Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis.

OBJECTIVE: Pain in knee osteoarthritis (OA) has historically been attributed to peripheral pathophysiology; however, the poor correspondence between objective measures of disease severity and clinical symptoms suggests that non-local factors, such as altered central processing of painful stimuli, also contribute to clinical pain in knee OA. Consistent with this notion, recent evidence demonstrates that patients with knee OA exhibit increased sensitivity to painful stimuli at body sites unaffected by clinical pain. DESIGN: In order to further investigate the contribution of altered pain processing to knee OA pain, the current study tested the hypothesis that symptomatic knee OA is associated with enhanced sensitivity to experimental pain stimuli at the knee and at remote body sites unaffected by clinical pain. We further anticipated that pain sensitivity would differ as a function of the OA symptom severity. Older adults with and without symptomatic knee OA completed a series of experimental pain assessments. A median split of the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) was used to stratify participants into low vs high OA symptom severity. RESULTS: Compared to controls and the low symptom group, individuals in the high symptom group were more sensitive to suprathreshold heat stimuli, blunt pressure, punctuate mechanical, and cold stimuli. Individuals in the low symptomatic OA group subgroup exhibited experimental pain responses similar to the pain-free group on most measures. No group differences in endogenous pain inhibition emerged. CONCLUSIONS: These findings suggest that altered central processing of pain is particularly characteristic of individuals with moderate to severe symptomatic knee OA.

Vitamin D, race, and experimental pain sensitivity in older adults with knee osteoarthritis.

OBJECTIVE: Low circulating serum levels of 25-hydroxyvitamin D (referred to hereafter as vitamin D) have been correlated with many health conditions, including chronic pain. Recent clinical practice guidelines define vitamin D levels <20 ng/ml as deficient and levels of 21-29 ng/ml as insufficient. Vitamin D insufficiency, including the most severe levels of deficiency, is more prevalent in black Americans. Ethnic and race group differences have been reported in both clinical and experimental pain, with black Americans reporting increased pain. The purpose of this study was to examine whether variations in vitamin D levels contribute to race differences in knee osteoarthritis pain. METHODS: The sample consisted of 94 participants (74% women), including 45 blacks and 49 whites with symptomatic knee osteoarthritis. Their average age was 55.8 years (range 45-71 years). Participants completed a questionnaire on knee osteoarthritis symptoms and underwent quantitative sensory testing, including measures of sensitivity to heat-induced and mechanically induced pain. RESULTS: Blacks had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat-induced and mechanically induced pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but did not predict self-reported clinical pain. Group differences in vitamin D levels significantly predicted group differences in heat pain and pressure pain thresholds at the index knee and ipsilateral forearm. CONCLUSION: These data demonstrate that race differences in experimental pain are mediated by differences in the vitamin D level. Vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in black Americans.

Brain imaging in fibromyalgia syndrome.

Fibromyalgia (FM) is a chronic musculoskeletal pain syndrome which is characterised by clinical pain as well as widespread hyperalgesia/allodynia to mechanical, thermal, electrical, and chemical stimuli. Lack of consistent tissue abnormalities in FM patients has more and more shifted the focus away from peripheral factors and towards central nervous system abnormalities including central sensitisation as well as aberrant pain facilitation and inhibition. Besides quantitative sensory testing, functional brain imaging has been increasingly utilised to characterise the abnormal pain processing of FM patients. Whereas initial work in FM patients identified abnormally increased pain-related brain activity within the thalamus, insula, anterior cingulate, S1, and prefrontal cortex (so-called 'pain matrix'), more recent research focused on altered 'connectivity' between multiple interconnected brain networks in these patients. Additionally, magnetic resonance spectroscopy studies demonstrated high concentration of the excitatory neurotransmitter glutamate in FM patients in pain-related brain areas which correlated not only with experimental but also with clinical pain ratings. Overall, functional brain imaging studies have provided compelling evidence for abnormal pain processing in FM, including brain activity that correlated with patients' augmented pain sensitivity (hyperalgesia/allodynia), temporal summation of pain, and prolonged pain aftersensations. Future imaging work needs to focus on identifying the neural correlates of FM patients' abnormal endogenous pain modulation which will likely not only shed more light on this important pain regulatory mechanism but may also provide useful information for future treatments of FM symptoms.

Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils.

In human neutrophils, as in other cell types, Ras-related guanosine triphosphate-binding proteins are directed toward their regulatory targets in membranes by a series of posttranslational modifications that include methyl esterification of a carboxyl-terminal prenylcysteine residue. In intact cells and in a reconstituted in vitro system, the amount of carboxyl methylation of Ras-related proteins increased in response to the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP). Activation of Ras-related proteins by guanosine-5'-O-(3-thiotriphosphate) had a similar effect and induced translocation of p22rac2 from cytosol to plasma membrane. Inhibitors of prenylcysteine carboxyl methylation effectively blocked neutrophil responses to FMLP. These findings suggest a direct link between receptor-mediated signal transduction and the carboxyl methylation of Ras-related proteins.

Genetic contributions to pain: a review of findings in humans.

Pain represents the major motivating factor for which individuals seek healthcare, and pain responses are characterized by substantial inter-individual differences. Increasing evidence suggests that genetic factors contribute significantly to individual differences in responses to both clinical and experimental pain. The purpose of this review article was to summarize the current literature regarding genetic contributions to pain, highlighting findings relevant to oral pain where available. A brief discussion of methodologic considerations is followed by a review of findings regarding genetic influences on clinical pain. Next, the literature examining genetic contributions to experimental pain responses is presented, emphasizing genetic associations that have been replicated in multiple cohorts. It is hoped that an enhanced understanding of genetic contributions to pain responses will ultimately improve diagnosis and treatment of clinical pain conditions.

Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome.

Although individuals with fibromyalgia syndrome (FMS) consistently report wide-spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind-up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind-up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2-5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after-sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.

Wegener's granulomatosis in a patient receiving propylthiouracil for Graves' disease.

CONTEXT: The use of propylthiouracil (PTU) in patients with Graves' disease has been associated with multiple complications including rash, leukocytoclastic vasculitis, pulmonary hemorrhage, glomerulonephritis, and the presence of perinuclear antineutrophilic cytoplasmic antibodies (pANCA). OBJECTIVES: To report the association of Wegener's granulomatosis (WG) with the use of PTU in a patient with Graves' disease and to review the spectrum of systemic vasculitis seen in patients with Graves' disease taking PTU. DESIGN: Retrospective review of data collected in a patient with WG. In addition, a Medline search (1980 to present) for PTU-associated vasculitis was conducted. RESULTS: We report WG in a patient treated with PTU who fulfilled the criteria of the American College of Rheumatology for this disease. Furthermore, his serum was positive for cytosolic antineutrophil cytoplasmic antibodies (cANCA) and anti-proteinase-3 (PR3) antibodies by indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA), respectively. WG is associated with high morbidity and mortality and usually requires extensive therapy with prednisone and cyclophosphamide. Our patient, however, did not need specific therapy except discontinuation of PTU to make a full recovery. In previous reports, PTU has been associated with different forms of vasculitis, but this is a the first description of classic WG in a patient treated with PTU. CONCLUSIONS: PTU is capable of causing WG in susceptible patients with Graves' disease. Our patient did not require specific therapy for vasculitis and improved after discontinuation of PTU.

The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome.

Exercise activates endogenous opioid and adrenergic systems, but attenuation of experimental pain by exercise has not been shown consistently. In this study, effects of exercise on temporal summation of late pain responses to stimulation of unmyelinated (C) nociceptors were assessed. When a preheated thermode was applied repetitively to glabrous skin of the hand in a series of brief contacts at rates of 0.2 to 0.5 Hz, the perceived intensity of late thermal sensations increased after successive contacts. This summation of pain sensations provides information regarding the status of central opioid and N-methyl-D-aspartate receptor systems. For normal subjects, temporal summation of late pain sensations was substantially attenuated when testing began 1.5 or 10 minutes after exercise. Individuals diagnosed with fibromyalgia syndrome (FMS) report generalized chronic pain that is increased after exercise. Therefore, we hypothesized that strenuous exercise would increase summation of late pain sensations in this cohort. Patients with FMS and control subjects exerted to similarly high metabolic rates, as shown by physiologic monitoring. Ratings of late pain sensations increased for patients with FMS after exercise, an effect opposite to a decrease in ratings for age/sex-matched control subjects. In contrast to this result for experimentally induced pain, clinical pain ratings were not substantially altered after strenuous exercise by patients with FMS.

Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome.

BACKGROUND: Patients with musculoskeletal pain syndrome including fibromyalgia (FM) complain of chronic pain from deep tissues including muscles. Previous research suggests the relevance of impulse input from deep tissues for clinical FM pain. We hypothesized that blocking abnormal impulse input with intramuscular lidocaine would decrease primary and secondary hyperalgesia and FM patients' clinical pain. METHODS: We enrolled 62 female patients with FM into a double-blind controlled study of three groups who received 100 or 200 mg of lidocaine or saline injections into both trapezius and gluteal muscles. Study variables included pressure and heat hyperalgesia as well as clinical pain. In addition, placebo factors like patients' anxiety and expectation for pain relief were used as predictors of analgesia. RESULTS: Primary mechanical hyperalgesia at the shoulders and buttocks decreased significantly more after lidocaine than saline injections (p = 0.004). Similar results were obtained for secondary heat hyperalgesia at the arms (p = 0.04). After muscle injections, clinical FM pain significantly declined by 38% but was not statistically different between lidocaine and saline conditions. Placebo-related analgesic factors (e.g., patients' expectations of pain relief) accounted for 19.9% of the variance of clinical pain after the injections. Injection-related anxiety did not significantly contribute to patient analgesia. CONCLUSION: These results suggest that muscle injections can reliably reduce clinical FM pain, and that peripheral impulse input is required for the maintenance of mechanical and heat hyperalgesia of patients with FM. Whereas the effects of muscle injections on hyperalgesia were greater for lidocaine than saline, the effects on clinical pain were similar for both injectates.

Temporal summation of second pain: variability in responses to a fixed protocol.

BACKGROUND: Temporal summation of second pain (TSSP) is relevant for the study of central sensitization, and refers to increased pain evoked by repetitive stimuli at a constant intensity. While the literature reports on participants whose pain ratings increase with successive stimuli, response to a TSSP protocol can be variable. The aim of this study was to characterize the full range of responses to a TSSP protocol in pain-free adults. METHOD: Three hundred twelve adults received a train of brief, repetitive heat stimuli at a fixed temperature and rated the intensity of second pain after each pulse. TSSP response (Δ in pain ratings) was quantified using the most common methods in the literature, and response groups were formed: TSSP (Δ > 0), no change (Δ = 0), and temporal decrease in second pain (TDSP) (Δ < 0). A cluster analysis was performed on the Δ values to empirically derive response groups. RESULTS: Depending on how TSSP response was quantified, 61-72% of the sample demonstrated TSSP, 11-28% had no change in pain ratings and 0-20% demonstrated TDSP. The cluster analysis found that the majority (59%) of participants fell in the no change cluster, 29% clustered into the TSSP group and 12% in the TDSP cluster. CONCLUSIONS: Using a fixed thermal paradigm, pain-free adults exhibit substantial variability in response to a TSSP protocol not well characterized by group-mean slopes. Studies are needed to determine TSSP response patterns in clinical samples, identify predictors of response and determine the clinical implications of response variability.

Evaluation of menstrual cycle effects on morphine and pentazocine analgesia.

Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08mg/kg) or pentazocine (0.5mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic, and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model analyses of variance. NOC women showed slightly greater heat pain sensitivity in the follicular vs luteal phase, while the reverse pattern emerged for OC women (P=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (P<0.05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs the luteal phase (P=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (P=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. Limited menstrual cycle effects on baseline pain responses were observed; however, morphine analgesia and side effects were greater during the follicular phase.

Overall fibromyalgia pain is predicted by ratings of local pain and pain-related negative affect--possible role of peripheral tissues.

OBJECTIVES: Despite variable numbers and intensities of local pain areas, fibromyalgia (FM) patients can provide overall clinical pain ratings. We hypothesized that the overall clinical pain is largely determined by the pain intensity of local body areas. Thus, we assessed the role of local body pains as predictors of overall clinical pain in FM patients. METHODS: Ratings of overall clinical pain intensity and pain-related negative affect (PRNA) were obtained from 277 FM patients. In addition, the patients identified painful body areas by shading a body pain diagram and rated the intensity of each pain area using a mechanical visual analogue scale (VAS). Hierarchical regression analyses were used to examine predictors of overall clinical FM pain intensity including PRNA, number of local pain areas, and maximal/average intensity of local pain areas. RESULTS: The average overall clinical pain rating of all FM patients was 4.6 (S.D. 2.3) VAS. The PRNA accounted for 19%, number of painful body areas for 9% and maximal/average local pain for 27% of the variance of overall clinical FM pain (P-values < 0.001). The combination of all factors predicted 55% of the variance in overall clinical pain intensity of FM patients. CONCLUSION: Peripheral factors (maximal/average local pain and number of painful body areas) predicted most of the variance of overall clinical FM pain, suggesting that the input of pain by the peripheral tissues is clinically relevant. About 19% of the pain variance was predicted by PRNA. Thus, peripheral pain and negative affect appear to be particularly relevant for overall FM pain and may represent important targets for future therapies.

Metabolism and excretion of methylproscillaridin by man.

0.5 mg 3H-proscillaridin-4-methylether was administered orally to 5 healthy males. Maximum plasma levels of total radioactivity were reached after one to two hours. In two subjects a second peak was observed between 6 and 12 hours. The plasma half life of total radioactivity was 51 hours. 20% and 56% respectively of the dose were eliminated in urine and faeces during the following 7 days. 55% of the total radioactivity in plasma, 80% in urine and 20% in faeces consisted of CHC13-insoluble compounds. 50-60% of the latter in plasma and urine could be hydrolysed by beta-glucuronidase. More than 90% of the split products were identified as conjugates of methylproscillaridin. TLC-separation of the CHC13-soluble fractions of plasma and urine yielded two unidentified metabolites, P2 and P3, as the main compounds, besides methylproscillaridin, proscillaridin and scillarenin. In faeces more than 90% of the non-polar fraction was identified as methylproscillaridin. Shortly after administration of 3H-methylproscillaridin, the radioactivity in plasma consisted mainly of CHC13-insoluble conjugates and of the metabolite P2.

Evidence for abnormal pain processing in fibromyalgia syndrome.

OBJECTIVE: To review the pathophysiology of fibromyalgia syndrome. DESIGN: Review of the literature available on Medline (1965-2001). RESULTS: Fibromyalgia syndrome is a chronic pain syndrome that predominantly afflicts women. It is characterized by widespread pain, insomnia, fatigue, and the presence of multiple tender points. Despite intensifying research, the etiology of fibromyalgia has remained unclear. Importantly, neither infections, trauma, nor psychiatric abnormalities consistently precede the onset of pain in patients with this syndrome. There is, however, mounting evidence for central pain processing abnormalities in almost all fibromyalgia patients. These anomalies include hyperalgesia, allodynia, abnormal temporal summation of second pain, neuroendocrine abnormalities, and abnormal activation of pain-related brain regions. CONCLUSIONS: Multiple abnormal findings in fibromyalgia patients strongly indicate a neuropathic pain syndrome, reminiscent of complex regional pain syndrome or postherpetic neuralgia. In addition, fibromyalgia syndrome seems to share similar characteristics with these neuropathic pain syndromes, including ineffective response to many analgesics.

Influenza A-associated bronchiolitis obliterans organizing pneumonia mimicking Wegener's granulomatosis.

We describe a patient with bronchiolitis obliterans organizing pneumonia (BOOP) requiring respiratory support and treated with corticosteroids and cytoxan for presumed Wegener's granulomatosis (WG). The diagnosis of WG was based on clinical presentation and strongly positive stains for anti-neutrophilic cytoplasmic antibodies (cANCA). The results of an open-lung biopsy were consistent with BOOP. Although BOOP has previously been described as one of the pulmonary manifestations of WG, other more specific histologic features of WG such as capillaritis or necrotizing vasculitis were lacking. Because influenza A virus was cultured from the patient's lung tissue, final assessment of the illness focused on this as the etiologic agent triggering the pulmonary syndrome. The presence of ANCA was considered to be nonspecific. The patient's condition improved with appropriate therapy for BOOP.

"Vasculitis look-alike" clinical syndromes.

Rheumatologists are sometimes asked to see patients with severe manifestations of vascular syndromes termed "pseudovasculitis," which often closely mimic autoimmune vasculitis. These syndromes include cholesterol embolism, fibromuscular dysplasia, antiphospholipid syndrome, ergotism, neurofibromatosis, and primary amyloidosis. In patients with suspected vasculitis, sometimes dramatic clinical findings may require urgent decision-making before all testing has been concluded. These circumstances make it particularly important for the clinician to consider pseudovasculitis in the differential diagnosis. Our review describes the common presentations of pseudovasculitis-which may include fever, weight loss, weakness, hypertension, and vascular occlusions-and emphasizes on their diagnostic features. A careful history and physical examination, laboratory and radiographic studies, as well as a high level of suspicion will help the clinician to consider pseudovasculitis in which treatment with immunosuppressive agents such as high dose corticosteroids or cytotoxic agents would be contraindicated and possibly disastrous.