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Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or bromyalgia patients
Roland Staud a,*, Michael E. Robinson b, Charles J. Vierck Jr c, Donald D. Price c,d
b

Department of Medicine, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221, USA Department of Clinical Health and Psychology, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221, USA c Department of Neuroscience, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221, USA d College of Dentistry, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221, USA Received 8 January 2002; accepted 13 August 2002

Abstract Diffuse noxious inhibitory control (DNIC) is part of a central pain modulatory system that relies on spinal and supraspinal mechanisms. Previous studies have shown that bromyalgia (FMS) patients are lacking DNIC effects on experimental pain, compared to normal control (NC) subjects. Because DNIC has a greater effect on second pain than on rst pain, we hypothesized that wind-up (WU) of second pain should be attenuated by a strong conditioning stimulus. Thus, we compared DNICs effect on WU in three groups of subjects: 11 NC males, 22 NC females, and 11 FMS females. To separately assess the contributions of distraction related mechanisms to inhibition of second pain, we designed the experiment in such a way that directed the subjects attention to either the test or conditioning stimulus. Repeated heat taps to the thenar surface of the right hand were used as test stimuli to generate WU of second pain. Immersion of the left hand into a hot water bath was the conditioning stimulus. As previous experiments have shown, DNIC requires a strong conditioning stimulus for pain attenuation, which may be at least partly dependent on a distraction effect. DNIC signicantly inhibited thermal WU pain in normal male subjects, but adding distraction to the DNIC effect did not increase the extent of this inhibition. In contrast, neither DNIC nor DNIC plus distraction attenuated thermal WU pain in female NCs. DNIC plus distraction but not DNIC alone produced signicant inhibition of thermal WU pain in female FMS patients. Our results indicate that DNIC effects on experimental WU of second pain are gender specic, with women generally lacking this pain-inhibitory mechanism. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
Keywords: Diffuse noxious inhibitory controls; Wind-up; Fibromyalgia

1. Introduction A recent study of bromyalgia (FMS) patients showed enhanced temporal summation of second pain, or windup (WU), compared to age/sex matched normal control (NC) subjects (Staud et al., 2001). The enhanced WU of FMS patients is likely related to activated N-methyl-d-aspartate (NMDA) and/or substance P receptors, as well as intracellular mechanisms of sensitization in dorsal horn neurons (Price and Dubner, 1977; Kellstein et al., 1990; Dubner, 1991; Price et al., 1994; Li et al., 1999). Because WU may contribute to neural processes that lead to hyperalgesia and persistent pain, it can be used to investigate central pain

* Corresponding author. Tel.: 11-352-392-4681; fax: 11-352-392-8483. E-mail address: staudr@u.edu (R. Staud).

mechanisms of FMS patients (Dickenson, 1990; Woolf and Thompson, 1991; Li et al., 1999; Staud et al., 2001). An important question about enhanced WU in FMS is whether it can be modulated by central inhibitory mechanisms. There are reasons to expect that endogenous or exogenous mechanisms of pain inhibition would be decient in FMS. Two studies have shown that tonic conditioning nociceptive stimulation reduces brief forms of experimental pain in healthy controls but not in FMS patients (Lautenbacher and Rollman, 1997; Kosek and Hansson, 1997). These ndings suggested a deciency of a pain-inhibitory phenomenon termed diffuse noxious inhibitory control or DNIC in FMS. Similarly, exercise has been shown to decrease WU pain in normal subjects in contrast to FMS patients, suggesting reduced endogenous analgesic mechanisms (Vierck et al., 2001). Results of these studies support a general hypothesis that FMS reects a disorder

0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S0 304-3959(02)00 325-1

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affecting modulation of pain sensitivity (Hernandez et al., 1994; Lautenbacher and Rollman, 1997; Kosek and Hansson, 1997). It is unclear as to whether deciencies in pain modulation mechanisms, such as DNIC, reect a characteristic that predisposes the development of FMS or one that is a consequence of the syndrome itself. Since it appears that FMS is much more prevalent in women than men, one may argue that the lack of DNIC in FMS does not reect a characteristic of this syndrome but a sex difference in pain modulation. A lack of pain modulatory mechanisms may therefore be just one of many predisposing factors in the development of FMS. Although we recognize that a more optimal experimental design would have included a group of male FMS patients, the difculty of recruiting such patients precluded our doing so. The present study was undertaken to determine whether differences existed in DNIC across normal male subjects (NC-M), normal female subjects (NC-F), and female FMS patients. Our study was designed to determine (a) whether NC-F have less DNIC in comparison to NC-M and (b) whether female FMS patients have less DNIC compared to NC-F. Conrmation of (a) would support the hypothesis that a deciency in DNIC reects a predisposing feature of FMS whereas conrmation of (b) would suggest that a deciency in DNIC is the result of a factor other than sex, such as a consequence of having FMS. Our present study focused on effects of DNIC on temporal summation of second pain for several reasons. The rst is that our previous work has shown that FMS patients have enhanced temporal summation of second pain in comparison to age/sex matched control subjects, and we think that this abnormality is a key feature of abnormal central processing in FMS (Staud et al., 2001). The second is based on a previous study that found DNIC to be most effective in reducing Cber mediated second pain (Price and McHafe, 1988). DNIC effects seem to depend on both local and descending pain-inhibitory mechanisms that inhibit nociceptive responses of dorsal horn spinal neurons (Le Bars et al., 1992; Bouhassira et al., 1992b). Consistent with relatively selective effects of DNIC on second pain, DNIC inhibits the C-ber mediated responses of dorsal horn neurons more than it inhibits the A-delta mediated responses of these same neurons (Price and McHafe, 1988). Therefore, we chose second pain summation as our experimental model, because this phenomenon is considered relevant to the development of central sensitization and persistent pain conditions (Price and Dubner, 1977; Price et al., 1997).

2.1. Subjects Eleven female FMS patients, 22 healthy female control subjects, and 11 healthy male controls were recruited for the study from the Health Science Center Outpatient Clinics and from FMS support groups. Most normal volunteers were employees at the University of Florida Health Science Center. Each subject practiced making numerical pain ratings to noxious heat stimuli of the types described below (Vierck et al., 1997). All subjects were right handed, and all were Caucasian except for one Asian female. The average age of FMS-F patients, NC-F, and NC-M was 52.9 (^6.3 SD) years, 35.8 (^12.0 SD) years, and 40.2 (^16.8 SD) years, respectively. A univariate analysis of variance (ANOVA) with age as the dependent factor, and sex and diagnosis as independent factors indicated no signicant difference between NC-F and NC-M subjects (F1; 41 0:92; P 0:342). There was, however, a significant age difference between NC-F and FMS-F patients (F1; 41 14:2; P 0:001). This age difference, however, had no effect on the experimental conditions involving FMS-F patients, because applying age in a correlational analysis of DNIC conditions did not result in signicant interaction effects (see Section 3.3). 2.2. Inclusion and exclusion criteria Inclusion criteria for participants were: (1) adults over the age of 18; (2) the ability to give informed consent; (3) NC subjects had to be healthy and pain-free, and FMS patients had to fulll the 1990 American College of Rheumatology Criteria for FMS (Wolfe et al., 1990). Exclusion criteria were: (1) a medical condition besides FMS; (2) current participation in another research protocol that could interfere or inuence the outcome measures of the present study; (3) the inability to give informed consent; (4) current use of analgesic drugs, anti-depressants, except amitriptyline (,50 mg/day), or cough suppressants. All subjects taking analgesic drugs or antidepressants before enrollment went through the appropriate wash-out period prior to study entry. Only one female FMS patient took amitriptyline 10 mg/day during the study. 2.3. Informed consent All prospective subjects had a pre-session screening with one of the physician-investigators (R.S.) who performed a comprehensive history and brief physical examination. If the subject met the study criteria, the physician explained the nature of the study, invited the subject to participate, and provided a copy of the informed consent form. 2.4. Experimental heat pain stimuli

2. Methods Subject recruitment procedures and the study protocol were approved by the University of Florida Institutional Review Board and met the guidelines of the 1975 Declaration of Helsinki.

WU was tested at the glabrous surface of the right hand with a thermode of 2.5 cm 2 surface area, pre-heated to 538C, which was brought in and out of skin contact by timed

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solenoid activation to produce trains of eight stimuli of 0.7 s duration each with inter-stimulus-intervals (ISI) of 2.0 s (onset to onset). A heat tap of 700 ms produces predominantly delayed second pain for stimulation of glabrous skin at the intensity used (Vierck et al., 1997; Staud et al., 2001). When rating the magnitude of second pain, subjects were instructed to attend to the peak of late sensation that is present approximately 1.01.5 s after the probe contacts the skin on each presentation. In the case of the hand, this latency is consistent with C-ber impulse conduction velocities of 0.71.0 m/s. The subjects were prompted to rate the rst and eighth stimulus in a train, using the numerical ratings scale (see below). The subjects were not asked to rate the sensation magnitude of all consecutive eight stimuli because of considerable task demands. These included focusing attention on the conditioning or test stimuli as well as switching attention at the end of a trial. Because previous results of thermal WU testing in FMS patients indicated hyperalgesia and central sensitization (Staud et al., 2001) the probe temperature for FMS patients was decreased to 528C to achieve non-painful sensations for the rst stimulus, as seen in NC subjects. The probe temperature was calibrated immediately prior to each testing session, using an Omega #450 ATH attachable surface temperature thermistor (probe #ON-409-PP). Use of the same thermistor throughout the experiment insured consistency between sessions and accurate stimuli from our apparatus. All subjects were blinded with regard to the temperatures used and to the hypotheses of the study. 2.5. Diffuse noxious inhibitory control stimuli All subjects underwent three trials on 1 day and in the same order (Table 1). Conditioning stimuli were applied to the left hand, and test stimuli were applied to the right hand. During testing, the subjects were prompted to immerse their left hand up to the wrist into a water bath of 478C (NC) or 468C (FMS) when the train of test stimuli to the right hand was initiated. The water was constantly recirculated to avoid laminar cooling around the hand. The water temperature chosen for FMS patients was lower because of the presence of heat hyperalgesia (Gibson et al., 1994). This temperature adjustment resulted in similar mean pain ratings of the FMS conditioning stimulus compared to NC (numerical pain

rating scale: 57.3 ^ 19.9 SD and 45.0 ^ 21.2 SD, respectively). Comparison of these pain ratings by independent ttest showed no statistical difference between groups (t 21:6, P 0:120). This approach was chosen to assure similar responses of central neurons that trigger DNIC. The duration of the conditioning stimulus was always 16 s, the time required for one train of WU stimuli. During testing, all subjects were prompted repeatedly to focus their attention either on the conditioning stimulus or the test stimulus.

2.6. DNIC stimulus sequence During the duration of each train of WU stimuli, the subjects rated the sensations of either the right (repetitive heat stimuli) or left hand (conditioning stimulus) as shown in Table 1. After the last stimulus of each series the subjects were prompted to immediately rate the sensation felt at the opposite extremity.

2.7. Pain rating method A standardized numerical scale was utilized for rating the magnitude of sensations produced by thermal stimulations. A printed copy of the ratings was constantly observable, and the subjects quickly became acquainted with the ratings. The scale was composed of integers in increments of 5, from 0 to 100, with the following verbal descriptors associated with increments of 10: 0 no sensation, 10 warm, 20 threshold heat pain, 30 very weak pain, 40 weak pain, 50 moderate pain, 60 slightly strong pain, 70 strong pain, 80 very strong pain, 90 nearly intolerable pain, and 100 intolerable pain. Previous experience with the scale has shown that increments of 5 provide appropriate resolution for the discriminable steps in late sensation intensity from threshold to nearly intolerable levels. The subjects were instructed to remove their hand from the water bath or test apparatus at any time when sensory intensity reached a nearly intolerable level, so that intolerable sensory levels would never be produced. The numerical scale was used instead of a visual analogue scale (VAS) because subjects were required to make rapid ratings, especially when asked to shift attention from one hand to another.

Table 1 Order of test stimuli and pain ratings obtained in all subjects during the application of test and conditioning stimuli a No. Trial WU stimuli (right hand) Conditioning stimuli (left hand) During the test the subjects rate the sensations at Immediately after the last test stimulus the subjects rate the sensation at

Experimental conditions 1 Baseline 2 DNIC 3 DNIC plus distraction

a

Yes Applied simultaneously Applied simultaneously

No Applied simultaneously Applied simultaneously

Right hand Right hand Left hand

Left hand (no stimuli applied) Left hand Right hand

Each subject underwent three trials, focusing attention and rating pain sensations initially on the site of the test stimulus or conditioning stimulus. After the last stimulus of each series the subjects were prompted to immediately focus their attention and rate pain sensations on the opposite site.

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2.8. Experimental design We used repetitive thermal stimuli that result in temporal summation of second pain (WU) as test stimuli because previous experiments have shown a stronger DNIC effect on second than on rst pain (Price and McHafe, 1988). Because DNIC effects require a strong noxious conditioning stimulus (Le Bars et al., 1992), we considered the possibility that distraction contributed to effects in previously reported DNIC studies (Stewart et al., 1988; Talbot et al., 1987, 1989; Willer et al., 1989; Lautenbacher and Rollman, 1997; France and Suchowiecki, 1999). Therefore we measured distraction effects on WU ratings by (1) providing conditioning and test stimuli of similar intensity and identical quality, and (2) purposefully exploiting the conditioning or test stimulus as a distraction tool. We specically tested the effects of distraction on the ratings of test stimuli in our study by instructing subjects to attend to either the conditioning stimulus or the test stimulus and to rate either the test or conditioning stimulus. Repetitive voice prompts were used to keep the subjects focused on rating the sensations of only the designated extremity during each train of stimuli. The effects of distraction were measured by prompting the subjects immediately after the last stimulus to rate the sensation experienced at the non-attended test site. For example, if on a given trial a subject was instructed to attend to the conditioning water bath stimulus, the subject would attend to and rate the pain from the water bath (left hand) during the trial and then rate the last heat tap (right hand) immediately after termination of the trial. The reverse would be true if the subject attended to the heat taps. 2.9. Statistical analysis A mixed model ANOVA with group (FMS vs. controls) as the between-subject factor and condition (baseline, DNIC, DNIC plus distraction) as the within-subject factor was used in two different sets of analysis, applying either the last tap (eighth tap) or the WU difference score (DS) as the dependent variable. Effects of the conditioning stimulus on WU were tested as interactions between group and experimental condition. 3. Results Separate ANOVAs were conducted for comparisons of NC-F and NC-M, and NC-F and FMS-F patients. 3.1. WU measurements Results of baseline WU testing are depicted in Fig. 1. The ratings of the rst and eighth (last) tap are shown for all subjects. A mixed model ANOVA indicated a signicant increase of mean pain ratings between taps in all subjects regardless of sex or diagnosis (F1; 41 118:7;

Fig. 1. Pain ratings (^ SD) of the rst (T1) and last (T8) heat tap in NC-F, NC-M, and FMS-F subjects. Statistical analysis showed temporal summation of heat pain in all groups. The dashed line indicates pain threshold.

P 0:000). WU was found to be greater in FMS-F patients than in NCs (F1; 41 6:68; P 0:013). In addition, NCM and NC-F subjects did not differ in their rate of WU (F1:41 0:64; P 0:427). 3.2. Femalemale NC comparisons Because many previous DNIC studies have been done in males, we compared WU of female and male NCs across the baseline, DNIC, and DNIC plus distraction conditions. Because WU is strongly related to the number of stimuli (Dickenson and Sullivan, 1987), the last rating of eight heat taps was analyzed for group comparisons. To control for rst tap differences between groups the maximal DS (eighth tap minus baseline rst tap rating) was computed. Whereas the eighth tap results provide a measure of maximal WU, the DSs best illustrate the magnitude of temporal summation by taking the ratings of the rst tap into account. 3.2.1. Analysis of maximal WU in NC With maximal WU (T8) as the dependent variable the ANOVA showed a signicant main effect for condition (F2; 62 4:32; P 0:017) as well as a signicant condition by sex interaction (F2; 31 3:33; P 0:042). The interaction effect was decomposed with simple contrasts which indicated that for NC-M both the DNIC condition (F1; 31 6:46; P 0:022) and the DNIC plus distraction condition (F1; 31 4:48; P 0:042) resulted in lower mean pain ratings when compared to baseline ratings. In contrast, results of within NC-F comparisons showed no signicant effects across all DNIC conditions (F1:31 0:50; P 0:487). Thus, DNIC reduced WU only in NC-M. Furthermore, NC-M showed greater attenuation of WU with DNIC plus distraction, although the difference between DNIC and DNIC plus distraction effects was not statistically signicant (F1; 31 3:37; P 0:076) (Fig. 2a). This result may, however, be related to the low number of NC-M in our study h2 0:098. 3.2.2. Analysis of DSs in NC When DSs of WU were obtained which take the rst and eighth tap into account, similar results were seen as in Section 3.2.1. The analysis showed a signicant main effect

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Fig. 2. (a) WU ratings after the eighth tap (^SD) of NC-F and NC-M subjects at baseline, during DNIC, and DNIC plus distraction (DNIC 1 DIST) conditions. The dashed line indicates pain threshold. (b) DS (maximal WU minus baseline rst tap ratings) of NC-F and NC-M during the same test conditions. Whereas pain ratings of NC-F remained unchanged during all conditions, NC-M subjects showed a signicant reduction of WU (T8: P 0:042; DS: P 0:042) during the conditioning stimulus. Ratings of DNIC 1 DIST were also statistically different from baseline, but not different from DNIC alone for NC-M subjects (T8: P 0:042; DS: P 0:022).

for condition (F2; 62 6:55; P 0:003) as well as a signicant condition by sex interaction (F2; 31 3:33; P 0:042). The interaction effect was decomposed with simple contrasts which again indicated that for the NC-M group both the DNIC condition (F1; 31 8:32; P 0:007) and the DNIC plus distraction condition (F1; 31 5:84; P 0:022) resulted in lower mean pain ratings when compared to baseline ratings. In contrast, results of within NC-F comparisons showed no signicant effect across all DNIC conditions (F1; 31 0:41; P 0:527). Thus DNIC reduced the DS only in NC-M, similar to maximal WU (eighth tap) analysis, and there was no difference between DNIC and DNIC plus distraction effects (F1; 31 4:26; P 0:065; Fig. 2b). 3.3. NC-FFMS comparisons Because all FMS patients were female, we compared their results only with NC-F. We used the same analysis as described in Section 3.1, but instead of NC-M we compared FMS-F with NC-F. Given the signicant age difference between both groups (see Section 2.1) we analyzed the effect of age on the ratings of the rst and eighth tap for all DNIC conditions using Pearson correlations. None of the correlations, however, approached statistical signicance, indicating that age was not a confounding variable in the analysis (r 0:027 to 20.107; all correlations: P . 0:05). 3.3.1. Analysis of maximal WU in NC-F and FMS-F For analysis of DNIC effects, the ratings of the last sensa-

tion in a train of WU stimuli were compared within and between groups (Fig. 3a). The results of the ANOVA showed a signicant effect for condition (F1; 31 6:14; P 0:004) as well as a condition by diagnosis interaction (F1; 31 3:31; P 0:043). Using simple contrasts, however, only the DNIC plus distraction condition of FMS-F patients was signicantly different from baseline ratings (F1; 31 4:4; P 0:043). 3.3.2. Analysis of DSs in NC-F and FMS-F The effects of DNIC on the DSs were compared in all female subjects (Fig. 3b). The ANOVA showed a signicant effect for condition (F1; 31 6:14; P 0:004) as well as a condition by diagnosis interaction (F1; 31 3:31; P 0:004). Simple contrasts, however, indicated again that only the DNIC plus distraction condition of FMS-F subjects differed signicantly from baseline ratings (F1; 31 4:5; P 0:042). 4. Discussion Heterotopic conditioning heat stimuli inhibited WU of second pain only in NC-M but not in NC-F or female FMS patients. We interpret our ndings as the result of signicant differences in pain modulation between men and women. These results suggest that deciencies in DNIC found in FMS patients of previous studies may be largely a result of the fact that most FMS patients are women and not because they have FMS. Thus, our results do not support the idea that a general deciency of central

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Fig. 3. (a) WU ratings after the eighth tap (^SD) of NC-F and FMS-F patients at baseline, during DNIC, and DNIC 1 DIST conditions. The dashed line indicates pain threshold. (b) DS (maximal WU minus baseline rst tap ratings) of NC-F and FMS-F during the same test conditions. Neither DNIC nor DNIC 1 DIST had an effect on WU in NC-F subjects. Although DNIC also had no effect on test stimuli in FMS-F patients, DNIC 1 DIST signicantly reduced mean ratings of WU sensations in FMS-F patients (T8: P 0:043; DS: P 0:042).

inhibitory mechanisms is a result of FMS per se. However, they suggest the possibility that less effective central inhibitory mechanisms in women as compared to men may be a predisposing factor in the development of FMS. 4.1. Sex differences in DNIC The inhibitory effects of DNIC in male subjects are consistent with a previous study that only used male subjects and found that DNIC more effectively inhibited second pain than rst pain (Price and McHafe, 1988). This study has been the only one to examine effects of DNIC on second pain and is the one most comparable to the present study. It is important to note, however, that several human psychophysical studies of DNIC have used predominantly male subjects (Talbot et al., 1989; Andersen et al., 1995; Terkelsen et al., 2001). Therefore, there may be an important sex difference with regard to the inhibitory effectiveness of DNIC. Similar DNIC effects among both men and women has been reported in one study (France and Suchowiecki, 1999) that used the RIII nociceptive exion reex as an outcome measure. However, this study is difcult to compare with ours because the authors used electric shock as the test stimulus, thus relying almost exclusively on A-delta ber input. Therefore, the sex differences observed in the present study may be specic to C-ber evoked pain and WU, a form of pain that may be more clinically relevant. 4.2. Distraction and DNIC FMS-F but not NC-F subjects showed a distraction effect by the conditioning stimulus, a result that is somewhat

puzzling. The lack of a distraction effect in NC-F is not likely the result of a small sample size, since there were 22 NC-F, and the effect was present in 11 FMS-F patients. The attenuation of WU by distraction in FMS-F patients may be the result of psychological characteristics of this group not present in NC-F. The inability to detect a difference between DNIC and DNIC plus distraction in NC-M may have been the result of the small number of male subjects, since this difference approached statistical signicance h2 0:097. It is important to consider that distraction may not be a completely separate mechanism from DNIC but could be one of its integral components, particularly when the distraction is the result of attending to same sensory modality as the test stimulus (i.e. heat-induced pain). The present study was designed to control for distraction by having subjects attend to the conditioning or test stimulus in a balanced manner. Other studies, attempting to control for distraction, have had subjects attend to a non-painful distracting stimulus (Talbot et al., 1989; Duker et al., 1999; Freeman et al., 2000). Overall, the effects of DNIC plus distraction showed a clear trend toward having greater effects than DNIC alone. Furthermore, the results of the present study are consistent with a previous study (Keogh et al., 2000) which showed that distraction was an effective pain coping strategy for men but not women. If DNIC is multidimensional and includes a distraction component, it could explain the lack of DNIC or DNIC plus distraction effects for NC women. It does not fully explain the reduction of pain by DNIC plus distraction in FMS women. The possibility that pain inhibition related to DNIC and

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distraction have separable yet overlapping mechanisms is supported by several considerations. DNIC represents a segmental spinal cord as well as supraspinal modulatory mechanism of nociception (Dickenson and Le Bars, 1987; Bouhassira et al., 1992a). Primates and humans show DNIC effects which, under conditions of brief stimulation, do not long outlast the duration of the conditioning stimulus (Le Bars et al., 1986; Roby-Brami et al., 1987; Price and McHafe, 1988; Peters et al., 1992). DNIC effects on electrical, thermal, or vibratory test stimuli have been described in NC (Kemppainen, 1983; Price et al., 1984; Terkelsen et al., 2001). In normal subjects, heterotopic painful stimuli induce simultaneous and parallel decreases in the sensation of pain and in the spinal nociceptive exion (RIII) reex evoked by electrical stimulation of the sural nerve. This inhibition of the RIII reex, however, is not seen in tetraplegic patients with clinically complete spinal cord transection (Le Bars et al., 1986). In addition, several lines of evidence suggest participation of the caudal medulla, including the subnucleus reticularis dorsalis, in the supraspinally mediated DNIC (Bouhassira et al., 1992b). Given these multiple spinal and supraspinal components of DNIC, it is entirely possible that DNIC is composed of multiple functional mechanisms, including those related to distraction. 4.3. DNIC effects on second pain and their possible relation to FMS Clearly, DNIC has little impact on rst pain as observed in other studies (Willer et al., 1984; Talbot et al., 1987, 1989) and is therefore not likely to be relevant for some forms of nociceptive stimulation. It is evident that DNIC modulates second pain to a greater extent than it modulates rst pain. This fact may help explain some of the reported sex differences in the prevalence of FMS between men and women (Wolfe et al., 1995). Second pain and WU of second pain reect a central mechanism that is likely to have a role in FMS. As shown by the combination of the present and a previous study (Price and McHafe, 1988), DNIC is less effective on second pain in women than men. Thus, reduced effectiveness of DNIC may be a predisposing factor in the development of FMS and may at least partly account for the higher prevalence of FMS among women. 4.4. The functional role of DNIC Although it is unlikely that the main physiologic effect of DNIC is related to long-term reduction in pain, it may play a role in the modulation of second pain. Alternatively, DNIC may be important for withdrawal reexes that remove a limb away from a noxious stimulus (Sherrington, 1948; Willer et al., 1984). The presence or absence of DNIC may be a factor, however, in the extent or probability that central sensitization occurs. As such, it may be a factor that has a role in the transition from acute pain to chronic pain.

5. Conclusions Our experiments show that DNIC can attenuate WU of second pain. Its effects, however, were limited to only NCM. In contrast, female subjects did not demonstrate reduced WU during DNIC. Female FMS patients, however, could attenuate WU through DNIC plus distraction. Therefore, the modulation of second pain and WU by DNIC may be sexspecic. Future studies need to address the question whether the lesser effects of DNIC on females represent a predisposing factor for the development of FMS. Although statistical analyses did not demonstrate a reliable relationship between age and DNIC measures in our study, the age differences between groups remains a potential confound.

Acknowledgements This work was supported by NIH grants NS-07261 and NS-38767 and BSCIRTF funds from the State of Florida and the Arthritis Foundation. The expert technical support of Mackensie W. Soto, Lene Sorensen, and Brian J. Dlouhy is gratefully acknowledged.

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