Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief

To investigate the influence of chronic nociceptive pain on endogenous pain modulation, the effect of heterotopic noxious conditioning stimulation (HNCS) on perception of various somatosensory modalities was assessed in 15 patients with painful osteoarthritis of the hip. Thirteen patients were re-assessed when pain-free 6-14 months following surgery. Sex- and age matched healthy subjects assessed at similar time intervals served as controls. The effects of HNCS were tested using the upper extremity submaximal effort tourniquet test. Subjects rated tourniquet-induced pain intensity on a visual analogue scale (VAS). Quantitative sensory testing (QST) was performed contralaterally to the maximally painful area in 13 patients and contralaterally to the second most painful area in two patients (i.e. lateral thigh n = 12, frontal thigh n = 1, lateral calf n = 2). Sensibility was assessed before, during and 45 min following the tourniquet test. Perception thresholds to light touch were assessed using von Frey filaments and pressure pain thresholds by pressure algometry. Perception thresholds to non-painful and painful warmth and cold were determined using a Thermotest. In both sessions, patients rated the tourniquet-induced pain higher than controls at the start (P < 0.003 and P < 0.006, respectively), but not at the end of the tourniquet test. Decreased sensitivity to light touch (P < 0.001) and innocuous cold (P < 0.002) was seen during the tourniquet in patients and controls alike, on both occasions, while perception thresholds to innocuous warmth and heat pain remained unaffected. In the first session, pressure pain thresholds increased during the tourniquet test in controls (P < 0.002), but not in patients. In the second session, pressure pain thresholds increased during the tourniquet test in controls (P < 0.001) and in patients (P < 0.02). In conclusion, no pressure pain modulation was induced by HNCS in patients before surgery, as opposed to controls, suggesting a dysfunction in systems subserving 'diffuse noxious inhibitory controls' (DNIC). Normal pressure pain modulation induced by HNCS was seen when patients were re-assessed in a pain-free state following surgery, indicating that the dysfunction of DNIC had been maintained by chronic nociceptive pain.     

Experimental muscle pain impairs descending inhibition

In chronic musculoskeletal pain conditions, the balance between supraspinal facilitation and inhibition of pain shifts towards an overall decrease in inhibition. Application of a tonic painful stimulus results in activation of diffuse noxious inhibitory controls (DNIC). The aims of the present experimental human study were (1) to compare DNIC, evoked separately, by hypertonic saline (6%)-induced muscle pain (tibialis anterior) or cold pressor pain; (2) to investigate DNIC evoked by concomitant experimental muscle pain and cold pressor pain, and (3) to analyze for gender differences. Ten males and 10 age matched females participated in two sessions. In the first session unilateral muscle pain or unilateral cold pressor pain were induced separately; in the second session unilateral muscle pain and unilateral cold pressor pain were induced concomitantly. Pressure pain thresholds (PPT) were measured around the knee joint before, during, and after DNIC induction. Cold pressor pain increased PPT in both males and females with greater increases in males. Hypertonic saline-evoked muscle pain significantly increased PPT in males but not in females. When cold pressor and muscle pain were applied concomitantly the PPT increases were smaller when compared to the individual sessions. This study showed for the first time that two concurrent conditioning tonic pain stimuli (muscle pain and cold pressor pain) cause less DNIC compared with either of the conditioning stimuli given alone; and males showed greater DNIC than females. This may explain why patients with chronic musculoskeletal pain have impaired DNIC.     

Computer-controlled pneumatic pressure algometry--a new technique for quantitative sensory testing.

Hand-held pressure algometry usually assesses pressure-pain detection thresholds and provides little information on pressure-pain stimulus-response function. In this article, a cuff pressure algometry for advanced pressure-pain function evaluation is proposed.The experimental set-up consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor and an electronic visual analogue scale (VAS) for constant pain intensity rating. Twelve healthy volunteers were included in the study. In the first part, hand-held algometry and cuff algometry were performed over the gastrocnemius muscle with constant compression rate. In the second part, the cuff algometry was performed with different compression rates to evaluate the influence of the compression rate on pain thresholds and other psychophysical data. Pressure-pain detection threshold (PDT), pain tolerance threshold (PTT), pain intensity, PDT-PTT time and other psychophysical variables were evaluated.Pressure-pain detection thresholds recorded over the gastrocnemius muscle with a hand-held and with a cuff algometer, were 482 +/- 19 kPa and 26 +/- 1.6 kPa, respectively. Pressure and pain intensities were correlated during cuff algometry. During increasing cuff compression, the subjective pain tolerance limit on VAS was 5.6 +/- 0.95 cm. There was a direct correlation between the number of compressions, the compression rate and pain thresholds.The cuff algometry technique is appropriate for pressure-pain stimulus-response studies. Cuff algometry allowed quantification of psychophysical response to the change of stimulus configuration.     

Psychophysics of phasic and tonic heat pain stimuli by quantitative sensory testing in healthy subjects.

The increased use of quantitative sensory testing in the study of pain raises the need to characterize various aspects of psychophysical response to noxious stimulation in healthy subjects. The present study aims to address several issues regarding the use of heat pain stimuli: (a) Are pain scores for short‐term repeated phasic stimuli consistent? (b) Does an exposure to tonic heat pain stimulus cause sensitization and change the scores for subsequent phasic stimuli? and (c) Are pain scores for phasic and tonic heat pain correlated? To address these questions, a series of four phasic heat pain stimuli of 47 °C were given to the forearms of 70 healthy volunteers, over the course of an hour. Pain scores by Visual Analog Scale (VAS) were obtained for each stimulus. In 50 subjects, a tonic heat pain of 70 s duration at 47.5 °C was given between the first and second phasic stimuli. Pain scores were obtained at four points along this tonic stimulus. Repeated measures ANOVA and a sensitive post hoc analysis indicated that, while the pain perception was reduced on the second, nearly immediate trial, subsequent VAS scores of pain perception were not different from the first (#1: 35.2±19.2; #2: 31.4±20.2, #3: 33.0±21.6; and #4: 33.2±20.1, respectively), with strong correlation among the phasic tests. The average tonic pain score was 53.7±23.1. Administration of tonic pain stimuli did not result in different VAS scores of subsequent phasic pain stimuli, compared to those subjects who did not receive tonic pain stimuli. Tonic and phasic pain were positively correlated (e.g., for the first phasic stimuli). However, no relation was found between the level of perceived pain, either for phasic or for tonic stimuli, and presence or absence of temporal summation during the tonic pain. In conclusion: (i) phasic pain scores assessments at 30′ and 60′ after baseline is consistent; (ii) tonic heat pain, despite relatively high VAS scores, does not cause a change in the scoring of subsequent phasic stimuli; and (iii) phasic and tonic pain scores correlate with each other. Thus, the normal pattern of pain perception is stable and not altered by single tonic pain stimulation.     

Psychophysical analysis of visceral and cutaneous pain in human subjects

Clinical evidence suggests that cutaneous and visceral pain differ in sensory, affective, and motivational realms, yet there has been little comparative characterization of these types of pain. This study uses psychophysical measures to compare directly visceral and cutaneous pain and sensitivity. Healthy subjects (10 males, seven females, age 19-29) evaluated perceptions evoked by balloon distention of the distal esophagus and contact heat on the upper chest. Subjects gave continuous ratings of pain intensity using an on-line visual analog scale (VAS), reported maximum pain intensity and unpleasantness on printed VASs, chose phrases from the McGill Pain Questionnaire and Spielberger State-Trait Anxiety Inventory, and drew the area of perceived sensation. For esophageal distention, the threshold for pain intensity was higher than that observed for unpleasantness, whereas for contact heat, pain and unpleasantness thresholds did not differ for either phasic (10s) or tonic (36s) stimulus application. The relative unpleasantness, calculated as the difference between the unpleasantness and the intensity ratings, was higher during esophageal distention than during either phasic or tonic cutaneous heat; this difference in relative unpleasantness was seen at all intensities of esophageal stimulation. Subjects chose significantly more affective words and reported more anxiety during visceral pain than during phasic cutaneous heat pain. A similar tendency was observed when visceral pain was compared to tonic cutaneous heat pain. Subjects also chose a wider range of words to describe visceral than cutaneous pain. On-line VAS ratings revealed greater pain sensation after stimulus termination during visceral than during phasic cutaneous pain; likewise, a similar tendency was observed between visceral and tonic cutaneous pain. Finally, visceral pain led to a more spatially diffuse sensation and was referred to the entire chest and sometimes to the back. Our results show that visceral pain is more unpleasant, diffuse, and variable than cutaneous pain of similar intensity, independent of the duration of the presented stimuli. The data suggest the likelihood of both similarities and differences in the neural substrates underlying visceral and cutaneous pain.     

The analgesic effect of codeine as compared to imipramine in different human experimental pain models

The hypoalgesic effect of single oral doses of 100 mg imipramine and 125 mg codeine was evaluated in a randomised, placebo-controlled, double-blind, 3-way cross-over experiment including 18 healthy volunteers. Pain tests were performed before and 90, 180, 270, 360 and 450 min after medication. The tests included determination of pain tolerance thresholds to pressure, pain detection/tolerance thresholds to single electrical sural nerve stimulation and pain summation at tolerance threshold to repetitive electrical sural nerve stimulation (temporal summation) and pain experienced during the cold pressor test, rated as peak pain intensity, pain average intensity and discomfort. Compared to placebo, imipramine significantly increased pressure pain tolerance threshold (P = 0.03) and increased pain tolerance threshold (P = 0.05) and pain summation threshold (P = 0.03), but not pain detection threshold to electrical stimulation. Imipramine did not cause significant changes in pain perception during the cold pressor test. Codeine significantly increased pressure pain tolerance threshold (P = 0.02), pain detection (P = 0.04) and pain tolerance threshold (P = 0.01) and pain summation threshold (P = 0.02) to electrical stimulation. In addition, codeine reduced the pain experienced during the cold pressor test (P = 0.04-0.003). It is concluded that both imipramine and codeine inhibit temporal pain summation, whereas only codeine reduces cold pressor pain. Pain summation may be a key mechanism in neuropathic pain. Imipramine has a documented effect on such pain conditions on temporal summation. The present study showed that codeine also inhibits temporal summation, which is in line with the clinical observations indicating that opioids relieve neuropathic pain.     

Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: diffuse noxious inhibitory controls in the trigeminal nerve territory.

The purpose of this study was to determine whether the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and pain intensity are inhibited by heterotopic ischemic stimulation. The tourniquet pressure with 50 mmHg greater than the individual's systolic pressure was applied to the left upper arm for 10 min as ischemic conditioning stimulation. The late component of SEP and visual analogue scale (VAS) were recorded at 4 times and both were significantly decreased when ischemic conditioning stimulation was applied. The maximum reductions in SEP amplitude and the VAS value were 26.1% and 21.2%, respectively, during ischemic conditioning stimulation. After-effect was observed 5 min after removal of the conditioning stimulation. The present study revealed that heterotopic ischemic stimulation attenuated the late component of SEP induced by electrical tooth stimulation, triggering diffuse noxious inhibitory controls (DNIC) and after-effects in the trigeminal nerve territory. It was also suggested that the DNIC effect differs, depending on the intensity, kind, and quality of the test and conditioning stimuli.     

Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain

In this study, we evaluated pain sensitivity in patients with fibromyalgia or other types of chronic, diffuse musculoskeletal pain to establish whether fibromyalgia represents the end of a continuum of dysfunction in the nociceptive system. One hundred and forty five patients and 22 healthy subjects (HS) completed an epidemiological questionnaire to provide information about fatigue, stiffness, sleep, the intensity of pain (VAS 0–100) and its extent both at onset and at present. Algometry was performed at all American College of Rheumatology (ACR) tender points and at ten control points. Patients were divided into five main groups: fibromyalgia (FS) patients, secondary-concomitant fibromyalgia (SCFS) patients, patients with widespread pain (WP) but not reaching the ACR criterion of 11 tender points, patients with diffuse multiregional pain (MP) not reaching the ACR criteria (widespread pain, tender point counts), and patients with multiregional pain associated with at least 11 tender points (MPTE). von Frey monofilaments were used to assess superficial punctate pressure pain thresholds. Heat and cold pain thresholds were determined with a thermal stimulator. Ischemic pain was assessed by the cold pressure test and the submaximal effort tourniquet test. The scores for stiffness and present pain intensity gradually increased concomitantly with the increase in tender point count and pain extent. The pressure pain thresholds for positive tender and positive control points were significantly lower in the SCFS, FS and MPTE groups than in HS, MP and WP groups, the latter three groups displaying similar values. In all groups, there were no differences in pain thresholds between positive tender and positive control points. The heat pain threshold and the pain threshold in the cold pressure test were lower in the FS and SCFS groups than in HS. The cold pressure tolerance was lower in patients with widespread pain than in HS. In the von Frey test, all patient groups except MP had similar values, which were significantly lower than in HS. Finally, all patient groups displayed lower tourniquet tolerance than HS. In each psychophysical test, patients with widespread pain and patients with multiregional pain showed similar thresholds; however, the thresholds in the MP or MPTE groups differed from those in the FS and SCFS groups. In the FS group, pain thresholds and pain tolerance did not differ according to the presence of ongoing pain at the stimulated site and were not correlated to ongoing pain. The results indicate that dysfunction in the nociceptive system is already present in patients with multiregional pain with a low tender point count; it becomes more and more severe as the positive tender point count and pain extent increase and it is maximal in fibromyalgia patients.     

Vagus nerve stimulation suppresses pain but has limited effects on neurogenic inflammation in humans.

Left vagus nerve stimulation reduces pain perception in humans. In animal studies it has been shown that beyond the inhibitory effect, which the vagus nerve exerts via its widespread central connections, there might be also a peripheral effect on nociceptors. In humans, the exact mechanisms of VNS-mediated analgesia are still unclear. To test whether VNS also affects activation of primary nociceptive afferents in humans, we investigated 11 patients before and after implantation of a vagus nerve stimulator by using tonic pressure as pain stimulus. Vasodilator axon reflexes ("neurogenic" inflammation) were quantified by laser-Doppler-imaging and served as surrogates for primary afferent activation. Pain was measured on a visual analogue scale (VAS). The squeezing experiment was performed three times at 15 min intervals in each session. As controls 9 healthy age- and gender-matched subjects were studied. As shown in our previous study, VNS significantly reduces pain to tonic pressure. Likewise, there was a moderate reduction of the blood flow within the area of the axon reflex, which indicates a possible but limited inhibitory effect of VNS on peripheral nociceptors. Our data suggests that VNS might affect peripheral nociceptor function in humans. Since VNS has been shown to be more effective in experimental procedures in which pain magnitude is amplified by central processing, further studies are warranted to elucidate whether the central or peripheral effect is most important for VNS-mediated analgesia.     

Experimental Referred Pain Extends Toward Previously Injured Location: An Explorative Study

Facilitated pain mechanisms have been demonstrated in musculoskeletal pain, but it is unclear whether a recent painful injury leaves the pain system sensitized. Pain characteristics were assessed in individuals who recently recovered from ankle pain (recovered pain group; n?=?25) and sex-matched control subjects (n?=?25) in response to tonic pressure pain and saline-induced pain applied at the shin muscle. Pain intensity and pain referral patterns were recorded bilaterally after the painful muscle stimulus. Pressure pain thresholds were measured at the lower legs and shoulder. Cuff pressure algometry on the lower leg was used to assess pain detection threshold, pressure evoking 6-cm pain score on a 10-cm visual analog scale, pain tolerance, temporal summation of pain, and conditioned pain modulation. Compared with in control subjects, saline-induced and pressure-induced pain in the shin muscle were more frequently felt as referred pain in the previously painful ankle (P < .05), and the pain area within the previously affected ankle was larger after saline-induced pain (P < .05). In the recovered pain group, conditioned pain modulation responses and the cuff pressure needed to reach a 6-cm pain score on a 10-cm visual analog scale was higher in the previously painful leg compared with in the contralateral leg (P < .05). No group differences were found in pressure pain threshold, pain detection threshold, pain tolerance, and temporal summation of pain.

止血带加压性疼痛导致交感神经兴奋性的改变

目的:研究止血带加压性疼痛是否导致了交感神经兴奋性的改变并参与双手皮肤血流量的调节.方法:20名健康成年男性受试者,实验前填写相应心理学量表,然后进行3次左上臂止血带加压,连续记录受试者的疼痛强度和不适度,同时用红外热像仪采集双手皮肤的温度.结果:加压性疼痛阈值逐渐降低[F(2,57)=128.36,P＜0.001],平均疼痛强度F[(2,57)=7.78,P＜0.01]和不适度[F(2,57)=5.16,P＜0.05]均逐渐降低.双手指温度差异值比较差异显著[F(1,19)=479.08,P＜0.001],3次加压之间差异显著[F(2,19)=86.63,P＜0.001];双手掌温度差异值比较差异显著[F(1,19)=126.08,P＜0.001],3次加压之间差异显著[F(2,19)=110.76,P＜0.001].3次比较,左手掌平均温度先升高后降低,右手掌、左右手指平均温度逐渐增高.结论:在止血带加压过程中,疼痛导致交感神经兴奋性的改变,参与了双手皮肤血流量的调节.     

The influence of experimental pain intensity in the local and referred pain area on somatosensory perception in the area of referred pain

The aim of this study was to investigate the influence of experimental pain intensity in the local and referred pain area on somatosensory perception thresholds in the area of referred pain. Pain was induced by intramuscular electrical stimulation of the left infraspinatus muscle in 12 healthy individuals. The stimulation corresponded to the local pain threshold ("mild local pain"), the referred pain threshold ("mild referred pain"), and a pain intensity corresponding to 2 on a 10-point category scale in the referred pain area ("moderate referred pain"). Quantitative sensory testing was performed to assess perception thresholds in the referred pain area and the homologous contralateral area before and during stimulation. Perception thresholds to light touch (LTTs), pressure pain (PPTs), and to innocuous as well as noxious warmth and cold were assessed. During stimulation the LTTs increased in the referred pain area compared to baseline, uninfluenced by pain intensity. Perception thresholds to innocuous cold and warmth increased bilaterally during the stimulation, without relation to pain intensity. Heat pain thresholds were not affected. Compared to baseline, PPTs increased bilaterally during stimulation corresponding to "mild local pain" and "mild referred pain", respectively, and a further increase was seen during "moderate referred pain". The decreased sensitivity to innocuous cold, warmth, and pressure pain was bilateral, indicating activation of endogenous net inhibitory mechanisms interacting bilaterally. We found no influence of pain intensity on somatosensory thresholds restricted to the referred pain area and light touch was the only affected modality in the referred pain area only.     

Heart rate changes as an autonomic component of the pain response

Autonomic variables have been recommended as measures of the affective-motivational component of the pain response in objective algesimetry. In the present study components of heart rate responses to painful heat stimuli and their relation to stimulus and sensation variables were analyzed. Twelve healthy subjects served. Sixty phasic stimuli of varying temperatures above and below pain threshold were delivered through a Marstock thermode in 1 session. Heart rate, respiration, and subjective stimulus ratings were recorded simultaneously. Phasic heat stimulation above and below pain threshold induced a tonic increase of the heart rate lasting up to more than 20 sec. High intensity stimulation generated steeper rises and greater mean increase than low intensity stimulation. In general, heart rate responses were more closely related to subjective sensation than to stimulus intensity. However, differential temporal analysis demonstrates that, until about 3 sec after stimulation, the autonomic response is determined solely by stimulus temperature, whereas, after approximately 6 sec, it is related only to subjective judgement. Accordingly, the heart rate responses reflect both a brief nocifensive reflex induced by the sensory component and, subsequently, a longer-lasting response which seems to be related to affective and/or cognitive evaluation. This separation of different stages of pain-processing by an autonomic indicator may be useful in clinical algesimetry.     

Comparison of the effect of video glasses and nitrous oxide analgesia on the perceived intensity of pain and unpleasantness evoked by dental scaling.

The aim of this study was to evaluate whether distraction induced by video glasses had an effect on the perceived intensity of pain and unpleasantness during dental scaling compared with the effect of nitrous oxide (N(2)O) analgesia. The pain stimulus was dental scaling (removal of dental calculus) with an ultrasonic scaler. As a standardised, non-dental painful stimulus, Von Frey filaments were used. A total of 26 patients with superficial chronic periodontitis were enrolled in this randomised, controlled clinical study. The effect of video glasses was compared with N(2)O in one session and the effect of video glasses versus a control situation in another. The patients rated the intensity of pain and unpleasantness evoked by dental scaling and Von Frey filament stimulation on 100-mm visual analogue scales (VAS). For dental scaling, there was no effect of video glasses on the perceived pain (p=0.85) or unpleasantness (p=0.73) nor of N(2)O (p=0.69 and p=0.51, respectively) compared with the control situation. Similarly, no significant difference was found between VAS scores in the video glasses and N(2)O session (p=0.48, p=0.58). A significant effect of video glasses and N(2)O(p<0.008) was found on the perceived pain intensity produced by Von Frey filament stimulation compared with the control situation, but no significant difference was seen between these methods (p=0.07). Post-treatment interviews of the patients revealed that 81% of the patients in the video and 65% in the N(2)O session stated that the method had some beneficial effect on their overall experience of the treatment situation. In conclusion, administration of video glasses or N(2)O did not affect the perceived intensity of pain and unpleasantness evoked by dental scaling.     

Pressure-pain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry.

This study assessed a newly developed cuff pressure algometry during discrete leg skin/muscle sensitization and anesthesia. Experimental setup consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and an electronic visual analog scale (VAS). The first experiment assessed cuff algometry before and after selective anesthesia of the skin and the muscle under the cuff. The second experiment assessed cuff algometry before and during skin and muscle sensitization with capsaicin cream and injection of capsaicin. Pressure-pain detection threshold, pressure equivalent to the pain intensity of 2 on the VAS (PVAS2), pressure-pain tolerance threshold, and pressure-pain stimulus-response (SR) function were evaluated. Local anesthesia of the muscle increased the pain thresholds significantly and shifted the average SR function to the right indicating desensitization, whereas cutaneous anesthesia did not affect the pressure thresholds and increased the slope of the SR function. Capsaicin cream did not affect pressure-pain tolerance threshold, whereas PVAS2 and the slope of the SR function were significantly decreased. Intramuscular capsaicin injection decreased the pain thresholds and did not affect the slope of the SR function. Both interventions shifted the SR function to the left. The cuff algometry reliably assessed the pressure-pain SR function during muscle sensitization/desensitization and might supplement conventional pressure algometry for standardized pressure-pain function assessment.     

Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients

Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS) patients. The present study assessed the effects of an NMDA-antagonist (ketamine) on these central mechanisms. FMS patients received either i.v. placebo or ketamine (0.3 mg/kg, Ketalar((R))50% decrease in pain intensity at rest by active drug on two consecutive VAS assessments). Fifteen out of 17 ketamine-responders were included in the second part of the study. Before and after ketamine or placebo, experimental local and referred pain was induced by intramuscular (i.m.) infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA) muscle. The saline-induced pain intensity was assessed on an electronic VAS, and the distribution of pain drawn by the subject. In addition, the pain threshold (PT) to i.m. electrical stimulation was determined for single stimulus and five repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was determined, and the pressure PT and pressure pain tolerance threshold were determined at three bilaterally located tenderpoints (knee, epicondyle, and mid upper trapezius). VAS scores of pain at rest were progressively reduced during ketamine infusion compared with placebo infusion. Pain intensity (area under the VAS curve) to the post-drug infusion of hypertonic saline was reduced by ketamine (-18. 4+/-0.3% of pre-drug VAS area) compared with placebo (29.9+/-18.8%, P<0.02). Local and referred pain areas were reduced by ketamine (-12. 0+/-14.6% of pre-drug pain areas) compared with placebo (126.3+/-83. 2%, P<0.03). Ketamine had no significant effect on the PT to single i.m. electrical stimulation. However, the span between the PT to single and repeated i.m. stimuli was significantly decreased by the ketamine (-42.3+/-15.0% of pre-drug PT) compared with placebo (50. 5+/-49.2%, P<0.03) indicating a predominant effect on temporal summation. Mean pressure pain tolerance from the three paired tenderpoints was increased by ketamine (16.6+/-6.2% of pre-drug thresholds) compared with placebo (-2.3+/-4.9%, P<0.009). The pressure PT at the TA muscle was increased after ketamine (42.4+/-9. 2% of pre-drug PT) compared with placebo (7.0+/-6.6%, P<0.011). The present study showed that mechanisms involved in referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest were attenuated by the NMDA-antagonist in FMS patients. It suggested a link between central hyperexcitability and the mechanisms for facilitated referred pain and temporal summation in a sub-group of the fibromyalgia syndrome patients. Whether this is specific for FMS patients or a general phenomena in painful musculoskeletal disorders is not known.     

Temporal summation of pain evoked by mechanical stimulation in deep and superficial tissue.

Temporal summation of deep tissue pain has been suggested to be facilitated in chronic musculoskeletal pain syndromes. This study aimed to test whether temporal summation of mechanical induced pressure pain is (1) more pronounced at short (1 second) interstimulus intervals (ISIs) compared with long ISI (30 seconds), (2) more potent than summation elicited by pure skin stimulation, and (3) attenuated in women compared with men. Twelve age-matched men and 12 women were included. A computer-controlled pressure stimulator with a probe surface of 1 cm2 was used to give 10 stimulations to the tibialis anterior, tibia periosteum, and the first web of the hand. Sequential stimulation at pressure pain threshold intensity was applied with different ISIs (1, 3, 5, 10, and 30 seconds). The pain intensity was assessed on a visual analog scale (VAS) after each individual stimulus. The VAS scores after the 10th stimulation with 1-second ISI were increased (P < .05) by 418% +/- 77%, 378% +/- 89%, and 234% +/- 66% compared with the first stimulation for tibia, tibialis anterior, and web, respectively. Temporal summation of pain was observed for all ISIs in tibialis anterior and tibia, eg, 30-second ISI evoked a VAS increase of 192% +/- 71 % (tibia) and 117% +/- 42% (tibialis anterior) compared with the first stimulation. The VAS score after the 10th web stimulation was smaller (P < .05) than that of the 10th tibialis anterior or tibia stimulation. A regression analysis between stimulation number and VAS score showed that the pain intensity increased progressively (1) more for 1-second ISIs compared with longer ISIs (P < .01) and (2) faster in deep tissue compared with skin (P < .01). No gender difference was observed. The temporal summation might be related to both central and peripheral mechanisms. PERSPECTIVE: Pain originating in deep tissue influences central pain processing systems more than superficial tissue. This might be of importance in patients with musculoskeletal pain.     

Activating endogenous visceral pain modulation: A comparison of heterotopic stimulation methods in healthy controls

All sensory input underlies modulation by endogenous central nervous system pathways. Dysfunctional endogenous pain modulation has been demonstrated in central sensitization and in several pain syndromes, including Irritable Bowel Syndrome (IBS) Activation of endogenous visceral pain modulation by heterotopic stimulation was compared using different methods. Rectal electrical or distension pain alone or with simultaneous (i.e. heterotopic) noxious hand or foot cold stimulation were investigated in randomized sequence in 14 male and 1 female healthy subjects.Mean pain intensities on a visual analogue scale of 0–100 (95% CI) during tonic rectal electrical and distension stimulation alone were 64 (52–76) and 55 (39–71), respectively. Rectal distension pain decreased by 36% (18–55) with simultaneous hand and by 45% (24–66) with simultaneous foot cold pain. Rectal electrical pain decreased by 45% (29–61) during hand and by 46% (28–64) during foot cold pain. Facilitation, i.e. increased rectal pain during heterotopic stimulation was observed in only 1 of 60 stimulation runs.Potent and consistent activation of endogenous visceral pain inhibition was achieved with heterotopic cold pain limb stimulation. Somato-visceral convergence did not affect the effectiveness of induction of endogenous visceral pain inhibition in healthy subjects, as hand and foot heterotopic stimulation resulted in similar pain inhibition. Pain facilitation, as shown earlier in IBS patients, was not evident in healthy controls.     

Referred pain is dependent on sensory input from the periphery: a psychophysical study

Muscle pain can be characterized by local pain and pain referred to distant somatic structures with concomitant cutaneous and deep somatosensory changes. The mechanisms responsible for referred muscle pain are poorly understood. The aim of this study was to study the origin of experimentally-induced referred muscle pain by anaesthetizing the skin overlying the referred pain area and to quantify deep somatosensory changes in the area. Fourteen healthy subjects (mean age = 25.1 years, range 22-34 years) were included in a placebo controlled study consisting of two sessions separated by 1 week. Two stimulation needles were inserted into the right anterior tibial muscle. Electrical stimuli (1Q Hz) were delivered by a computer-controlled constant current stimulator. The intensity required to generate referred pain was determined and the circumference of the referred pain area was marked. At the centre of the area, pressure pain threshold and pinprick perception threshold were determined. Either an anaesthetic cream (EMLA, Astra AB, Sweden) or a placebo cream (Astra AB, Sweden) covered by an occlusive dressing was applied to the marked referred pain area for 90 min. Afterwards, a 600-s stimulation at 150% of the referred pain threshold was induced while the VAS score of referred pain was recorded continuously. Pressure pain threshold and pinprick perception threshold were determined before, during and 5 min after the prolonged stimulation. A significantly lower referred pain visual analogue scale (VAS) score was recorded during the interval from 50 to 150s (p=0.04). The area under the referred pain VAS score vs time curve tended to be lower (22.7%) with the application of skin anaesthetic (p=0.07). The mean referred pain threshold and the mean referred pain area did not differ significantly between the two sessions (p>0.6). No difference was found in pressure pain threshold between the two treatments or between the four recordings during each session (p>0.8). Pinprick perception threshold increased significantly after EML application (p<0.04). Decreased referred pain intensity with application of anaesthetic cream at the referred pain site indicates that referred muscle pain depends on input from the periphery (skin) in humans.