Tactile and pain thresholds in the intra- and extra-oral regions of symptom-free subjects

Pain 115 (2005) 308–315 www.elsevier.com/locate/pain

Tactile and pain thresholds in the intra- and extra-oral regions of symptom-free subjects Osamu Komiyamaa,b, Antoon De Laata,* a

Department of Oral and Maxillofacial Surgery, School of Dentistry, Oral Pathology and Maxillo-Facial Surgery, Catholic University of Leuven, Kapucijnenvoer 7, B-3000 Leuven, Belgium b Department of Clinical Oral Physiology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakaecho-nishi Matsudo, Chiba 271-8587, Japan Received 22 September 2004; received in revised form 17 February 2005; accepted 3 March 2005

Abstract The aim of the present study was to evaluate the tactile detection threshold (TDT), the filament-prick pain detection threshold (FPT), the pressure pain threshold (PPT), and the pressure pain tolerance detection threshold (PTOL) at multiple measuring points in the orofacial region of normal subjects. Sixteen males and 16 females (age range from 20 to 41 years) participated. The TDT and the FPT were measured on the cheek skin overlying the central part of the masseter muscles (MM), on the maxillary gingiva, and at the tip of the tongue, using Semmes–Weinstein monofilaments. The PPT and PTOL were measured at the central part of the MM, using a pressure algometer. The pain intensity during the FPT, PPT and the PTOL measurements was assessed on a numeric rating scale (NRS). The tongue tip had the lowest value in TDT and FPT compared to the other sites. Females showed a significantly lower TDT and FPT at the cheek skin than males. Further, measurements of PPT and PTOL confirmed the previously reported higher thresholds in males. In contrast, while the intra-oral threshold measurements revealed no gender differences, a significantly higher pain perception as evaluated using NRS, was seen in the males. A strong correlation was found between the pain responses at the same measuring site (FPT, PPT, and PTOL over the MM). In addition, the TDT and the pain responses were also correlated positively. q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Tactile detection threshold; Filament-prick pain detection threshold; Pressure pain threshold; Pressure pain tolerance detection threshold; Gender; Trigeminal sensory testing

1. Introduction Studies on the processing of sensory stimuli may help to better understand the pathophysiology of pain and contribute to its diagnosis. The processing of noxious and non-noxious stimuli differs among clinical pain conditions, possibly reflecting a different etiology of the sensory signs and symptoms. In nociceptive pain for instance, Hollins et al. (1996) reported that the vibrotactile threshold is significantly elevated on the cheek skin in the temporomandibular disorder patients, while Voerman et al. (2000) found that chronic cervicobrachialgia patients showed a systematic elevation of the * Corresponding author. Tel.: C32 16 33 24 54; fax: C32 16 33 24 37. E-mail address: [email protected] (A. De Laat).

light touch detection threshold on the skin of the painprovoking segment. Chong et al. (2002) reported that of five neuropathic pain patients with sensory deficits who tolerated gabapentin therapy, three showed marked improvement of their sensory deficits along with the pain alleviation. Further, Kosek et al. (1996) reported that fibromyalgia patients had a higher pressure pain sensitivity compared to normal subjects, and also had increased sensitivity to light touch in the site of maximal pain compared to the homologous contralateral side. Leffler et al. (2000) found an elevation of the pressure pain threshold and light touch sensation in subacute/chronic lateral epicondylalgia patients. These authors also reported that patients suffering from rheumatoid arthritis of longer duration, exhibited both increased sensitivity to pressure pain and additional sensory

0304-3959/$20.00 q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2005.03.006

O. Komiyama, A. De Laat / Pain 115 (2005) 308–315

abnormality in the skin overlying a painful and inflamed joint (Leffler et al., 2002). Similar to many cases of clinical pain, experimental cutaneous heat-induced pain (Apkarian et al., 1994) and cold-induced pain (Bolanowski et al., 2000) seem to significantly reduce the low-threshold mechanosensitivity at the pain site. Stohler et al. (2001) found that the experimentally induced pain in the masseter muscle reduced the cutaneous mechanosensitivity at the site of the pain. In contrast to these findings, Svensson et al. (1998) measured the mechanical sensitivity in the pain area occurring after injection of hypertonic saline in the masseter muscle. The psychophysical ratings of punctuate Semmes–Weinstein monofilament stimulation were significantly increased 12 min after the start of hypertonic saline infusion as compared to baseline and post-baseline ratings at the site of infusion. In the oral and facial region, the tactile detection threshold (TDT), and the filament-prick pain threshold (FPT), have been evaluated with Semmes–Weinstein monofilaments, and the pressure pain threshold (PPT) and the pressure pain tolerance detection threshold (PTOL), have been studied using a pressure algometer (Drobek et al., 2002; Graven-Nielsen et al., 1997; Isselee et al., 1997; Ohrbach and Gale, 1989). No known attempt, however, has been made to compare TDT, FPT, PPT and PTOL measurements at multiple measuring points in the orofacial region. Consequently, the aim of the present study was to test the following questions. (1) Is there a relation between light touch thresholds (TDT), pain thresholds (FPT and PPT), and pain tolerance thresholds (PTOL)? (2) Are these measures different between males and females, and do they vary according to the site of stimulation?

Table 1 Descriptive data [meanGstandard deviation (SD)] of the subjects’ characteristics and measurements Gender Number Age Height Weight

Male 16 25.4G4.6 180.9G8.5 75.6G12.6

Measurement

Site

Tactile detection threshold

Cheek skin (L) Cheek skin (R) Maxillary gingiva (L) Maxillary gingiva (R) Tongue tip Thenar skin

Filament-prick pain detection threshold (FPT)

Numeric rating scale value (NRS) for FPT

Pressure pain threshold (PPT)

Cheek skin (L) Cheek skin (R) Maxillary gingiva (L) Maxillary gingiva (R) Tongue tip Thenar skin Cheek skin (L) Cheek skin (R) Maxillary gingiva (L) Maxillary gingiva (R) Tongue tip Thenar skin Masseter muscle (L) Masseter muscle (R) Thenar muscle

NRS for PPT

2. Material and methods 2.1. Subjects Subjects were recruited from university students and staff. All were Caucasian, and asymptomatic for pain in the head and neck region. This was defined as absence of jaw dysfunction and headaches, and absence of subjective pain or soreness of the masticatory muscles. Subjects could also not participate when they were currently taking medication or received other treatment that could not be interrupted for the study, if general health problems (e.g. metabolic disease, neurological disorders, vascular disease, etc.) or periodontal disease was present, or in case of a history of drug abuse, recent facial or cervical trauma. Since a previous study (Isselee et al., 2002) indicated that pain thresholds were lower in the menstrual phase, females were not tested during their menstrual phase, and smokers were excluded. Sixteen males and 16 females (age range from 20 to 41 years) (Table 1) participated. The subjects were informed about the study in a standardized way and signed an informed consent form. The institutional ethics committee approved the study.

309

Female 16 25.3G5.5 168.1G6.7 59.9G8.2

2.56G0.24 2.59G0.23 3.59G0.30

2.21G0.24 2.16G0.23 3.59G0.32

3.62G0.30

3.55G0.29

1.95G0.15 2.75G0.22

1.94G0.17 2.65G0.25

5.90G0.33 5.90G0.35 5.49G0.17

5.19G0.60 5.30G0.51 5.29G0.35

5.49G0.23

5.29G0.35

5.10G0.19 5.91G0.31

4.96G0.31 5.40G0.52

1.8G0.9 1.9G0.9 2.7G0.9

1.6G0.9 1.7G0.9 1.9G0.9

2.7G0.9

1.9G0.9

2.8G0.9 2.1G1.2

1.9G0.9 1.7G1.2

212.3G54.9

147.7G36.3

204.1G43.7

146.2G33.5

396.1G115.8

261.9G84.2

3.4G1.1

2.8G0.9

Pressure pain tolerance threshold (PTOL)

Masseter muscle (L) Masseter muscle (R)

424.4G84.6

318.8G75.6

412.5G80.2

308.8G75.7

NRS for PTOL

Masseter muscle (L) Masseter muscle (R)

7.0G1.2

6.0G1.4

7.0G1.2

5.9G1.3

SD for measurement data were pooled values over the three sessions. L, left; R, right.

2.2. Tactile detection threshold and filament-prick pain detection threshold The tactile detection threshold (TDT) and the filament-prick pain threshold (FPT) were measured (1) on the cheek skin (CS) overlying the central part of the left and right masseter muscles midway between the upper and lower borders and 1 cm posterior to the anterior border, (2) on the right and left maxillary gingival (MG) at a point 5 mm cranial to the line connecting the cervical rim of the canine and the lateral incisor, (3) at a point 5 mm proximal to the anterior tip of the tongue (TT) on the midline, and

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(4) on the skin overlying the palm side of the thenar muscle on the point connecting the longitudinal axis of the thumb and index finger (Thenar Skin: TS). The sequence of the measurement sites was randomized. Semmes–Weinstein monofilaments with 20 different diameters were used (Premier Products, USA). The number of the filaments (1.65–6.65) corresponds to a logarithmic function of the equivalent forces of 0.0045–447 g. At first, TDT was examined. The subjects were instructed to close their eyes during the whole test procedure and to raise their hand as soon as they felt the stimulus in the test site. The filament was applied vertically on the test site and slowly pressure was applied until the filament bowed. The time needed to bow the filament was standardized to approximately 1.5 s. The stimulus was maintained for approximately 1.5 s and then removed in 1.5 s. Quick applications and bouncing of the filaments against the skin were avoided. At each site, the test started with the number (No.) 4.74 filament. If the subject raised his/her hand, it was considered a positive response, and the next filament applied was one step lower (No. 4.56). This procedure was repeated with decreased filament diameters until the subject no longer felt the pressure. This was considered as a negative answer. Again, the filament with a higher pressure was applied. This procedure continued until eight positive and eight negative peaks were recorded and the threshold (TDT) was calculated as the average of these values (number of the filament). If the subject still had a positive response while applying the lowest fiber (No. 1.65), this filament was considered the threshold. Two ‘blank’ (placebo) trials were performed after peaks 5 and 11. During these control trials, the filament did not make contact with the tissue. If the subject did not report a sensation during the blank stimuli, the test was continued. If he did, the test was discontinued and the subject was questioned about what kind of stimulus was perceived. The whole procedure was explained again to the subject and afterwards the test was restarted (Jacobs et al., 2002). After the TDT measurements, the FPT was examined. The stimuli were applied in the same way as for the TDT, but the subjects were instructed to open their eyes and to raise their hand as soon as they felt not only pressure but also pain in the test area. If the subject had no positive response for the thickest fiber (No. 6.65), this number was recorded as the threshold. No placebo stimulus was applied. There was a time lag of 3 min between the measurements on a similar site in order to avoid sensitization. Furthermore, after the examination, the pain intensity experienced at the FPT was assessed on a numeric rating scale (NRS) where 0 cm indicated ‘no pain’ and 10 cm indicated ‘worst pain imaginable’. Recently, it has been argued that the interpretation of NRS-anchors could differ inter-individually (Manning et al., 2001; Robinson et al., 2004). In order to limit the number of hypothesis in the present study, it was assumed that the right anchor of NRS worst pain imaginable was interpreted in a similar manner by males and females. 2.3. Pressure pain threshold and pressure pain tolerance detection threshold A pressure algometer (Somedic, Sweden) was used to test the sensitivity to stimuli applied to the masseter muscles. The pressure pain threshold (PPT) was defined as the amount of pressure (kPa), which the subjects first perceived to be painful (Svensson et al., 1995). The PPT was determined with a constant application rate of

30 kPa/s and a probe diameter of 1 cm. The subject pushed a button to stop the pressure stimulation when the threshold was reached. These measurements were done at least 5 min after the FPT measurements. Measuring points were (1) the central part of the right and left masseter muscles (MM) midway between the upper and lower borders and 1 cm posterior to the anterior border and (2) the palm side of the thenar muscle on the point connecting the longitudinal axis of the thumb and index finger (Thenar muscle: TM). These test points were identical to the ones used for measuring TDT and FPT. At the start of each session, the subjects were familiarized with the measurement procedure and the equipment via a demonstration on the right forearm, and they were instructed to keep their teeth slightly apart to avoid contraction of the jaw-closing muscles during the stimulation. The measurements of the PPT were done three times for each point and randomized by a generator. There was a time lag of 2 min between the series of measurements. The mean value of the three measurements was used for further statistical analysis. The pressure pain tolerance detection threshold (PTOL) was defined as the pressure producing the maximum amount of pain the subjects were willing/able to accept. The PTOL was measured in the same way as the PPT. However, the test was applied just once at the end of the whole experimental session and only on the masseter muscles. There was a time lag of 5 min between the right and left measurements in order to avoid sensitization, and the sequence of the measurement sides was randomized. After each examination, the average pain intensity during the PPT measurement and the PTOL measurement was assessed on a NRS where 0 cm indicated no pain and 10 cm indicated the worst pain imaginable. 2.4. Measurement sessions For each subject, a series of measurement sessions was scheduled in order to evaluate the reproducibility. Sessions 1 and 2 were separated by 1 week, and a third session was done 3 weeks after the second session. The test sites on (the skin overlying) the masseter muscle were chosen by manual palpation, and marked with a washable ball-point. In order to assure the reproducibility of the test locations during subsequent sessions, the marked spots were then transferred to a translucent, pliable plastic template with five reference points (nose, both ears, bilateral eyebrows) to be used in subsequent sessions (Isselee et al., 1997). 2.5. Statistical analysis Descriptive statistics were used to summarize all measurements. The mean values and standard deviation of TDT, FPT, PPT, PTOL and NRS pooled over three sessions in each gender and each test area were calculated. The design of the experiment corresponds to a repeated measurements framework. Since the response variables are assumed to be continuous, a linear mixed-effects model was used in each case to capture the main effects of gender, sites, and sessions. Moreover, age, body-mass index (weight (kg)/height2 (m): BMI) and NRS values were considered for an adequate fit of the covariance matrix. Holm’s method was used to adjust P-values for multiple comparisons. In the next step, a correlation analysis between the TDT, FPT, PPT and PTOL at the left and right same measuring point (TDT and FPT at the CS, PPT and PTOL at the MM) was performed.

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The significance level for each test was set to aZ5%. All analyses were performed within the R environment (release 2.0.1) for Windows. The linear mixed-effects models were fitted with the functions lme and gls from the nlme package.

3. Results 3.1. Tactile detection threshold Depending on the test area, the TDT ranged from 1.95G 0.15 to 3.62G0.30 for males and from 1.94G0.17 to 3.59G 0.32 for females. There was no significant age (PZ0.566) and BMI effect (PZ0.395). There was also no session effect (PZ0.545). The only significant factors were gender (P!0.001) and site (P!0.001). After correction for multiple comparisons, the TT had a significantly lower threshold compared to the other test sites (P!0.001) and the MG had a significantly higher threshold compared to the other test sites (P!0.001) in both males and females (Table 1 and Fig. 1). Males had a significantly higher TDT at the CS than females (P!0.001). 3.2. Filament-prick pain threshold The FPT ranged from 5.10G0.19 to 5.91G0.31 in males and from 4.96G0.31 to 5.40G0.52 in females. Only four female subjects felt a filament-prick pain already with the first filament and consequently started with a descending series of measurements. Also for FPT, no significant age (PZ0.364), BMI (PZ0.645), session effect (PZ0.174) or NRS effect (PZ0.536) were observed. As for TDT, the only significant factors were gender (P!0.001) and site (P!0.001). After correction for multiple comparisons, the TT had a significantly lower threshold compared to the other testing sites in both males and females (P!0.001) (Table 1 and Fig. 1), and the MG had a significantly lower threshold compared to the CS and TS in males (P!0.001), Males had a significantly higher FPT at the CS and TS than females (P!0.001). The NRS values for FPT ranged from 1.8G0.9 to 2.8G0.9 in males and 1.6G0.9 to 1.9G0.9 in females. No significant age and BMI effect (PZ0.680 for age, PZ0.312 for BMI), or session effects (PZ0.075) were present. The only significant factors were gender (PZ0.003) and site (P!0.001). After correction for multiple comparisons, there was a significantly higher NRS value at the MG and TT compared to the CS and TS in males (MG–CS: P!0.001, MG–TS: PZ0.002, TT–CS: P!0.001, TT–TS: PZ0.001). Males indicated a significantly higher NRS at the MG (PZ0.041, right; PZ0.030, left) and the TT (PZ0.030) than females (Table 1 and Fig. 1).

Fig. 1. Mean and standard error of tactile detection threshold (A), filamentprick pain detection threshold (FPT) (B), and perceived pain intensity during measurement of FPT (C). *P!0.05 when compared between the genders. †P!0.05 when compared between the sites.

3.3. Pressure pain threshold The analysis revealed no significant age and BMI effect (PZ0.648 for age, PZ0.665 for BMI), nor NRS effect (PZ0.157). The significant factors were gender (P!0.003) and site (P!0.001). Males had a significant higher PPT than females in the left and right MM, and TM (P!0.001). In addition, the TM had a significant higher PPT than the MM (P!0.001). Further, there was a significant systematic change from the first to the third session (session effect, PZ0.012). In each gender and each site, the PPT significantly decreased

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Table 2 Systematic changes of pressure pain threshold from first to third session Site Masseter muscle

Side Right Left

Thenar muscle

Gender Male Female Male Female Male Female

Session First

Second

Third

216.5G49.8 147.2G38.2 218.7G64.8 147.6G41.2 415.0G146.4 256.6G80.9

191.9G46.9 143.1G38.8 208.1G63.0 140.9G45.0 383.6G119.5 253.8G96.6

203.8G46.5 148.2G37.4 210.2G59.9 154.6G38.5 389.7G103.1 275.1G89.1

A significant systematic change from the first to the third session was found (session effect, PZ0.012).

from the first to the second session (PZ0.012) and significantly increased from the second to the third session (PZ0.025), but there was no significant difference between the first and the third session (PZ0.700) (Table 2 and Fig. 2). Regarding the NRS value for PPT, no significant effects could be found (PZ0.9659 for age, PZ0.4347 for BMI, PZ0.1388 for gender, PZ0.2258 for session).

3.4. Pressure pain tolerance detection threshold There were no significant age, BMI, session, NRS or site effects (PZ0.582 for age, PZ0.165 for BMI, PZ0.059 for session, PZ0.057 for NRS, PZ0.325 for site). Males had a significant higher PTOL compared to the females in left and right MM (PZ0.004) (Table 1 and Fig. 2). 3.5. Correlation between the different stimulus modalities Correlation analysis was based on the averaged responses across the sessions, because there were no great differences in the obtained correlation model per session. Due to the small sample size, the analysis was performed on the whole subject sample (nZ32). Significant correlations were found between TDT and FPT on the left side (rZ0.348: Pearson’s correlation coefficient, PZ0.049), and between the TDT and PTOL on the right side (rZ0.351, PZ0.046). In addition, a strong correlation between the FPT, PPT, and PTOL was found on both the left and right side (Table 3).

4. Discussion The evaluation of tactile function could be helpful in the diagnosis and assessment of clinical and experimental pain. Table 3 The results of the correlation analysis between the tactile detection threshold (TDT), filament-prick pain threshold (FPT), pressure pain threshold (PPT), and pressure pain tolerance threshold (PTOL) TDT Left

Right Fig. 2. Mean and standard error of pressure pain threshold (PPT) and pressure pain tolerance (PTOL) (A), and perceived pain intensity during measurement of PPT and PTOL (B). *P!0.05 when compared between the genders.

TDT FPT PPT PTOL TDT FPT PPT PTOL

1.0 0.348* 0.180 0.326 1.0 0.213 0.200 0.351*

FPT

PPT

1.0 0.550** 0.417*

1.0 0.757**

1.0 0.615** 0.541**

1.0 0.817**

Pearson’s correlation coefficients: *P!0.05, **P!0.01.

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However, normative data are lacking. As a first step in this direction, TDT measurements were compared at different test sites. The threshold was lowest at the TT, followed by the CS and the TS, while the value at the MG was highest. This is in accordance with previous studies (Aviv et al., 1992; Cordeilo et al., 1997). The observed differences between the various skin regions with regard to the psychophysical thresholds illustrate the variability of the tested afferents, their density, and/or variations in the processing within the central nervous system of tactile information (Johansson et al., 1980). This issue has not been resolved and can be addressed only by correlative microneurographic and psychophysical studies conducted on human volunteers (Essick, 1992). Clinical and experimental pain appears to modify the tactile thresholds (Chong et al., 2002; Leffler et al., 2000). Future studies could detail these changes, also using the presently reported data. Our data show that the TDT measurements were significantly lower in females than in males at the CS. Stohler et al. (2001) used five custom made and standardized filaments and applied them repeatedly (20 times) to the cheek skin of symptom-free subjects. The number of positive responses was counted in order to estimate the likelihood of detecting each filament. They found no significant gender difference, but also in their study, females reported positively to stimulation with weak filaments (0.5 mN or lower) more frequently. Also using the two-point perception threshold (Chen et al., 1995) and direction discrimination (Essick et al., 1988), on extra-oral sites, gender differences have been reported. The Semmes–Weinstein monofilaments used for determining TDT in the present study cause an indentation of the skin during the measurement. The force required to produce a certain amplitude or gradient of this skin displacement varies with the stiffness of the tissue (Johansson et al., 1980). Female and male skin may vary regarding physical properties. It has been pointed out already that female skin appears to have a higher elasticity and extensibility (Cua et al., 1990; Leveque et al., 1980). This difference of skin properties between the genders may therefore explain (in part) the present result of TDT at the CS. In both genders, the TT had the lowest FPT compared to the other sites. Since the TT also had a lowest TDT, one could consider this area as the most sensitive to tactile and painful stimulation in the orofacial region. In males, the MG had a lower FPT and a higher TDT compared to the CS and TS. This peculiar but consistent finding suggests that the MG might be less responsive to tactile sensation, but is more sensitive to painful stimulation in males. Significant differences between the males and females were observed regarding the FPT measured at the CS. In addition to the previously mentioned difference in skin indentation, psychosocial gender differences concerning pain perception and expression might also account for this difference (Otto and Dougher, 1985). Although the intra-oral FPT results showed no significant differences for gender, the pain perception as evaluated by

313

NRS obtained during the FPT measurement was significantly higher in male subjects than in females. This finding may suggest that male subjects chose almost the same filament for their pain threshold as females, but at that moment expressed their intra-oral pain as more intense than females. Future research is needed to see whether at identical stimulus intensity, males express less pain than females. In the present study, males had a significant higher PPT and PTOL than females, which corresponds to a previous study (Chesterton et al., 2003). The PPT had a significant session effect and a systematic variability over the three sessions, as has been reported previously (Isselee et al., 1997; Kosek et al., 1993). This might indicate an adaptation to the experimental situation as a result of the learning process or familiarization with the experimental procedure for a PPT measurement (Isselee et al., 2001). The mean PPT in the left and right masseter muscles was 210 kPa for males and 147 kPa for females, while the PTOL was 420 and 310 kPa, respectively. These results are very similar to those of Svensson et al. (1995). The PTOL was nearly two-fold higher than the PPT, which corresponds well to previous studies (Jensen et al., 1992; Plesh et al., 1998). In addition to gender differences, the PPT and PTOL may be affected by other physical differences, such as weight and height, and different criteria for reporting the threshold (NRS value). The present results, however, illustrate that the BMI or the NRS as covariate did not effect the gender difference, clearly confirming that males have a higher PPT and PTOL than females. The measuring points used for TDT and FPT on the cheek were the same as those for PPT and PTOL. There were significant correlations between the TDT and FPT at the left side, and between the TDT and the PTOL at the right side. These findings are very interesting in the light of an interaction between sensation to light touch and pain, and may support previous findings which documented the change of light touch sensation in pain patients (Kosek et al., 1996; Voerman et al., 2000). However, more research on larger samples will be needed in order to completely understand the exact correlation between the TDT and the painful stimulation. A strong correlation was found between the FPT, PPT, and PTOL measured at the cheek/masseter muscle. Systematically, females had lower values than males. In contrast to a single method, more useful information may be obtained by a combined determination of TDT, FPT, PPT, and PTOL. Especially in patients, this combination of measurements might elucidate to what extent the pain perception results from deep tissues or also from an abnormal superficial perception associated with the changes in TDT or FPT. There are some limitations in this study. In the FPT measurements, all male subjects started with ascending series. By contrast, four female subjects felt pain already on the first (No. 4.74) filament and consequently started with a descending series. There might have been some form of

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sensitization or traumatization as a result of the first measurement. Therefore, in future studies, a ‘lower’ first filament is to be used in the determination of the FPT. Also, it is well known that the phases of the menstrual cycle affect sensory and pain perception in females (see Reilly et al., 1999 for meta-analysis). Some researchers reported systematic changes of sensory perception during the menstrual phase (Bajaj et al., 2001; Isselee et al., 2002) and consequently, the subjects of the present study were not tested then. However, other possible fluctuations in pain sensitivity during the menstrual cycle were too difficult to investigate at present in view of the limited number of subjects (Fillingim and Ness, 2000). It has been reported that subjects tolerate pain longer when they are tested by an experimenter of the opposite sex (Kallai et al., 2004; Levin and De Simone, 1991). In the present experiments, all measurements were performed by the same male experimenter, which consequently does not question the lower threshold values observed in the females. In view of the possible gender differences regarding interpretation of ‘most imaginable pain’ on the NRS (Robinson et al., 2004), it was clear that the present gender differences exceeded by far the possible variability caused by this interpretation bias. From the present results, a detailed clarification of the causes for the observed gender differences is impossible. Prior research of pain thresholds using other forms of noxious stimulation suggests that a variety of factors may contribute, including hormonal alterations (Fillingim et al., 1997; Pfleeger et al., 1997), blood pressure (Fillingim and Maixner, 1996), and psychological factors (Fillingim et al., 1996). In addition, other investigators have reported that sex role expectancies (Otto and Dougher, 1985) and anxiety (Dougher et al., 1987) may moderate gender differences (Fillingim et al., 1999). More studies are needed in this respect. In the present study, the TDT, FPT, PPT, and PTOL at multiple measuring points in the orofacial region of normal subjects were evaluated. The gender and site differences in the orofacial region were also characterized. A moderate correlation was found between the touch sensation and the pain sensation, while strong correlations were present between the pain responses to the different stimulus modalities used. In future studies, a comprehensive evaluation and the combination of results from various stimulation modalities, may better clarify the pain mechanisms and gender characteristics, as well as comparisons between normal subjects and patients.

Acknowledgements The authors sincerely wish to thank Dr Kris Bogaerts and Mr Dimitris Rizopoulos, Biostatistical Center, School of Public Health, Catholic University of Leuven, Leuven, Belgium, for the statistical analysis and advise, and Dr Hans

Isselee, Department of Rehabilitation, St Jan Hospital, Bruges, Belgium, for the use of the algometer.

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