Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls

Pain, 64 (1996) 415-423 © 1996 Elsevier Science B.V. All rights reserved 0304-3959/96/$15.00

415

PAIN 2902

Research Reports Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls Eva Kosek a, ,, Jan Ekholm

a

and Per H a n s s o n b

a Department of Rehabilitation Medicine, Karolinska Institute /Hospital, S-171-76 Stockholm (Sweden), and b Neurogenic Pain Unit, Department of Rehabilitation Medicine, Karolinska Institute ~Hospital, S-171- 76 Stockholm (Sweden)

(Received 2 May 1995, accepted 25 May 1995)

Summary This study aimed at evaluating the influence of submaximal isometric contraction on pressure pain thresholds (PPTs) in 14 fibromyalgia (FM) patients and 14 healthy volunteers, before and after skin hypoesthesia. PPTs were determined with pressure algometry over m. quadriceps femoris before, during and following an isometric contraction. Maximum voluntary contraction (MVC) was assessed using a computerized dynamometer. A contraction of 22% MVC on average was held until exhaustion (max. 5 min) and PPTs were assessed every 30 sec. A local anesthetic cream and a control cream were applied following a double-blind design and PPTs were reassessed. In healthy volunteers.PPTs increased during contraction ( P < 0.001), then decreased after the end of contraction (P < 0.001) but remained above precontraction values during the 5 min of post-contraction assessments (P < 0.001). In FM patients PPTs decreased in the middle of the contraction period (P < 0.05) and remained below precontraction levels during the rest of the contraction period (P < 0.05) and during the 5 rain of post-contraction assessment (immediately post-contraction NS; 2.5 rain post-contraction P < 0,01; 5 min post-contraction P < 0.05). The normalized PPTs were :significantly lower in patients than in controls during contraction (start P < 0.01; middle P < 0.001; end P < 0.001) and at all times during post-contraction assessments (P < 0.001). Anesthetic cream raised PPTs at rest in controls (P < 0.01) but not in FM patients, and did not influence contraction or post-contraction PPTs in either group. Therefore, the increased pressure pain sensibility in FM patients is more pronounced deep to the skin. The observed decrease of PPTs during isometric contraction in FM patients could be due to sensitization of mechanonociceptors caused by muscle ischemia a n d / o r dysfunction in pain modulat!on during muscle contraction. Key words: Pressure algometry; Isometric contraction; Fibromyalgia; Sensitization; Pain modulation

Introduction Fibromyalgia (FM) is a syndrome of unknown pathophysiology consisting of generalized pain, tenderness, sleep disturbance and pronounced fatigue (Boissevain and McCain 1991). Patients complain of increased pain during physical activity and of postexertional exacerbation of pain and tenderness (Jacobsen et al. 1993), and muscular ischemia has been postulated as one possible causative factor. Morphological

* Corresponding author: Eva Kosek, M.D., Department of Rehabilitation Medicine, Karolinska Hospital, POB 60 550, S-171 76 Stockholm, Sweden. Tel.: (46) 8-7295432; FAX: (46) 8-307729. SSDI 0304-3959(95)00112-3

abnormalities indicating muscle ischemia (Kalayan-Raman et al. 1984; Bengtsson et al. 1986; Yunus et al. 1986; Drewes et al. 1993), decrease in high-energy phosphate compounds (Bengtsson and Henriksson 1989), reduced rate of phosphorylation (Frey et al. 1992) and abnormal capillary microcirkulation (Lund et al. 1986; Bennett et al. 1989) have been found in FM patients. Contrary to this, reports of normal overall rate and pattern of utilization of oxygen during exercise (Sietsema et al. 1993), normal biochemical response to work and recovery (Jacobsen et al. 1992) and normal fatigue mechanisms (Stokes et al. 1993) among these patients have appeared. Dysfunction of endogenous pain modulation has been put forward as a basis for etiology and pathogen-

416 esis in FM (Smythe 1979; Moldofsky 1982; Yunus 1992). Observations supporting this suggestion include findings of a deranged serotonin metabolism. Low serum levels of the serotonin precursor tryptophan (Russell et al. 1989; Yunus et al. 1992), and serum serotonin (Russell et al. 1992a), as well as low levels of the serotonin metabolite 5-HIAA in the cerebrospinal fluid (CSF) (Houvenagel et al. 1990; Russell et al. 1992b) have been reported in FM patients. In this context, Moldofsky and Warsh (1978) found an inverse relation between free tryptophan in plasma and pain reactivity in FM. Other authors (Klein et al. 1992) found a normal serum serotonin concentration, but reported the presence of antibodies possibly directed against the serotonin receptor. In addition, increased levels of substance P (SP) in CSF have been found in FM patients (VaerCy et al. 1988). This could either depend on increased activity in primary afferents (Henry 1982; Besson and Chaouch 1987), as supported by the finding of increased peripheral neurogenic inflammation in FM (Littlejohn et al. 1987), or it could derive from spinal cord intrinsic neurons a n d / o r neurons originating in the brainstem (Skirboll et al. 1983; Besson and Chaouch 1987). Based on the finding that SP has an inhibitory effect on spinal nociceptive reflexes only in the presence of a serotonin agonist (Murphy and Zemlan 1987), it could be speculated that in FM patients, SP released as a result of activation of the descending pain inhibitory system could have a paradoxal facilitatory effect on nociceptive transmission in the absence of sufficient amounts of serotonin. Other mechanisms such as impaired function in the neuroendocrine axis have been proposed as a pathophysiological basis for FM. A decreased sympathetic response to cold pressor test, auditive stimuli (VaerCy et al. 1989) and exercise (Van Denderen et al. 1992) has been demonstrated, as well as a reduced response to exercise of the hypothalamo-pituitary-adrenal axis (Van Denderen et al. 1992). A hypereactive pituitary with a relative adrenal hyporesponsiveness (Griep et al. 1993) and insufficient growth hormon release (Bennett et al. 1992) have also been reported, with possible implication~ for muscle pain and dysfunction. Muscle blood flow is impaired at relatively low contraction levels (5-50% MVC) (Sylvest and Hvid 1959; Edwards et al. 1972; Richardson 1981; J~irvholm et al. 1988; SjCgaard et al. 1988), implying that muscles are frequently forced to work under ischemic conditions. Muscle ischemia can cause sensitization of mechanonociceptors (Mense 1990), so the mechanical component of a contraction becomes an effective nociceptive stimulus (Mense and Stahnke 1983). However, dorsal horn neurons mediating nociceptive activity from muscle nociceptors are normally under strong, tonically active, descending inhibitory control (Mense 1990; Hoheisel and Mense 1990). Therefore, it is conceivable that

nociceptive input from muscle is normally subjected to strong inhibition and thus does not cause pain in normal subjects. Sensitization of mechanonociceptors a n d / o r defects in pain inhibitory mechanisms could explain the increased pain during muscular work in FM patients. In this context, Bengtsson et al. (1989) found that opioids given epidurally to FM patients decreased perceived exertion and the number of pain and tender points. They also demonstrated total disappearance of tender points after epidural injection of lignocaine. These findings stress the importance of afferent input for the maintainance of fibromyalgia symptoms. Tenderness in FM has been assessed by the semiobjective method of pressure algometry, the reliability of which has been reported previously (Jensen et al. 1986; Ohrbach and Gale 1989a,b; Kosek et al. 1993). Despite some conflicting results (Campbell et al. 1983; Simms et al. 1988), there is an increasing body of evidence in favor of a generalized lowering of pressure pain thresholds in FM patients (Lautenschl~iger et al. 1988; Quimby et al. 1988; Tunks et al. 1988; Wolfe et al. 1990; Mikkelsson et al. 1992; Granges and Littlejohn 1993; Kosek et al. 1995). As mentioned earlier, FM patients complain of increased pain during muscle contraction. However, no studies of pain threshold changes during physical activity in FM patients have, to our knowledge, appeared. We hypothesized that if FM is primarily a disorder of endogenous pain modulatory systems, the PPT increase normally seen during and following isometric contraction (Kosek and Ekholm 1995) would be smaller or absent. Furthermore, if metabolic derangement in muscles is present in FM patients, an additional decrease in PPT due to additional sensitization of muscle mechanonociceptors would be expected. The purpose of this study was to investigate wether abnormal sensibility to pressure pain develops during and following a prolonged isometric contraction in FM patients. The following questions were addressed: How does submaximal isometric contraction influence PPTs in FM patients (a) with intact skin sensibility, (b) after skin hypoesthesia?

Methods

Subjects Patients. Fourteen femalefibromyalgiapatients, with an average age of 45.6 years (range: 29-59 years), participated in the study. They were all outpatients in a medical rehabilitationclinic. All had widespread pain (includingall 4 body quadrants) and tenderness in 11 or more of the 18 specifictender sites accordingto the diagnostic criteria of the American College of Rheumatology(Wolfe et al. 1990). The averagedurationof generalizedpain was 4.8 years(range: 1-11 years). All the patients had normal laboratorytests regarding erythrocyte sedimentation rate, hematologycount, liver enzymes, creatinine kinase, thyroid function tests and tests for rheumatoid

417 factor and antinuclear antibodies. None suffered from any current dermatological problems. Three patients were ort antidepressive medication (30 mg imipramin, 25 mg amitriptylin, and 10 mg clomipramin, respectively) on a daily basis. Controls. Fourteen female volunteers, with an average age of 36.8 years (range: 20-54 years), participated in the study. None of the subjects suffered from any musculoskeletal or dermatological problems. The study was approved by the Regional Ethical Committee and all the subjects gave their informed consent to participation.

Material The pressure algometer (Somedic Sales AB, Farsta, Sweden) consisted of a gun-shaped handle and a 10-mm-diameter rod with a pressure-sensitive strain gauge at the tip. It was connected to a power supply, an amplifier, and a digital display. The rod had a flat end covered with 2 mm of rubber to avoid painful skin stimuli due to sharp metal edges. The display indicated pressure (kPa) and rate of pressure force increase. The scale enabled the examiner to keep a fairly constant rate of pressure increase. In this study a rate of 50-60 kPa/s was chosen. The subject indicated the point at which the pressure became painful by pressing a push-button which froze the current pressure intensity on the display. The algometer was calibrated before assessment in each subject. Maximal isometric strength was assessed in a computerized isokinetic system (Kin-Com 125E, Chattanooga Corp., Chattanooga, TN). The same system was used for biofeedback of the contraction force level to the subject and recording of force during the contraction.

immediately following contraction and every 30 sec during 5 min of rest after the contraction. An anesthetic cream (EMLA, eutectic mixture of lidocain and prilocain Astra, S6dert~ilje, Sweden) or a control cream (ACO Fuktkrfim, ACO AB, Stockholm, Sweden) was then applied to an area of 40 cm e covering the 3 points to be examined (1~.2 g / c m z) and kept "under occlusive cover for 60 min. The same procedure was repeated in the same session with the other leg. Although the study aimed at following a double-blind design, most subjects responded with vasoconstriction to the EMLA cream. After removal of the cream, skin sensibility was reassessed following the previously described procedure. PPTs were reassessed during rest, during contraction and following contraction.

Statistics Since typical PPTs at rest vary in the range of 100-500 kPa in healthy controls and 50-150 kPa in FM patients, we found it natural to consider the relative effect of contraction and anesthetic cream on PPTs, and consequently used a multiplicative model. To transform this into an additive model suitable for ANOVA the natural logarithms of the PPTs were taken as data for a repeated-measures design (Milliken 1990). To eliminate variations, e.g., those due to different measurement sites, the logarithm of the precontraction PPT at the corresponding site for each data was subtracted. The impact of cream treatment on precontraction PPTs was analyzed with Student's 2-tailed t test. The confidence interval for relative frequency of positive anesthetic effect for warmth was computed using the binominal distribution. The touch perception threshold was calculated as the mean value of the descending and ascending determination in each site and differences between means were analyzed with Student's 2-tailed t test.

Procedure The subject was comfortably seated in the Kin-Com apparatus with back support and fixed with a waistbelt and a strap around the chest. Care was taken to ensure full support of the whole thigh against the seat. The leg to be examined was strapped above the ankle to the measuring device. The maximum isometric knee extensor strength at 90° of knee fie)don was determined 3 times with l min of rest between trials. The best value was used for calculating 25% of maximal voluntary contraction (25% MVC). The middle part of the quadriceps (midway between the groin and the apex of patella) was identified and marked. Two additional sites, 25 mm proximal and distal to this site, were also marked. Skin sensibility to warmth was systematically assessed by rolling a warm metallic roller (40°C) over the indicated sites and reference sites on adjacent skin. The subjects were asked to compare the sensation over the sites to be used for assessments with the sensation experienced over the reference sites. The sensibility was graded as '0' if anesthesia to warmth was total, '1' if there was decreased sensibility compared with adjacent reference skin areas and '2' if normal. To test touch perception thresholds, von Frey filaments (Aesthesiometer, Stoelting, IL) were used according to the modified method of limits (Weinstein 1962) with one descending and ascending assessment for each site. The pressure pain threshold for each site was assessed using the pressure algometer. All assessments were made by the same investigator (E.K.). The subjects were informed that the investigation aimed at determining the individual pain threshold, not pain tolerance. The algometer was demonstrated and the subjects were instructed to' push the button exactly at the moment when the pressure sensation became painful. Two pre-trial assessments were performed on sites not included in the study to familiarize the subjects with the pressure algometry procedure. PPTs were determined twice for each site in a balanced, sequential order. The subject was then instructed to maintain an isometric contraction of 25% MVC with the help of visual biofeedback from the isokinetic system computer screen until exhaustion, or for a maximum of 5 min (knee extension, 90° knee flexion). During the contraction PPTs were assessed in rotation over the 3 points, with 1 assessment every 30 sec during contraction, 1

Results The results from the control group have been presented in detail elsewhere (Kosek and Ekholm 1995). The absolute PPTs before cream application were on average 103.6 kPa in patients and 270.6 kPa in controls ( P < 0.001). The average MVC corresponded to 75.7 Nm in patients and 119.4 Nm in controls ( P < 0.001). All subjects were asked to maintain 25% of MVC with the assistance of visual biofeedback, which meant holding a force indicator in the middle of a bar indicating 20-30% MVC. The healthy subjects tended to lie toward the lower end of the bar and succeeded in holding a fairly constant contraction level. The fibromyalgia patients held an average contraction level of 22.3% before E M L A cream, 22.1% after E M L A cream and 21.6% before and after control cream, respectively. There was no significant difference from controls except for a higher % MVC before E M L A cream in patients ( P < 0.05). In FM patients the total range of the average contraction level was 17.2-29.2%. Their average duration of contraction was 3.90 min before E M L A cream, 3.97 min before control cream, 3.83 min after E M L A cream and 4.00 rain after control cream, total range 1.5-5 rain. There was no significant difference from healthy controls. Prior to any intervention 1 subject reported decreased sensibility to warmth on all 3 sites and 1 over 1 site intended to receive E M L A cream (average 1.91). One subject reported decreased sensibility to warmth

418 1.75

Normalized PPT

Open Fibromyalgia patients Solid Healthy controls 0 •

Before cream

A •

Control cream

1.50

1.25 -

1.00

0.75

.

.

Rest

.

.

Start <

.

.

Middle Contraction

.

.

End ~

.

.

0 mln q

2.5 mln

5 rain It

Postcontrection

Fig. 1. Mean normalized PPTs for fibromyalgia patients (n = 14) and healthy controls (n = 14) before, during and following an isometric contraction of m. quadriceps femoris. In controls, PPT rose at the start of contraction, continued to rise until the middle of the contraction period and then remained at this level until the end of contraction. PPTs then decreased but remained slightly higher than precontraction values during the 5-min period of post-contraction assessments. In patients there was no statistically significant change in PPT at the start of contraction, the PPTs decreased from the start to the middle of the contraction period and remained decreased until the end of contraction. After the end of contraction, PPTs remained lower than precontraction values during the 5-min period of postcontraction assessments. The normalized PPTs were significantly lower in patients than in controls during all contraction and postcontraction assessments. No statistically significant effect on PPTs was induced by EMLA or control cream during or following contraction.

over all 3 sites and 1 over 2 sites intended to receive control cream (average 1.89). After the application of E M L A cream and control cream the average scores for temperature sensibility were 1.04 and 1.89, respectively. Relative frequency of positive anesthetic effect (graded as 0 or 1) was 84.4 ___10.6% ( P < 0.05). The mean perception threshold to von Frey filaments was before and after E M L A cream 0.34 g and 1.03 g, respectively, a statistically significant increase ( P < 0.001). The values before and after control cream were 0.34 g and 0.33 g, respectively (NS). When reassessing precontraction PPTs after each cream application we found no difference compared to baseline values. There was no difference in PPT between the sites intended for E M L A cream (right leg in 7 subjects and left leg in 7) and for control cream, respectively. After cream application there was no significant difference in PPTs between sites treated with E M L A cream and control cream. The normalized PPT values during the first two contractions and after cream application are depicted in Fig. 1. In controls, PPT increased at the start of contraction ( 1 / 2 min; P < 0 . 0 0 1 ) , continued to increase until the middle of the contraction period ( P < 0.001), and then remained at this level until the end of contraction. In patients there was no statistically signif-

icant change in PPT at the start of contraction. The PPTs decreased from the start to the middle of the contraction period ( P < 0.05) and remained decreased until the end of contraction ( P < 0.05). In controls PPTs decreased after the end of contraction ( P < 0.001), but remained elevated compared to precontraction values ( P < 0.001) during the 5-min period of post-contraction assessments. In patients there was no change in PPTs after the end of contraction, and PPTs remained decreased compared to precontraction levels (immediately post-contraction NS; 2.5 min post-contraction P < 0.01; 5 min post-contraction P < 0.05). The normalized PPTs were significantly lower in patients than in controls during contraction (start P < 0.01; middle P < 0.001; end P < 0.001) and at all times during post-contraction assessments ( P < 0.001). There was no statistically significant difference in either group between the anesthetised side and the control cream side during or following contraction. To eliminate the possible influence of age, strength, and endurance, 5 patients with FM were matched with

1.75

Normalized PPT

O Fibromyalgia patients • Healthy controls

1.50

1.25

1.00

0.75

Rest

Start

Middle Contraction

End

0 mln

2.5 mln

5 mln

Posteontrsctlon

Fig. 2. Mean normalized PPTs and standard errors of mean (SEM) for fibromyalgia patients (n = 5) and sex-, age-, strength- and endurance-matched healthy controls (n = 5), before, during and following an isometric contraction of m. quadrieeps femoris. Since there was no impact of cream treatments during or following contraction in either group, the data from contractions before and following cream treatment have been pooled. In controls PPTs increased at the start of contraction (P < 0.001), continued to rise until the middle of contraction (P < 0.05) and then remained at this level until the end of contraction. After contraction PPTs decreased ( P < 0.01), but remained elevated compared to precontraction values immediately post-contraction (P < 0.001; 2,5 rain post-contraction P < 0.001; 5 min post-contraction P < 0.01). In fibromyalgia patients there was a trend toward PPT increase (NS) at the start of contraction. Then PPTs decreased until the middle of contraction ( P < 0.01) and remained at this level during the rest of the contraction period. After contraction, PPTs remained decreased (P < 0.05) at the 2,5; and 5 min post-contraction assessments compared to precontraction levels. The normalized PPTs were significantly lower in patients than in controls at the middle of contraction ( P < 0.01), at the end of contraction (P < 0.001), and at 2,5 and 5 min post-contraction (P < 0.05).

419

5 controls. The average age was 44 years in the patient group and 45 years in the control group. The MVC was 134.61 Nm in patients and 129.37 Nm in controls, a non-significant difference. The average contraction level was 21.0% in patients and 21.1% in controls and the average contraction time was 3.0 and 3.7 min, respectively, non-significant differences. In Fig. 2 a comparison of normalized PPTs between patients and controls is demonstrated. Since there was no effect of cream treatments during or following contraction in either group, the data from contractions before and after cream application have been pooled. In controls, PPTs increased at the start of contraction (P < 0.001), continued to increase until the middle of contraction (P < 0.05) and then remained at this level until the end. In FM patients there was a trend toward PPT increase (NS) at the start of contraction. PPTs then decreased until the middle of contraction (P < 0.01) and then remained at tlhis level during the rest of the contraction period. After contraction, PPTs decreased in controls (P < 0.01) but remained above precontraction values (immediately post-contraction P < 0.001; 2.5 min post-contraction P < 0.001; 5 min post-contraction P < 0.01). In patients, PPTs remained decreased during the post-contraction period compared to precontaction levels (immediately post-contraction NS; 2.5 min post-contraction P < 0.05; 5 rain post-contraction P < 0.05). The normalized PPT was significantly lower in patients than in controls in the middle of contraction (P < 0.01), at the end ot contraction (P < 0.001) and at 2.5 (P < 0.01) and 5 min (P < 0.05) post-contraction, respectively. Discussion

FM patients did not demonstrate an increase in PPTs during and following an isometric contraction of m. quadriceps, as seen in controls. In fact, PPTs decreased during contraction and remained lowered during the 5 min of post-contraction assessments. The percentage of MVC and the endurance time were comparable in patients and controls. The average absolute MVC in FM patients corresponded to 63.4% of that of the controls. FM patients have been reported to have lower muscular strength (Jacobsen et al. 1987, 1991; Jacobsen and Danneskiold-Samsoe 1989) and endurance (Jacobsen and Danneski¢ld-SamsCe 1992) in knee-extensors, as well as decreased strength in other muscles (B~ickman et al. 1988; Jacobsen et al. 1992; Nordenski61d and Grimby 1993). A superimposed electrical stimulation during MVC normalized the strength (B~ickman et al. 1988) and revealed a high degree of submaximal contraction in FM patients (Jacobsen et al. 1991). It could therefore be argued that our patients did not fully activate their muscles, thus explaining the failure of PPT modulation. How-

ever, even when 5 FM patients and 5 controls were age-, sex-, strength- and endurance-matched the same differences appeared. Furthermore, in a pilot study (Kosek et al., unpublished) PPTs increased in healthy individuals during contractions corresponding to 15% of MVC, indicating that PPTs would be expected to increase even if the contraction in patients corresponded to a lower 'true' MVC. Muscle afferent A6 and C fibers, activated by isometric contraction (Mense and Stahnke 1983), could be responsible for an afferent inhibition of pressure evoked activity in the nociceptive system. Interestingly, segmental inhibitory effects on nociceptive neurons following intrasegmental stimulation of A 6 and C fibers have been reported (Woolf 1983; Chung et al. 1984a,b). Several, but not all, of our patients/controls complained of pain in the contracting muscle during the later phase of contraction and following contraction. It could not be excluded, however, that even low-grade input in nociceptive afferents, below the pain perception level, could contribute to inhibitory influence on nociceptive transmission in the dorsal horn. In addition, inhibitory influence from activity in the motor systems onto the sensory system (Hagbarth and Kerr 1954; Lindblom and Ottosson 1957; Paalasmaa et al. 1991; Pertovaara et al. 1992), as well as stimulation of low-threshold afferents that normally inhibit transmission of high-threshold afferents according to the gate theory (Melzack and Wall 1965; Wall 1978), could be partly responsible for the PPT increase during contraction in controls. Dysfunction of one or several of the above-mentioned pain inhibitory mechanisms in fibromyalgia could, at least partially, explain the abnormal PPT response during contraction in FM patients. There is evidence that systems involved in cardiovascular regulation are linked to endogenous pain regulatory systems (Randich and Maixner 1984; Zamir and Maixner 1987; Bandler et al. 1991). Sustained isometric Contraction is a potent stimulus to induce an increase in heart rate, cardiac output and blood pressure (Lind et al. 1964; Donald et al. 1967; Kilbom and Brundin 1976). Further, isometric contractions activate the sympathetic nervous system with a continuous increase in plasma adrenalin and noradrenalin (V~llestad et al. 1992). Adrenal enkephalins are secreted with catecholamines (Viveros et al. 1979) and are believed to mediate some types of opioid stress-induced analgesia (Viveros et al. 1979; Lewis et al. 1982; Terman et al. 1984). Stress-induced analgesia (Wilier and Albe-Fessard 1980; Wilier et al. 1981; Pertovaara et al. 1987), as well as exercise-induced analgesia (Pertovaara et al. 1984; Kemppainen et al. 1985, 1986, 1990; Guieu et al. 1992) have been reported to be effective in man. It is, however, difficult to distinguish clearly between stressinduced and exercise-induced analgesia (Pertovaara et al. 1987; Padawer and Levine 1992). Based on this, we

420

suggest that in healthy individuals, the effects of isometric contraction on the cardiovascular regulatory system and the sympathetic nervous system could be involved in the pain modulation seen during and following contraction. Defective reactivity of the sympathetic nervous system in fibromyalgia patients in response to cold pressor test and auditive stimuli has been reported (VaerCy et al. 1989). Van Denderen et al. (1992) demonstrated a diminished response to exercise by the sympathetic nervous system as well as the hypothalamic-pituitary-adrenal axis. Reports of severe fibromyalgia after hypophysectomy (Disdier et al. 1991) further support a role of neuroendocrine dysfunction in FM. The response of the cardiovascular and sympathetic nervous systems to isometric contraction is believed to have several physiologically important implications. The increase in blood pressure is important to counteract the intramuscular compression of the vessels (Humphreys and Lind 1963; Lind et al. 1964; Lind 1983). A vasoconstrictive response in inactive muscles is crucial to further increase blood flow through the contracting muscle (Humphreys and Lind 1963; Lind et al. 1964; Clement and Pannier 1980; Lind 1983). The pressor response is, principally, a function of the relative tension generated (% MVC) and is independent of the activated muscle mass or the absolute force developement (Lind et al. 1964; Donald et al. 1967; Lind 1983). If contraction is maintained at a given % MVC, blood pressure, cardiac output and pulse rate increase steadily until the end of contraction (Humphreys and Lind 1963; Donald et al. 1967). The FM patients in our study obtained the same % MVC as controls, offsetting this as the major explanation for differences in response. If, however, the adaptation to isometric contraction were deficient, this could explain muscle ischemia in FM patients. The suggested lack of adaptive mechanisms would reduce the ability to perform even low-level contractions and low-intensity repetitive work with short pauses. Difficulties in performing these tasks are well known characteristics of FM patients. Furthermore, muscle ischemia could cause sensitization of mechanonociceptors (Mense 1990), so that the mechanical component of a contraction would become an effective stimulus for nociceptive afferents (Mense and Stahnke 1983). This would be expected to cause a decrease in PPTs during and following contraction, as seen in our FM patients. Thus, defects in the function of the physiologically linked cardiovascular/ sympathetic and pain regulatory systems could explain both the lack of pressure pain threshold modulation and the actual decrease of PPTs during and following contraction in FM patients. Further studies are needed to confirm or reject this hypothesis. Skin hypoesthesia was induced with local anesthetic cream, EMLA. The effect of EMLA cream on skin

analgesia is well documented (Evers et al. 1985; Arendt-Nielsen and Bjerring 1988; Arendt-Nielsen et al. 1990; Bjerring and Arendt-Nielsen 1990; Juhlin and Evers 1990). To avoid spread to subcutaneous tissues (Bjerring and Arendt-Nielsen 1990) the application period was limited to 60 min. Cutaneous sensibility testing indicated a decreased perception to warmth and light touch in both healthy controls and fibromyalgia patients. We refrained from testing analgesic effects in order to avoid tissue damage possibly influencing the subsequent PPT assessments. The lack of increase in PPTs after induced skin hypoesthesia in patients, as opposed to controls, indicates a relatively higher pressure pain sensibility in deeper tissues in patients. This accords with our earlier findings (Kosek et al. 1995). If FM patients have a dysfunction of pain modulation, muscle tenderness could be relatively more pronounced than skin tenderness due to the greater degree of tonic inhibition normally affecting deep nociceptive input (Mense 1990; Yu et al. 1990). In conclusion, fibromyalgia patients demonstrated a decrease in PPTs during and following isometric contraction of about 22% MVC of m. quadriceps. This is in contrast to healthy controls, who reported an increase in PPT using the same protocol. The decrease in PPT reported by the FM patients could result from sensitization of mechanonociceptors due to muscle ischemia a n d / o r be caused by an abnormal absence of pain modulation during muscle contraction. Such abnormalities could explain the increased pain reported by fibromyalgia patients during and following exertion.

Acknowledgements This study was supported by grants from the Karolinska Institute, Magnus Bergvall Foundation, and the Swedish Medical Research Council, Project no. 5720. We wish to thank Professor U. Lindblom for valuable discussion and advice concerning assessment of skin sensibility.

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