Charles J. Vierck

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

&NA; 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.

Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome

&NA; Individuals diagnosed with fibromyalgia syndrome (FMS) report chronic pain that is frequently worsened by physical activity and improved by rest. Palpation of muscle and tendinous structures suggests that nociceptors in deep tissues are abnormally sensitive in FMS, but methods of controlled mechanical stimulation of muscles are needed to better characterize the sensitivity of deep tissues. Accordingly, force‐controlled mechanical stimulation was applied to the flexor digitorum muscle of the forearm in a series of brief contacts (15 stimuli, each of 1 s duration, at 3 or 5 s interstimulus intervals). Repetitive stimulation was utilized to determine whether temporal summation of deep muscular pain would occur for normal subjects and would be enhanced for FMS subjects. Moderate temporal summation of deep pain was observed for normal controls (NC), and temporal summation was greatly exaggerated for FMS subjects. Temporal summation for FMS subjects occurred at substantially lower forces and at a lower frequency of stimulation. Furthermore, painful after‐sensations were greater in amplitude and more prolonged for FMS subjects. These observations complement a previous demonstration that temporal summation of pain and after‐sensations elicited by thermal stimulation of the skin are moderately enhanced for FMS subjects. Abnormal input from muscle nociceptors appears to underlie production of central sensitization in FMS that generalizes to input from cutaneous nociceptors.

Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients

&NA; We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat‐induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre‐drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A‐delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap‐induced windup when compared with age‐ and sex‐matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A‐delta‐nociceptive afferent input. Heat and cold‐induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 &mgr;g/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations.

Clinical and pre-clinical pain assessment: Are we measuring the same thing?

a Department of Neuroscience, College of Medicine, Comprehensive Center for Pain Research, University of Florida, 200 Newell Drive, McKnight Brain Institute, Gainesville, FL, USA b Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL, USA c Department of Molecular Medicine and Surgery, Section of Clinical Pain Research, Karolinska Institutet and Department of Neurosurgery, Pain Center, Karolinska University Hospital, Stockholm, Sweden

Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome

Patients with fibromyalgia syndrome (FMS) report chronic pain related to abnormal sensitivity of muscles that is reflected by so‐called tender points (TP). TP represent areas of abnormal mechanical pain thresholds that have only shown a minor correlation with clinical pain of FMS patients and seem to be better suited for predicting distress. Pain‐related negative affect (PRNA), abnormal temporal summation of second pain (termed wind‐up or WU), and abnormal WU decay are frequently present in FMS patients. WU and WU decay can provide measures of central sensitization, which may contribute to clinical FMS pain. We therefore investigated the role of WU, WU decay, TP count, and PRNA as predictors of clinical pain in FMS subjects. Fifty‐five FMS subjects rated their clinical pain at entry into the study using a visual analogue scale (VAS). After a TP evaluation, all subjects received two trials of thermal WU and WU decay testing. Hierarchical regression analysis demonstrated that the combination of PRNA ratings, TP count, and WU decay ratings predicted 49.7% of the variance of clinical pain in FMS. This model demonstrates independent relationships of biological and psychological factors to clinical pain and underscores the important role of abnormal peripheral and central pain mechanisms for FMS. Therefore, the combination of PRNA, TP count, and WU decay may provide an excellent measure for future clinical studies of FMS patients.

Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls

&NA; Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU‐maintenance or WU‐M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU‐M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7 s duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 s by stimuli delivered at 0.16 and 0.08 Hz (WU‐M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU‐M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU‐M, and increased WU‐related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU‐M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization.

Pain following spinal cord injury: animal models and mechanistic studies.

Charles J. Vierck Jr.*, Phillip Siddall, Robert P. Yezierski Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610-0244, USA McNight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610-0244, USA Pain Management and Research Centre, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia The Miami Project, University of Miami, Miami, FL 33136, USA Department of Neurological Surgery, University of Miami, Miami, FL 33136, USA Department of Anatomy and Cell Biology, University of Miami, Miami, FL 33136, USA

Selective Reduction of Second Pain Sensations by Systemic Morphine in Humans

&NA; A variety of forms of painful stimulation were delivered to human subjects in order to determine whether therapeutic dosages of systemic morphine might produce significant attenuation of some forms of phasic pain that are tolerable for experimental usage. Consistent with previous reports, simple application of thermal or electrical energy to the skin (for 3 sec) produced sensations of pain that were not significantly reduced by prior administration of morphine. Similarly, subjects that were trained to focus their attention on the magnitude of the immediate (first) pain sensation evoked by brief electrical or mechanical stimulation did not report reduction by morphine of pain attributed to conduction in myelinated peripheral nociceptors. In contrast, the magnitude of late (second) pain sensations produced by brief pulses of electrical, thermal or mechanical stimuli to the same subjects was consistently reduced significantly by doses of 5 or 10 mg of morphine. The simplest interpretation of the effect on second pain intensity is that morphine preferentially attenuates input from unmyelinated nociceptors. This conclusion was reinforced by an experiment in which chemicals were applied to the skin. Morphine reduced pain produced by capsaicin (presumed to selectively excite unmyelinated peripheral afferents) but did not diminish pain elicited by bradykinin (presumed to excite A&dgr; and C nociceptors). Comparing long duration pains from chemical stimulation (lasting in excess of 5 min) with briefer pains elicited by 50 msec to 3 sec of stimulation did not support the notion that morphine acts selectively on tonic pain. Also, after‐sensations that could be discerned following second pain were not eliminated by morphine, and paired pulse facilitation of first pain sensations remained after administration of morphine, indicating that temporal summation is not preferentially reduced. Regardless of duration, frequency or latency, pain arising exclusively from unmyelinated nociceptors was attenuated substantially, but other elicited sensations were not reliably affected. For example, detection thresholds for warmth were unaffected by morphine, demonstrating that input from all unmvelinated afferents is not reduced.

Feasibility and Safety of Neural Tissue Transplantation in Patients with Syringomyelia

Transplantation of fetal spinal cord (FSC) tissue has demonstrated significant potential in animal models for achieving partial anatomical and functional restoration following spinal cord injury (SCI). To determine whether this strategy can eventually be translated to humans with SCI, a pilot safety and feasibility study was initiated in patients with progressive posttraumatic syringomyelia (PPTS). A total of eight patients with PPTS have been enrolled to date, and this report presents findings for the first two patients through 18 months postoperative. The study design included detailed assessments of each subject at multiple pre- and postoperative time points. Outcome data were then compared with each subjects own baseline. The surgical protocol included detethering, cyst drainage, and implantation of 6-9-week postconception human FSC tissue. Immunosuppression with cyclosporine was initiated a few days prior to surgery and continued for 6 months postoperatively. Key outcome measures included: serial magnetic resonance imaging (MRI) exams, standardized measures of neurological impairment and functional disability, detailed pain assessment, and extensive neurophysiological testing. Through 18 months, the first two patients have been stable neurologically and the MRIs have shown evidence of solid tissue at the graft sites, without evidence of donor tissue overgrowth. Although it is still too soon to draw any firm conclusions, the findings from the initial two patients in this study suggest that intraspinal grafting of human FSC tissue is both feasible and safe.

Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity

&NA; Orofacial pain has been well‐characterized clinically, but evaluation of orofacial pain in animals has not kept pace. The objective of this study was to describe behavioral responses to facial thermal stimulation and inflammation with/without an analgesic using a novel operant paradigm. Animals were trained to voluntarily place their face against a stimulus thermode (37.7–57.2 °C) providing access to positive reinforcement. These contingencies present a conflict between positive reward and tolerance for nociceptive stimulation. Inflammation was induced and morphine was provided as an analgesic in a subset of animals. Six outcome measures were determined: reward intake, reward licking contacts, stimulus facial contacts, facial contact duration, ratio of reward/stimulus contacts, and ratio of facial contact duration/event. Animals displayed aversive behaviors to the higher temperatures, denoted by a significant decrease in reward intake, total facial contact duration, and reward licking events. The number of facial contacts increased with increasing temperature, replacing long drinking bouts with more frequent short drinks, as reflected by a low ratio of facial contact duration/event. The number of reward licking/facial contact events was significantly decreased as the thermal stimulus intensity increased, providing another pain index derived from this operant method. These outcomes were significantly affected in the direction of increased nociception following inflammation, and these indices of hyperalgesia were reversed with morphine administration. These data reflect an orofacial pain behavior profile that was based on an animals responses in an operant escape paradigm. This technique allows evaluation of nociceptive processing and modulation throughout the neuraxis.