurons. Since these structures possibly represent functional units of sympathetic pain, we attempted to characterize the neuropeptidergic phenotype of basketed DRG neurons. We performed double-labeling immunohistochemistry for tyrosine hydroxylase and neuropeptides on DRG sections, 2 weeks following L5 spinal nerve ligation (a well-characterized animal model of sympathetic pain). We found that basketed DRG neurons typically do not contain substance P, calcitonin gene-related peptide, galanin, neuropeptide tyrosine, or vasoactive intestinal polypeptide, and we conclude that if sympathetic baskets contribute to neuropathic pain, the involvement of these neuropeptides is unimportant.     

The efficiency of alprazolam for seasonal affective disorder (SAD, autumn/winter type)]

Tricyclic antidepressants, or "tricyclics" as they are commonly called, are effective in reducing pain in chronic neurological and musculoskeletal disorders. Tricyclics appear to be effective in the control of chronic orofacial pain of non-inflammatory origin, and include amitriptyline, doxepin, nortriptyline and desipramine. Daily doses of the medications are smaller for the management of pain than doses typically used in the treatment of depression. Certain medical conditions may contraindicate tricyclic trials, while others may warrant starting at a lower dose with more conservative dose adjustments. Common side effects include dry mouth, sedation, constipation and orthostasis. Tricyclics are just one therapeutic modality which can be considered in the management and treatment of chronic refractory orofacial pain that is suspected to arise from neurogenic or myofascial etiologies.     

Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

Neuropathic pain accompanies peripheral nerve injury following a variety of insults including metabolic disorders, traumatic injury, and exposure to neurotoxins such as vincristine and taxol. Vincristine, a microtubule depolymerizing drug, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias and dysesthesias (Sandler et al., [1969] Neurology 19:367-374; Holland et al. [1973] Cancer Res. 33:1258-1264). The recent development of an animal model of vincristine-induced neuropathy provides an opportunity to investigate mechanisms underlying this form of neuropathic pain. Systemic vincristine (100 microg/kg) produces hyperalgesia to mechanical stimuli during the second week of administration, which persists for more than a week (Aley et al. [1996] Neuroscience 73:259-265). To test the hypothesis that changes in microtubule structure in nociceptive sensory neurons accompany vincristine-induced hyperalgesia, we analyzed unmyelinated axons in saphenous nerves of vincristine-treated rats. This study constitutes the first quantitative ultrastructural analysis of the cytoskeleton of unmyelinated axons in peripheral nerve during neuropathic hyperalgesia. There was no evidence of unmyelinated fiber loss or a decrease in the number of microtubules per axons. There was, however, a significant decrease in microtubule density in unmyelinated axons from vincristine-treated rats. This decrease in microtubule density was due to a significant increase in the cross-sectional area of unmyelinated axons, suggesting swelling of axons. In addition, vincristine-treated axons had significantly fewer microtubules cut in cross-section and significantly more tangentially oriented microtubules per axon compared to controls. These results suggest that vincristine causes disorganization of the axonal microtubule cytoskeleton, as well as an increase in the caliber of unmyelinated sensory axons.     

12-O-tetradecanoylphorbol-13-acetate inhibits aminophospholipid translocase activity and modifies the lateral motions of fluorescent phospholipid analogs in the plasma membrane of bovine aortic endothelial cells

Interstitial cystitis (IC) is a relatively uncommon and enigmatic disorder characterized by pain in the bladder and pelvic region, typically accompanied by urinary urgency and frequency. Fibromyalgia is a more common disorder, with the prominent symptoms being diffuse musculoskeletal pain and fatigue, and it has been well established that there is substantial clinical overlap between fibromyalgia and chronic fatigue syndrome (CFS). Although genitourinary and musculoskeletal symptoms predominate in IC and fibromyalgia respectively, both disorders share a number of features, including similar demographics, "allied conditions" (e.g. irritable bowel syndrome, headaches, etc.), natural history, aggravating factors, and efficacious therapy. We hypothesized that there was substantial clinical overlap between fibromyalgia and IC, and examined cohorts of individuals with these two disorders in parallel, to compare the spectrum of symptomatology. Sixty fibromyalgia patients, 30 IC patients, and 30 age-matched healthy controls were questioned regarding current symptomatology. A dolorimeter examination was also performed in the three groups to assess peripheral nociception. We found that the frequency of current symptoms was very similar for the fibromyalgia and IC groups. Both the fibromyalgia and IC patients displayed increased pain sensitivity when compared to healthy individuals, at both tender and control points. These data suggest that IC and fibromyalgia have significant overlap in symptomatology, and that IC patients display diffusely increased peripheral nociception, as is seen in fibromyalgia. Although central mechanisms have been suspected to contribute to the pathogenesis of fibromyalgia for some time, we speculate that these same types of mechanisms may be operative in IC, which has traditionally been felt to be a bladder disorder.     

A systematic approach to evaluate the modification of lens proteins by glycation-induced crosslinking

Normal gait requires the dynamic integration of central and peripheral nervous systems acting on an intact musculoskeletal framework. A number of specific disease processes, as well as aging, may compromise this interaction. Despite the complexity of human gait, most common gait disorders can be identified by the experienced clinician, using the fundamental tools of history and physical examination.     

Postherpetic neuralgia: irritable nociceptors and deafferentation

Postherpetic neuralgia (PHN) is a common and often devastatingly painful condition. It is also one of the most extensively investigated of the neuropathic pains. Patients with PHN have been studied using quantitative testing of primary afferent function, skin biopsies, and controlled treatment trials. Together with insights drawn from an extensive and growing literature on experimental models of neuropathic pain these patient studies have provided a preliminary glimpse of the pain-generating mechanisms in PHN. It is clear that both peripheral and central pathophysiological mechanisms contribute to PHN pain. Some PHN patients have abnormal sensitization of unmyelinated cutaneous nociceptors (irritable nociceptors). Such patients characteristically have minimal sensory loss. Other patients have pain associated with small fiber deafferentation. In such patients pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (allodynia). In these patients, allodynia may be due to the formation of new connections between nonnociceptive large diameter primary afferents and central pain transmission neurons. Other deafferentation patients have severe spontaneous pain without hyperalgesia or allodynia and presumably have lost both large and small diameter fibers. In this group the pain is likely due to increased spontaneous activity in deafferented central neurons and/or reorganization of central connections. These three types of mechanism may coexist in individual patients and each offers the possibility for developing new therapeutic interventions.     

Dextromethorphan potentiates the effect of morphine in rats with peripheral neuropathy

Neuropathic pain responds poorly to opioids. We now report that combination of systemic morphine (2 mg/kg) and dextromethorphan (45 mg/kg), a clinically available antitussive with NMDA-antagonist properties, markedly alleviated mechanical and cold allodynia-like behavior in a rat model of peripheral mononeuropathy. Neither drug produced a significant effect on its own at these doses. The anti-allodynic effect of morphine plus dextromethorphan was reversed by naloxone. The present results suggest that a combination of NMDA-antagonist and opiates might be effective in treating neuropathic pain. Furthermore, the effect of this drug combination is mainly mediated via opioid receptors.     

Pharmacological Management of Chronic Pain: I. Fibromyalgia and Neuropathic Pain.

This brief review surveys pharmacotherapy for some of the most common forms of chronic pain: musculoskeletal pain and neuropathic pain. Head pain is among the most common types of chronic pain, but will be discussed in a separate column. Because the extensive pharmacopoeia for pain cannot be distilled into a brief article, this summary focuses only on psychotropic agents used in the management of chronic pain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Trigeminal neuropathic pain: pathophysiological mechanisms examined by quantitative assessment of abnormal pain and sensory perception

OBJECTIVE: This study was undertaken to examine the pathophysiological characteristics of trigeminal neuropathic pain. METHODS: The study included 23 consecutive patients with trigeminal neuropathic pain (15 patients with pain after nerve injury and 8 patients with pain of spontaneous origin). For each patient, quantitative examination of sensory and pain perception was performed in the painful facial skin area, and results were compared with the findings for the contralateral nonpainful facial skin area. RESULTS: In the painful facial skin area of patients with neuropathic pain after nerve injury, we demonstrated increased temperature and tactile thresholds, as well as abnormal temporal summation of pain (i.e., repetitive nonpainful skin stimulation produced an abnormal progressive increase of pain intensity, with abnormal radiation of pain and aftersensation). In the painful skin area of patients with pain of spontaneous origin, temperature and tactile thresholds were not increased, but heat pain and cold pain thresholds were significantly reduced, indicating heat and cold hyperalgesia. The characteristics of temporal summation of pain were not significantly altered in the painful facial skin area in this group of patients. CONCLUSION: This clinical study provides evidence that the pathophysiological mechanisms of trigeminal neuropathic pain after nerve injury involve impaired function of both small unmyelinated fibers and large myelinated fibers. An explanation for the finding of abnormal temporal summation of pain may involve hyperexcitability of central wide-dynamic range neurons. The results suggest that other mechanisms are involved in trigeminal neuropathic pain of spontaneous origin. Reduced heat and cold pain thresholds indicate heat and cold hyperalgesia, which possibly may be explained by sensitization of peripheral C nociceptors.     

Arteriovenous differences in plasma concentrations of catechols in rats with neuropathic pain

BACKGROUND: Alterations in cutaneous temperature, sweating, and cutaneous blood flow in patients with pain states, such as reflex sympathetic dystrophy and causalgia, have been interpreted as evidence for exaggerated sympathetic outflow. It was determined whether pain behavior in a rat model of sympathetically maintained pain is associated with alterations in regional sympathoneural function. METHODS: Peripheral neuropathy was induced in 29 Sprague-Dawley rats by ligation of the left L5 and L6 spinal nerves. Sixteen other rats had sham surgery (nerve exposure without ligation). Animals were tested for behavioral signs of allodynia (decreased paw withdrawal thresholds to mechanical stimuli) at 2 and 4 weeks after the surgery. Arterial and iliac venous blood samples (left, affected; right, control) were obtained at 2 weeks (NP2, n = 14) and 4 weeks (NP4, n = 15) after neuropathic or sham (n = 8 at 2 and 4 weeks) surgery. Plasma concentrations of dihydroxyphenylalanine, dihydroxyphenylacetic acid, dopamine, norepinephrine, and the intraneuronal norepinephrine metabolite, 3,4-dihydroxyphenylglycol, were analyzed in arterial and left and right iliac venous samples. RESULTS: A decrease in paw withdrawal threshold was observed in neuropathic (NP2 and NP4) but not sham-operated rats. Affected and control limbs did not differ in arteriovenous differences in concentrations of dihydroxyphenylalanine, dihydroxyphenylacetic acid, dopamine, or 3,4-dihydroxyphenylglycol. No differences were observed between sham-operated and neuropathic animals in these arteriovenous increments. In contrast, affected limbs of NP2 rats had a reduced arteriovenous increment in norepinephrine concentrations, compared to that in the control side (P < 0.05). CONCLUSIONS: No neurochemical evidence of sympathetic hyperactivity is observed in the rat model of neuropathic pain; if anything, norepinephrine release is decreased in the affected limb. Autonomic disturbances in neuropathic pain are therefore more likely the result of receptor supersensitivity than increased local sympathoneural traffic.     

Different types of centrally acting antihypertensives and their targets in the central nervous system

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for clinically relevant, centrally acting antihypertensives, such as clonidine, guanfacine, and alpha-methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT1A-receptors is assumed to induce peripheral sympathoinhibition, whereas for ketanserin the central mechanism is unknown in detail. More recently central imidazoline (I1) receptors have been proposed as the major target for the newer antihypertensives rilmenidine and moxonidine. Clonidine, however, is assumed to be mixed I1- and alpha2-receptor agonist. The distinction between central I1- and alpha2-receptors may potentially offer the design of new antihypertensives, acting like clonidine but with fewer side effects. Finally, the amino acid pathways should be considered as potential targets for centrally acting antihypertensives. Experimental compounds on this basis are available but clinical implications appear to be very remote. In the present survey an outline is given of the various pathways, neurotransmitters, and receptors involved in the central regulation of blood pressure. The different types of centrally acting antihypertensives are subsequently discussed on this basis.     

Pain analysis is vital in rheumatic diseases. Pain often causes much worry to patients

The article consists of a synthesis of a rheumatic pain symposium held at the annual meeting of the Swedish Medical Association in 1996. Various aspects of pain in rheumatic diseases were discussed, such as physiological, neurohumoral and neurogenic mechanisms, sensory stimulation treatment, differentiation of mechanical and inflammatory pain, quality enhancement by improved co-operation between primary and tertiary care facilities, pharmacological treatment with (centrally and peripherally acting) opioids, selective cyclo-oxygenase inhibitors, and NMDA (N-methyl-D-aspartate) receptor antagonists. For patients with rheumatic disorders exacerbated by pain problems, as for other patients, a pain diagnosis is of fundamental importance. This can be achieved by analysis of the social, psychological, physiological and medical factors contributing to the cause and degree of pain and to pain behaviour, and of the extent to which the pain may be nociceptive (i.e., inflammatory, mechanical, or ischaemic in origin), neurogenic or idiopathic. Pain analysis should be followed by individualised treatment focused on the patient's most crucial problems, thus enhancing the prospect of optimal treatment outcome.