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Gender differences in pressure pain threshold in healthy humans
Pain 101 (2003) 259–266 www.elsevier.com/locate/pain
Gender differences in pressure pain threshold in healthy humans Linda S. Chesterton a,*, Panos Barlas b, Nadine E. Foster b, G. David Baxter c, Christine C. Wright d a
Department of Physiotherapy Studies, McKay Building, Keele University, University Park, Staffordshire, ST5 5BG, England, UK b Department of Physiotherapy Studies, Keele University, England, UK c School of Rehabilitation Sciences, University of Ulster, Jordanstown, N. Ireland, UK d School of Health and Social Sciences, Coventry University, England, UK Received 4 June 2002; accepted 4 September 2002
Abstract Aims of investigation: To quantify the magnitude of putative gender differences in experimental pressure pain threshold (PPT), and to establish the relevance of repeated measurements to any such differences. Methods: Two separate studies were undertaken. A pressure algometer was used in both studies to assess PPT in the first dorsal interosseous muscle. Force was increased at a rate of 5 N /s. In study 1, two measurements were taken from 240 healthy volunteers (120 males, 120 females; mean age 25 years) giving a power for statistical analysis of b ¼ 0:80 at a ¼ 0:01. In study two, 30 subjects (15 males, 15 females mean age 28 years) were randomly selected from study one. Fourteen repeated PPT measurements were recorded at seven, 10 min intervals. Mean PPT data for gender groups, from both studies, were analysed using analysis of covariance with repeated measures, and age as the covariate. Results: The mean PPT for each of the two measurements in study one showed a difference between gender of 12.2 N (f ¼ 30:5 N, m ¼ 42:7 N) and 12.8 N (f ¼ 29:5 N, m ¼ 42:3 N), respectively, representing a difference of 28% with females exhibiting a lower threshold. In study two, the mean difference calculated from 14 PPT repeated measurements over a 1 h period was comparable to that in study one at 12.3 N (range 10.4–14.4 N) again females exhibited the lower threshold. The differences in mean PPT values between gender were found to be significant in both study one, at (P , 0:0005, F ¼ 37:8, df ¼ 1) and study two (P ¼ 0:01, F ¼ 7:6, df ¼ 1). No significant differences were found in either study with repeated measurement (P ¼ 0:892 and P ¼ 0:280), or on the interaction of gender and repeated measurement after controlling for age (P ¼ 0:36 and P ¼ 0:62). Conclusion: Healthy females exhibited significantly lower mean PPTs in the first dorsal interosseous muscle than males, which was maintained for fourteen repeated measures within a 1 h period. This difference is likely to be above clinically relevant levels of change, and it has clear implications for the use of different gender subjects in laboratory based experimental designs utilising PPT as an outcome measure. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Gender differences; Pressure pain threshold; Experimental pain; Algometry
1. Introduction Experimentally induced pressure pain threshold (PPT) has been used extensively to evaluate the perception of pain, and the efficacy of therapeutic interventions for the treatment of pain (Kosek and Ordeberg, 2000a,b; Hong et al., 1993; Ohrbach and Gale, 1989a; Fischer, 1987a). Treatment induced changes in PPT observed in laboratory settings are proposed to correlate well with changes in clinical status of pain, and as such PPT is considered a useful experimental model (Fischer, 1987b). Much of the literature regarding PPT quantification suggests that there are robust differences between genders, with females exhibiting lower thresholds (Fillingim, 2000; Fillingim and Maixner, 1995). * Corresponding author. Tel.: 144-1782-583808; fax: 144-1782584255. E-mail address: [email protected] (L.S. Chesterton).
This difference is reported to be independent of anatomical measurement site, although a trend for greater divergence in more richly innervated anatomical areas has been suggested (Fillingim et al., 1999). A number of individual studies (see Table 1) and a meta-analysis investigating gender differences in response to mechanically induced pain (Riley et al., 1998) support putative differences and show females to exhibit lower thresholds. Indeed, the meta analysis revealed that mechanical stimuli demonstrated the most consistent gender differences in pain threshold when compared with other forms of experimental stimuli; the mean measurement effect size for PPT was calculated as 0.82 (adjusted to 0.59 when weighted for study sample size; Riley et al., 1998). Based on this calculation, Riley et al. (1998) suggest that studies failing to identify a gender difference in PPT have utilised designs with inadequate power. They calculate that a minimum of 41 subjects per group is required for
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)00 330-5
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Table 1 Summary of studies, supporting gender differences in PPT Source Brennum et al. (1989)
a
Site of measurement
Number of subjects
Number of points
Subject status
Fingers and toes
15 males 15 females 26 males 26 females
24
Healthy
5
Healthy
9
Buchanan and Midgley (1987) a Calcaneum, tibia, thumb, forefinger, forehead Fischer (1986)
M. upper trapezius, M. pectoralis major, M. levator scapulae, M. teres Major, M.supraspinatus M. deltoid, lumbar paraspinals (L4), M. gluteus medius
24 males 26 females
Fischer (1987a) a
M. upper trapezius, M. pectoralis major, M. levator scapulae, M. teres major, M.supraspinatus M. deltoid, lumbar paraspinals (L4), M. gluteus medius
24 males 26 females
9
Healthy
Hogeweg et al. (1992)
Spinal process of : C6, T1,T3, T6, T10, L1, L3, L5, and articular points at the elbow, knee, ankle
14 males 14 females
12
Healthy
Jensen et al. (1992) a
M. temporalis left and right
352 females 385 males
2
Drawn at random from 1000 individuals identified on the National Central Person register – Copenhagen
Merskey and Spear (1964)
Forehead Tibia
2
Healthy
Otto and Dougher (1985) a
Takala (1990) Vanderweeen et al. (1996)
a
28 white males 11 black males 10 white females Second phalanx of the middle finger, non- 40 males dominant hand 40 females
M.upper trapezius M. levator scapulae 14 trigger points on both sides of the body described by Travell and Simons (1983). Eight paravertebral points, 6 points in the shoulder and arm
63 males 20 females 15 males 15 females
Healthy
1 Healthy
Working population Not stated 14
Chronic unilateral pain in the shoulder and arm
Denotes inclusion in the meta analysis by Riley et al. (1998).
comparative studies to give a power of 0.70 in the analysis. However, details of this calculation were not provided, and the authors concede that their analysis only included studies in which adequate data were provided and it is not therefore a comprehensive interpretation of all the available literature. Table 2 shows a number of studies where gender differences in PPT were not found. Although most of these studies do not satisfy the recommended sample size suggested by Riley et al. (1998), there is a sufficient number to convey a lack of consensus and confusion across the literature. Interestingly, one large study (n ¼ 207) included in Table 2 by Lee et al. (1994) (reporting no gender differences overall) does identify some significant gender differences within the results. However, these were observed in less than 50% of the measured sites (six of the 13 anatomical points). This would appear to contrast with suggestions by Fillingim et al. (1999) that gender differences are independent of measurement site. Lee et al. (1994) however, propose that
age may have played a confounding role in some of the differences noted (although their statistical analysis does not appear to support this notion). Not withstanding these results, the findings may be in accord with Berkley (1997) who suggests that reported gender differences are small, are inconsistently reported in experimental conditions and are subject to variations based upon experimental protocols. Unruh (1997) and Fillingim and Maixner (1995) also state that approximately 50% of all existing studies find no gender difference, although they suggest these are generally studies of less experimental rigour. Berkley (1997) does, however, agree with Fillingim and Maixner (1995) in that, where differences have been reported, they tend to show females with lower thresholds. Thus, the direction of gender differences is not in dispute, but the magnitude and relevance remain debateable. Many studies have evaluated protocols of repeated threshold measurements using pressure algometry and
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Table 2 Summary of studies, which do not support gender differences in PPT Source
Site of measurement
Number of subjects
Isselee et al. (1997)
M.temporalis anterior left and right M. masseter superficialis left and right M.temporalis anterior left and right M. masseter superficialis left and rights M. temporalis anterior left and right
11 females 11 males 12 males 9 females 12 males 12 females 104 males 103 females
Isselee et al. (1998) Jensen et al. (1986) Lee et al. (1994)
Sandrini et al. (1994) Vatine et al. (1993)
M.temporalis (anterior, middle, posterior) left and right M.masseter (deep, anterior, inferior) left and right M. pterygoid left and right M. posterior digastric M. sternocleidomastoid (superior, middle) M. splenius capitus M. trapezius M. trapezius M. frontalis Mastoid processes, malleoli, and sternum
found the technique to show high levels of reliability (Antonaci et al., 1998; Nussbaum and Downes, 1998; Isselee et al., 1997; Kosek et al., 1993; Brennum et al., 1989; List et al., 1989). Although a high degree of variability in PPT levels between individual subjects has also been shown, this aspect does not appear to impact upon the reliability of the measurement technique (Fischer, 1987a). One aspect of PPT measurements that has not however been reported is the relevance of gender in response to repeated measurements. This issue may be important since Sarlani and Greenspan (2002) have shown that greater temporal summation can occur in females compared to males, in response to rapidly applied mechanical evoked pain at supra threshold levels (12 trains of ten repetitive stimuli at intervals of 1– 6 s). Whilst this study did not demonstrate an overall gender difference, interaction effects for stimulus order and gender were clearly demonstrated; with stimuli later in the repetition trains causing females to give higher pain ratings. The statistical power of Sarlani and Greenspan’s (2002) study was not reported and the sample size is relatively small (n ¼ 20). Nevertheless this effect has also been demonstrated in response to electrical pain (Arendt-Nielsen et al., 1994; Price, 1972) and thermal pain (Fillingim et al., 1998; Price et al., 1977). It is, therefore, possible that there are variable gender responses to repeated threshold measurements. Many prospective experimental studies have used repeated measures as a protocol and include both gender groups for example, Alves-Guerreiro et al. (2001); Kosek and Ordeberg (2000b); Fischer (1987b); Hong et al. (1993). A differential response between groups to the outcome measure would confound the results recorded and therefore this issue requires further investigation. This study formed part of a multifaceted investigation into the hypoalgesic effects of electrostimulation. Since gender differences may play an important role in response
26 males 24 females 14 males 10 females
Number of points
Subject status
6
Healthy
10
Healthy
2
Healthy Healthy
13
Healthy 11 3
Healthy
to such analgesic interventions and ultimately pain management strategies (Wesselman, 1997), this investigation aims to gain a better understanding of the gender differences in response to the pressure pain threshold model of experimental pain used in our larger investigation. The adopted experimental protocol in terms of the number and sequence of repeated measures reflects that used within our laboratory on previous occasions (Barlas et al., 2002; Chesterton et al., 2002). Other centres investigating therapeutic interventions have also used experimental PPT, induced via a pressure algometer, and measured at the first dorsal interosseous muscle or palmar muscles. In these cases similar measurement intervals have been used, but with less repetitions (Alves-Guerreiro et al., 2001; McDowell et al., 1999; Walsh et al., 1995; Wylie et al., 1995). Similar repeated measures time protocols have however, been reported using different models of experimental pain e.g. (Johnson and Tabasam, 1999). Therefore use of this method allows results from the larger study to be compared across a broad section of the literature and exploring the issue of potentially different gender responses is therefore important. The purposes of this study were therefore, first, to quantify the magnitude of gender differences in PPT measured at the first dorsal interosseous muscle, and second, to establish the effect of 14 repeated measures over a 1 h period on any recorded gender difference. These effects have not been previously reported. To address the shortcomings identified in previous literature, the first experiment was designed to allow statistical analysis at a power of 80% at a ¼ 0:01.
2. Method The study was designed as two separate experiments and was granted ethical approval from university research ethics committee. Both experiments used the same equipment and
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measurement protocol. Experimenters and subjects were unaware of the purpose of the study and both were unable to see the algometer display. The difference between the two studies lay in the number of repeated measures taken and the number of subjects recruited. 2.1. Subjects 2.1.1. Study 1 A sample of 240 healthy volunteers (120 females, 120 males) was recruited from the University student and staff populations. The mean age of the sample was 25 years (SD ¼ 7, range 19–57 years). Prior to participation, subjects were screened for relevant contraindications: peripheral neuropathy, pain symptoms, and history of trauma or surgery to the dominant hand, current medication, diabetes or pregnancy. The experimental procedure was explained to each subject, who then signed a consent form. 2.1.2. Study 2 From the original sample of 240, 30 subjects (15 females, 15 males) were randomly selected (by computer generated randomised list) and consented to take part in experiment 2. The mean age of this sample was 28 years (SD ¼ 9, range 19–48 years).
mately 10–15 s apart. For experiment 2, recordings were made at six further time points, each 10 min apart. At each time point, two PPT measures were again taken, approximately 10–15 s apart. Thus for experiment 2, 12 extra measures were taken, giving a total of 14 PPT measures collected per subject, over a period of 60 min. One experimenter collected all PPT data from an individual subject and seven experimenters were used in total. The inter-rater reliability for the seven experimenters was tested prior to the study (unpublished data Chesterton et al., 2002) with ICC (2,1) ¼ 0.90 (95% CI 0.81–0.96). Shrout and Fleiss (1979) define reliability as excellent where analysis reports ICC to be .0.75. 2.4. Data analysis Data for both experiments 1 and 2 were analysed using analysis of covariance (ANCOVA) with time as a within subject factor, gender as a between subject factor and age as a covariate. All statistical analyses were carried out using statistical package for social science (SPSS) for Windows Version 10, at significance level a ¼ 0:01.
3. Results
2.2. Equipment
3.1. Study 1
Pressure pain was induced using a pressure algometer (Salter Abbey Weighing Machines Ltd, England) with a flat circular metal probe dressed in several layers of lint and measuring 1.1 cm in diameter. Force was displayed digitally in increments of 0.1 N. The algometer was mounted vertically on a purpose built calibrated iron stand to enable force to be applied at a controlled and steady rate.
Summaries of descriptive statistics for PPT measures are given in Table 3, which shows the mean PPT values for each gender. The difference in the mean PPT between genders was 12.2 and 12.8 N for the first and second measurements, respectively. The distribution of individual PPT values with respect to gender and measurement occasion is depicted in Fig. 1. The boxplots show the stability of PPT values across two repeated measures (15 s apart), the consistent median difference of approximately 12–13 N between gender groups, and the expected heterogeneous nature of individual PPT measures in both gender groups. Statistical analysis revealed significant differences in mean PPT values between gender (P , 0:0005, df ¼ 1, F ¼ 37:8), with no significant difference in mean PPT between two repeated measures (P ¼ 0:892, df ¼ 1, F ¼ 0:018) or interaction between gender and repeated measures (P ¼ 0:35, df ¼ 1,F ¼ 0:855), when adjusting for age.
2.3. Pressure pain threshold measurement procedure PPT was defined as the amount of force required to elicit a sensation of pain distinct from pressure or discomfort (Fischer, 1987a). The PPT measurement point was marked in the middle of the muscle belly of the first dorsal interosseous muscle (Chesterton et al., 2002). Subjects were instructed in the application of the algometer and given a demonstration. They then underwent two practice PPT measurements using their non-dominant hand and were coached in differentiating their report of tactile and painful stimulus. Subjects were asked to say ‘stop’ immediately when a discernible sensation of pain, distinct from pressure or discomfort, was felt. At this point, the experimenter immediately retracted the algometer (Fischer, 1987b). The digital display continued to show the value of pressure applied at the moment the algometer was retracted. The algometer was applied perpendicularly to the skin and lowered at a rate of approximately 5 N/s until PPT was reached, as indicated by subjects’ verbal report. For experiment 1, two PPT measures were performed approxi-
Table 3 Experiment 1: mean PPT (Newtons) Standard deviation (SD) by gender, mean difference and % difference between gender for measure 1 and 2 (n ¼ 240)
Females Males Mean difference % difference
Sample size
PPT measurement 1 PPT measurement 2 (SD) N (SD) N
120 120
30.5 (14.5) 42.7 (17.5) 12.2 28
29.5 (13.7) 42.3 (18.0) 12.8 30
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3.2. Study 2 The mean PPT values for the gender groups at each time point are depicted in Fig. 2. These values are seen to remain relatively stable, giving a mean gender difference over all time points of 12.3 N(range 10.4–14.4 N). The mean PPT values over all time points for females were 27.5 N compared to males at 39.8 N. Repeated measures ANCOVA (correcting for violation of sphericity assumptions using the Green House Geisser method) showed a significant difference in PPT between gender (P ¼ 0:01, df ¼ 1, F ¼ 7:66), with no significant difference in mean PPT values for repeated measures (P ¼ 0:28, df ¼ 4.7, F ¼ 1:28) or for the interaction between gender and repeated measures (P ¼ 0:62, df ¼ 4.7, F ¼ 0:62) again adjusting for age. 4. Discussion The purpose of this study was first to quantify, with adequate power, the magnitude of gender differences in PPT measured at the first dorsal interosseous muscle. The second objective was to establish the effect of repeated PPT measures on the recorded difference. No previous studies have reported the magnitude of PPT between genders at this anatomical point, or indeed, the effect of repeated measures at 10 min intervals on PPT gender differences. Results show females to report a lower mean PPT 212.2 to 212.8 N compared with males. This value cannot be compared directly with those from other studies because different anatomical measurement sites produce varying
Fig. 1. Experiment 1: Data distribution summaries for PPT measures 1 and 2 for male (n ¼ 120) and female (n ¼ 120Þ groups The rectangular boxes correspond to the 25–75% inter-quartile ranges for each dataset and indicate the variability for the middle 50% of measures. The thick black line across each box represents the median. The vertical lines outside the box (whiskers) connect the largest and smallest values not categorised as outliers. PPTs outside of this range (more than 1.5 box lengths away from the box) are shown as outliers and are depicted by the small circles. There were no extreme values recorded (values greater than three box lengths away from the box). The location of the median lines and the approximately equal length of the whiskers suggest approximate symmetry in all datasets. The overlapping boxes, show that the lower values for the middle 50% of males, falls within the same PPT range as the upper values of the middle 50% of females.
Fig. 2. Experiment 2: Line graph of mean PPT (N) for each gender group with repeated measures at 10 min intervals over one hour. Mean PPT for group (n ¼ 30) and mean of two PPT readings taken at each time point error bars ¼ standard error of the mean.
levels of normative PPT values (Hogeweg et al., 1992; Petersen et al., 1992; Ohrbach and Gale, 1989b; GereczSimon et al., 1989). However, by calculating the mean percentage difference between genders for the mean PPT recorded in experiment 1 at 28%, the results can be compared with other studies using similar calculations of the mean percentage difference from the data presented. This necessitates the use of only those studies supplying raw data and in this instance, only studies using sample sizes of n . 41 were selected for comparison, as suggested by Riley et al. (1998). Using this approach Jensen et al. (1992) reported females to demonstrate an average PPT of 20% less than males when measured at both left and right temporal muscles of 737 healthy subjects. Data reported by Fischer (1987a) shows an average gender difference of 27% (range 5 to 35%) in mean PPT measured at nine common trigger points in 50 healthy volunteers. Whereas Lee et al. (1994) report an average difference of 12% (range 26 to 27%) across 13 different measurement sites in 207 subjects. These comparisons tend to suggest that whilst gender differences do occur, the magnitude is not consistent as suggested by Berkley (1997), and is dependent upon the anatomical measurement site. Whilst the results from our study show statistically significant differences between genders in mean PPT at the first interosseous muscle, the clinical relevance of such differences should also be considered. A review of the literature revealed no investigations devoted to this topic. Therefore, studies using PPT in addition to other clinical indicators of change were reviewed, and three studies identified are discussed in relation to gender effects. In a study of 50 patients, Fischer (1990) used 93 PPT recordings to identify correlations between clinical ‘hot spots’ identified in thermographs and tender spots identified by PPT measurement. When a tender spot was defined by a PPT measuring 1.5 Kg/ cm 2 (14.7 N) less than the corresponding contralateral anatomical site, a correlation of 97.8% was shown with thermograph reports. Where the definition of tender spots was refined to require a 2 Kg/cm 2 (19.6 N) difference in
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PPT at contralateral sides, an 87% correlation was still achieved. Hong et al. (1993) reported a double blind, controlled trial of 84 patients and 24 healthy volunteers comparing the effects of heat, ultrasound, stretch and deep massage in relieving myofascial trigger point pain. Statistically significant increases in PPT in response to therapeutic interventions ranged from 1.1 to 2.6 Kg (9.9–20.2 N) (P , 0:05), with negligible changes seen in control groups. In a study by Pratzel (1998), similar levels of change in PPT were accompanied by significant improvements in VAS scores of patient reported pain intensity. A double blind, randomised, placebo controlled trial was used to investigate the analgesic effect of a standard physical therapy programme and repeated sulphur bath treatments (bath additives contained polysulfide and huminic acid). Twenty patients with rheumatic disease, showed an average increase of 1.1 Kg/cm 2 (9.9 N) in the mean PPT value of 16 anatomical sites measured in each patient. This compared with an increase of 0.4 Kg/cm 2 reported in placebo groups (placebo bath additives contained huminic acids only and baths could not be distinguished by smell or colour). In the same study, the single point defined by each patient as giving maximum pain was recorded separately. In this instance, an average increase of 1.5 Kg/cm 2 in mean PPT was shown in treatment groups compared with controls (standard physical therapy programme only). Although these examples represent changes in PPT due to pathology or in response to a therapeutic intervention, and are not gender specific, a difference in the level of PPT of greater than 1 Kg/cm 2 has typically implied clinically relevant changes. It is suggested by Price et al. (1986) that clinical and experimental pain are reduced by similar levels in response to therapeutic intervention (specifically to opiate intervention). Therefore, one might conclude that, the mean gender difference in PPT seen in this study i.e. 12.2 N (1.2 Kg/cm 2), is likely to be above the implied level of clinically relevant change identified, and thus has important implications for experimental research and clinical practice. However, we accept that results using a single anatomical measure will only provide an indication of potential gender differences in other PPT measures. Therefore the recommendations that can be made based on these results are limited to sample selection and analysis techniques. The results suggest that it is prudent to use designs that incorporate either single gender groups, or where analysis requires ‘within-subject’ comparisons (and gender will not confound results), samples should have equal gender mix within intervention groups. Additionally the generalisation of results across genders would seem inappropriate in experimental studies and further investigations are required to establish clinically relevant changes in PPT for both gender groups. It is also important to note that the relevance of gender dependent differences in experimental pain compared with clinical pain remains speculative and further research is required (Fillingim, 2000). Indeed, the literature widely suggests that gender is only one factor
that may influence the experience of pain and, although the underlying reasons for gender differences have been extensively investigated, the precise physiological and psychological mechanisms underlying the difference remain unclear. Other proposals have included; the notion of gender role expectancy, age, personality, familial influence, cultural and hormonal factors (Isselee et al., 2001; Rollman and Lautenbacher, 2001; Fillingim, 2000; Fillingim et al., 2000; Fillingim and Ness, 2000; Fillingim et al., 1998; Helme and Gibson, 1997; Thomas and Rose 1991; Zatzick and Dimsdale 1990; Otto and Dougher 1985; Keele 1972). In experimental designs, the gender of the subject in relation to the experimenter is suggested to influence responses (Levine and De Simone, 1991), while anxiety and fear have also been reported to reduce PPT (Buchanan and Midgley, 1987). Due to the sheer number of variables, Lautenbacher (1997) suggests that it is impossible to account for all relevant characteristics, which may contribute to apparent differences in gender reports of pain and indeed these factors (with the exception of age) have not been considered in this analysis, which is an obvious limitation. Within the second experiment of this study, results showed a post hoc observed power of 0.76. However, due to the relatively small sample size (n ¼ 30) and known heterogeneity in PPT measures, it would be prudent to consider the conclusions to be indicative of a response and again further large studies, which include more anatomical measurement sites, would be beneficial. Nevertheless, the indication is that the use of repeated measures applied in this way produces a stable response over a 1 h period within both gender groups and also reflects the reliability of the measurement technique. Results from two quick and successive measurements in experiment 1 (n ¼ 240) support this notion of reliability with greater statistical power. Even so, experimental designs should consider the use of standardising heterogeneous baseline PPT measures to reflect change against the standard, rather than using absolute levels of measured PPT. This will reduce the effect of gender differences, and other potentially confounding variables, which have been associated with the PPT measurement, for example age (Edwards and Fillingim, 1999; Jensen et al., 1992; Brennum et al., 1989). In conclusion, the results from this study show that there is a significant difference between genders in the mean PPT measured at the first interosseous muscle of at least 12.2 N (1.23 Kg/cm 2), with females showing lower thresholds. The magnitude of this difference was largely unaffected by 14 repeated measurements (seven trains of two repeated stimuli) over a 1 h period and PPT measured in this way is shown to be stable, independent of gender. Nevertheless the magnitude of the observed differences between genders is likely to be at a clinically relevant level. It is therefore recommended that, in order to reduce potential bias in experimental protocols, single gender samples are used or, gender is matched across all experimental groups.
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Gender differences in pressure pain threshold in healthy humans Linda S. Chesterton a,*, Panos Barlas b, Nadine E. Foster b, G. David Baxter c, Christine C. Wright d a
Department of Physiotherapy Studies, McKay Building, Keele University, University Park, Staffordshire, ST5 5BG, England, UK b Department of Physiotherapy Studies, Keele University, England, UK c School of Rehabilitation Sciences, University of Ulster, Jordanstown, N. Ireland, UK d School of Health and Social Sciences, Coventry University, England, UK Received 4 June 2002; accepted 4 September 2002
Abstract Aims of investigation: To quantify the magnitude of putative gender differences in experimental pressure pain threshold (PPT), and to establish the relevance of repeated measurements to any such differences. Methods: Two separate studies were undertaken. A pressure algometer was used in both studies to assess PPT in the first dorsal interosseous muscle. Force was increased at a rate of 5 N /s. In study 1, two measurements were taken from 240 healthy volunteers (120 males, 120 females; mean age 25 years) giving a power for statistical analysis of b ¼ 0:80 at a ¼ 0:01. In study two, 30 subjects (15 males, 15 females mean age 28 years) were randomly selected from study one. Fourteen repeated PPT measurements were recorded at seven, 10 min intervals. Mean PPT data for gender groups, from both studies, were analysed using analysis of covariance with repeated measures, and age as the covariate. Results: The mean PPT for each of the two measurements in study one showed a difference between gender of 12.2 N (f ¼ 30:5 N, m ¼ 42:7 N) and 12.8 N (f ¼ 29:5 N, m ¼ 42:3 N), respectively, representing a difference of 28% with females exhibiting a lower threshold. In study two, the mean difference calculated from 14 PPT repeated measurements over a 1 h period was comparable to that in study one at 12.3 N (range 10.4–14.4 N) again females exhibited the lower threshold. The differences in mean PPT values between gender were found to be significant in both study one, at (P , 0:0005, F ¼ 37:8, df ¼ 1) and study two (P ¼ 0:01, F ¼ 7:6, df ¼ 1). No significant differences were found in either study with repeated measurement (P ¼ 0:892 and P ¼ 0:280), or on the interaction of gender and repeated measurement after controlling for age (P ¼ 0:36 and P ¼ 0:62). Conclusion: Healthy females exhibited significantly lower mean PPTs in the first dorsal interosseous muscle than males, which was maintained for fourteen repeated measures within a 1 h period. This difference is likely to be above clinically relevant levels of change, and it has clear implications for the use of different gender subjects in laboratory based experimental designs utilising PPT as an outcome measure. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Gender differences; Pressure pain threshold; Experimental pain; Algometry
1. Introduction Experimentally induced pressure pain threshold (PPT) has been used extensively to evaluate the perception of pain, and the efficacy of therapeutic interventions for the treatment of pain (Kosek and Ordeberg, 2000a,b; Hong et al., 1993; Ohrbach and Gale, 1989a; Fischer, 1987a). Treatment induced changes in PPT observed in laboratory settings are proposed to correlate well with changes in clinical status of pain, and as such PPT is considered a useful experimental model (Fischer, 1987b). Much of the literature regarding PPT quantification suggests that there are robust differences between genders, with females exhibiting lower thresholds (Fillingim, 2000; Fillingim and Maixner, 1995). * Corresponding author. Tel.: 144-1782-583808; fax: 144-1782584255. E-mail address: [email protected] (L.S. Chesterton).
This difference is reported to be independent of anatomical measurement site, although a trend for greater divergence in more richly innervated anatomical areas has been suggested (Fillingim et al., 1999). A number of individual studies (see Table 1) and a meta-analysis investigating gender differences in response to mechanically induced pain (Riley et al., 1998) support putative differences and show females to exhibit lower thresholds. Indeed, the meta analysis revealed that mechanical stimuli demonstrated the most consistent gender differences in pain threshold when compared with other forms of experimental stimuli; the mean measurement effect size for PPT was calculated as 0.82 (adjusted to 0.59 when weighted for study sample size; Riley et al., 1998). Based on this calculation, Riley et al. (1998) suggest that studies failing to identify a gender difference in PPT have utilised designs with inadequate power. They calculate that a minimum of 41 subjects per group is required for
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)00 330-5
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Table 1 Summary of studies, supporting gender differences in PPT Source Brennum et al. (1989)
a
Site of measurement
Number of subjects
Number of points
Subject status
Fingers and toes
15 males 15 females 26 males 26 females
24
Healthy
5
Healthy
9
Buchanan and Midgley (1987) a Calcaneum, tibia, thumb, forefinger, forehead Fischer (1986)
M. upper trapezius, M. pectoralis major, M. levator scapulae, M. teres Major, M.supraspinatus M. deltoid, lumbar paraspinals (L4), M. gluteus medius
24 males 26 females
Fischer (1987a) a
M. upper trapezius, M. pectoralis major, M. levator scapulae, M. teres major, M.supraspinatus M. deltoid, lumbar paraspinals (L4), M. gluteus medius
24 males 26 females
9
Healthy
Hogeweg et al. (1992)
Spinal process of : C6, T1,T3, T6, T10, L1, L3, L5, and articular points at the elbow, knee, ankle
14 males 14 females
12
Healthy
Jensen et al. (1992) a
M. temporalis left and right
352 females 385 males
2
Drawn at random from 1000 individuals identified on the National Central Person register – Copenhagen
Merskey and Spear (1964)
Forehead Tibia
2
Healthy
Otto and Dougher (1985) a
Takala (1990) Vanderweeen et al. (1996)
a
28 white males 11 black males 10 white females Second phalanx of the middle finger, non- 40 males dominant hand 40 females
M.upper trapezius M. levator scapulae 14 trigger points on both sides of the body described by Travell and Simons (1983). Eight paravertebral points, 6 points in the shoulder and arm
63 males 20 females 15 males 15 females
Healthy
1 Healthy
Working population Not stated 14
Chronic unilateral pain in the shoulder and arm
Denotes inclusion in the meta analysis by Riley et al. (1998).
comparative studies to give a power of 0.70 in the analysis. However, details of this calculation were not provided, and the authors concede that their analysis only included studies in which adequate data were provided and it is not therefore a comprehensive interpretation of all the available literature. Table 2 shows a number of studies where gender differences in PPT were not found. Although most of these studies do not satisfy the recommended sample size suggested by Riley et al. (1998), there is a sufficient number to convey a lack of consensus and confusion across the literature. Interestingly, one large study (n ¼ 207) included in Table 2 by Lee et al. (1994) (reporting no gender differences overall) does identify some significant gender differences within the results. However, these were observed in less than 50% of the measured sites (six of the 13 anatomical points). This would appear to contrast with suggestions by Fillingim et al. (1999) that gender differences are independent of measurement site. Lee et al. (1994) however, propose that
age may have played a confounding role in some of the differences noted (although their statistical analysis does not appear to support this notion). Not withstanding these results, the findings may be in accord with Berkley (1997) who suggests that reported gender differences are small, are inconsistently reported in experimental conditions and are subject to variations based upon experimental protocols. Unruh (1997) and Fillingim and Maixner (1995) also state that approximately 50% of all existing studies find no gender difference, although they suggest these are generally studies of less experimental rigour. Berkley (1997) does, however, agree with Fillingim and Maixner (1995) in that, where differences have been reported, they tend to show females with lower thresholds. Thus, the direction of gender differences is not in dispute, but the magnitude and relevance remain debateable. Many studies have evaluated protocols of repeated threshold measurements using pressure algometry and
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Table 2 Summary of studies, which do not support gender differences in PPT Source
Site of measurement
Number of subjects
Isselee et al. (1997)
M.temporalis anterior left and right M. masseter superficialis left and right M.temporalis anterior left and right M. masseter superficialis left and rights M. temporalis anterior left and right
11 females 11 males 12 males 9 females 12 males 12 females 104 males 103 females
Isselee et al. (1998) Jensen et al. (1986) Lee et al. (1994)
Sandrini et al. (1994) Vatine et al. (1993)
M.temporalis (anterior, middle, posterior) left and right M.masseter (deep, anterior, inferior) left and right M. pterygoid left and right M. posterior digastric M. sternocleidomastoid (superior, middle) M. splenius capitus M. trapezius M. trapezius M. frontalis Mastoid processes, malleoli, and sternum
found the technique to show high levels of reliability (Antonaci et al., 1998; Nussbaum and Downes, 1998; Isselee et al., 1997; Kosek et al., 1993; Brennum et al., 1989; List et al., 1989). Although a high degree of variability in PPT levels between individual subjects has also been shown, this aspect does not appear to impact upon the reliability of the measurement technique (Fischer, 1987a). One aspect of PPT measurements that has not however been reported is the relevance of gender in response to repeated measurements. This issue may be important since Sarlani and Greenspan (2002) have shown that greater temporal summation can occur in females compared to males, in response to rapidly applied mechanical evoked pain at supra threshold levels (12 trains of ten repetitive stimuli at intervals of 1– 6 s). Whilst this study did not demonstrate an overall gender difference, interaction effects for stimulus order and gender were clearly demonstrated; with stimuli later in the repetition trains causing females to give higher pain ratings. The statistical power of Sarlani and Greenspan’s (2002) study was not reported and the sample size is relatively small (n ¼ 20). Nevertheless this effect has also been demonstrated in response to electrical pain (Arendt-Nielsen et al., 1994; Price, 1972) and thermal pain (Fillingim et al., 1998; Price et al., 1977). It is, therefore, possible that there are variable gender responses to repeated threshold measurements. Many prospective experimental studies have used repeated measures as a protocol and include both gender groups for example, Alves-Guerreiro et al. (2001); Kosek and Ordeberg (2000b); Fischer (1987b); Hong et al. (1993). A differential response between groups to the outcome measure would confound the results recorded and therefore this issue requires further investigation. This study formed part of a multifaceted investigation into the hypoalgesic effects of electrostimulation. Since gender differences may play an important role in response
26 males 24 females 14 males 10 females
Number of points
Subject status
6
Healthy
10
Healthy
2
Healthy Healthy
13
Healthy 11 3
Healthy
to such analgesic interventions and ultimately pain management strategies (Wesselman, 1997), this investigation aims to gain a better understanding of the gender differences in response to the pressure pain threshold model of experimental pain used in our larger investigation. The adopted experimental protocol in terms of the number and sequence of repeated measures reflects that used within our laboratory on previous occasions (Barlas et al., 2002; Chesterton et al., 2002). Other centres investigating therapeutic interventions have also used experimental PPT, induced via a pressure algometer, and measured at the first dorsal interosseous muscle or palmar muscles. In these cases similar measurement intervals have been used, but with less repetitions (Alves-Guerreiro et al., 2001; McDowell et al., 1999; Walsh et al., 1995; Wylie et al., 1995). Similar repeated measures time protocols have however, been reported using different models of experimental pain e.g. (Johnson and Tabasam, 1999). Therefore use of this method allows results from the larger study to be compared across a broad section of the literature and exploring the issue of potentially different gender responses is therefore important. The purposes of this study were therefore, first, to quantify the magnitude of gender differences in PPT measured at the first dorsal interosseous muscle, and second, to establish the effect of 14 repeated measures over a 1 h period on any recorded gender difference. These effects have not been previously reported. To address the shortcomings identified in previous literature, the first experiment was designed to allow statistical analysis at a power of 80% at a ¼ 0:01.
2. Method The study was designed as two separate experiments and was granted ethical approval from university research ethics committee. Both experiments used the same equipment and
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measurement protocol. Experimenters and subjects were unaware of the purpose of the study and both were unable to see the algometer display. The difference between the two studies lay in the number of repeated measures taken and the number of subjects recruited. 2.1. Subjects 2.1.1. Study 1 A sample of 240 healthy volunteers (120 females, 120 males) was recruited from the University student and staff populations. The mean age of the sample was 25 years (SD ¼ 7, range 19–57 years). Prior to participation, subjects were screened for relevant contraindications: peripheral neuropathy, pain symptoms, and history of trauma or surgery to the dominant hand, current medication, diabetes or pregnancy. The experimental procedure was explained to each subject, who then signed a consent form. 2.1.2. Study 2 From the original sample of 240, 30 subjects (15 females, 15 males) were randomly selected (by computer generated randomised list) and consented to take part in experiment 2. The mean age of this sample was 28 years (SD ¼ 9, range 19–48 years).
mately 10–15 s apart. For experiment 2, recordings were made at six further time points, each 10 min apart. At each time point, two PPT measures were again taken, approximately 10–15 s apart. Thus for experiment 2, 12 extra measures were taken, giving a total of 14 PPT measures collected per subject, over a period of 60 min. One experimenter collected all PPT data from an individual subject and seven experimenters were used in total. The inter-rater reliability for the seven experimenters was tested prior to the study (unpublished data Chesterton et al., 2002) with ICC (2,1) ¼ 0.90 (95% CI 0.81–0.96). Shrout and Fleiss (1979) define reliability as excellent where analysis reports ICC to be .0.75. 2.4. Data analysis Data for both experiments 1 and 2 were analysed using analysis of covariance (ANCOVA) with time as a within subject factor, gender as a between subject factor and age as a covariate. All statistical analyses were carried out using statistical package for social science (SPSS) for Windows Version 10, at significance level a ¼ 0:01.
3. Results
2.2. Equipment
3.1. Study 1
Pressure pain was induced using a pressure algometer (Salter Abbey Weighing Machines Ltd, England) with a flat circular metal probe dressed in several layers of lint and measuring 1.1 cm in diameter. Force was displayed digitally in increments of 0.1 N. The algometer was mounted vertically on a purpose built calibrated iron stand to enable force to be applied at a controlled and steady rate.
Summaries of descriptive statistics for PPT measures are given in Table 3, which shows the mean PPT values for each gender. The difference in the mean PPT between genders was 12.2 and 12.8 N for the first and second measurements, respectively. The distribution of individual PPT values with respect to gender and measurement occasion is depicted in Fig. 1. The boxplots show the stability of PPT values across two repeated measures (15 s apart), the consistent median difference of approximately 12–13 N between gender groups, and the expected heterogeneous nature of individual PPT measures in both gender groups. Statistical analysis revealed significant differences in mean PPT values between gender (P , 0:0005, df ¼ 1, F ¼ 37:8), with no significant difference in mean PPT between two repeated measures (P ¼ 0:892, df ¼ 1, F ¼ 0:018) or interaction between gender and repeated measures (P ¼ 0:35, df ¼ 1,F ¼ 0:855), when adjusting for age.
2.3. Pressure pain threshold measurement procedure PPT was defined as the amount of force required to elicit a sensation of pain distinct from pressure or discomfort (Fischer, 1987a). The PPT measurement point was marked in the middle of the muscle belly of the first dorsal interosseous muscle (Chesterton et al., 2002). Subjects were instructed in the application of the algometer and given a demonstration. They then underwent two practice PPT measurements using their non-dominant hand and were coached in differentiating their report of tactile and painful stimulus. Subjects were asked to say ‘stop’ immediately when a discernible sensation of pain, distinct from pressure or discomfort, was felt. At this point, the experimenter immediately retracted the algometer (Fischer, 1987b). The digital display continued to show the value of pressure applied at the moment the algometer was retracted. The algometer was applied perpendicularly to the skin and lowered at a rate of approximately 5 N/s until PPT was reached, as indicated by subjects’ verbal report. For experiment 1, two PPT measures were performed approxi-
Table 3 Experiment 1: mean PPT (Newtons) Standard deviation (SD) by gender, mean difference and % difference between gender for measure 1 and 2 (n ¼ 240)
Females Males Mean difference % difference
Sample size
PPT measurement 1 PPT measurement 2 (SD) N (SD) N
120 120
30.5 (14.5) 42.7 (17.5) 12.2 28
29.5 (13.7) 42.3 (18.0) 12.8 30
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3.2. Study 2 The mean PPT values for the gender groups at each time point are depicted in Fig. 2. These values are seen to remain relatively stable, giving a mean gender difference over all time points of 12.3 N(range 10.4–14.4 N). The mean PPT values over all time points for females were 27.5 N compared to males at 39.8 N. Repeated measures ANCOVA (correcting for violation of sphericity assumptions using the Green House Geisser method) showed a significant difference in PPT between gender (P ¼ 0:01, df ¼ 1, F ¼ 7:66), with no significant difference in mean PPT values for repeated measures (P ¼ 0:28, df ¼ 4.7, F ¼ 1:28) or for the interaction between gender and repeated measures (P ¼ 0:62, df ¼ 4.7, F ¼ 0:62) again adjusting for age. 4. Discussion The purpose of this study was first to quantify, with adequate power, the magnitude of gender differences in PPT measured at the first dorsal interosseous muscle. The second objective was to establish the effect of repeated PPT measures on the recorded difference. No previous studies have reported the magnitude of PPT between genders at this anatomical point, or indeed, the effect of repeated measures at 10 min intervals on PPT gender differences. Results show females to report a lower mean PPT 212.2 to 212.8 N compared with males. This value cannot be compared directly with those from other studies because different anatomical measurement sites produce varying
Fig. 1. Experiment 1: Data distribution summaries for PPT measures 1 and 2 for male (n ¼ 120) and female (n ¼ 120Þ groups The rectangular boxes correspond to the 25–75% inter-quartile ranges for each dataset and indicate the variability for the middle 50% of measures. The thick black line across each box represents the median. The vertical lines outside the box (whiskers) connect the largest and smallest values not categorised as outliers. PPTs outside of this range (more than 1.5 box lengths away from the box) are shown as outliers and are depicted by the small circles. There were no extreme values recorded (values greater than three box lengths away from the box). The location of the median lines and the approximately equal length of the whiskers suggest approximate symmetry in all datasets. The overlapping boxes, show that the lower values for the middle 50% of males, falls within the same PPT range as the upper values of the middle 50% of females.
Fig. 2. Experiment 2: Line graph of mean PPT (N) for each gender group with repeated measures at 10 min intervals over one hour. Mean PPT for group (n ¼ 30) and mean of two PPT readings taken at each time point error bars ¼ standard error of the mean.
levels of normative PPT values (Hogeweg et al., 1992; Petersen et al., 1992; Ohrbach and Gale, 1989b; GereczSimon et al., 1989). However, by calculating the mean percentage difference between genders for the mean PPT recorded in experiment 1 at 28%, the results can be compared with other studies using similar calculations of the mean percentage difference from the data presented. This necessitates the use of only those studies supplying raw data and in this instance, only studies using sample sizes of n . 41 were selected for comparison, as suggested by Riley et al. (1998). Using this approach Jensen et al. (1992) reported females to demonstrate an average PPT of 20% less than males when measured at both left and right temporal muscles of 737 healthy subjects. Data reported by Fischer (1987a) shows an average gender difference of 27% (range 5 to 35%) in mean PPT measured at nine common trigger points in 50 healthy volunteers. Whereas Lee et al. (1994) report an average difference of 12% (range 26 to 27%) across 13 different measurement sites in 207 subjects. These comparisons tend to suggest that whilst gender differences do occur, the magnitude is not consistent as suggested by Berkley (1997), and is dependent upon the anatomical measurement site. Whilst the results from our study show statistically significant differences between genders in mean PPT at the first interosseous muscle, the clinical relevance of such differences should also be considered. A review of the literature revealed no investigations devoted to this topic. Therefore, studies using PPT in addition to other clinical indicators of change were reviewed, and three studies identified are discussed in relation to gender effects. In a study of 50 patients, Fischer (1990) used 93 PPT recordings to identify correlations between clinical ‘hot spots’ identified in thermographs and tender spots identified by PPT measurement. When a tender spot was defined by a PPT measuring 1.5 Kg/ cm 2 (14.7 N) less than the corresponding contralateral anatomical site, a correlation of 97.8% was shown with thermograph reports. Where the definition of tender spots was refined to require a 2 Kg/cm 2 (19.6 N) difference in
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PPT at contralateral sides, an 87% correlation was still achieved. Hong et al. (1993) reported a double blind, controlled trial of 84 patients and 24 healthy volunteers comparing the effects of heat, ultrasound, stretch and deep massage in relieving myofascial trigger point pain. Statistically significant increases in PPT in response to therapeutic interventions ranged from 1.1 to 2.6 Kg (9.9–20.2 N) (P , 0:05), with negligible changes seen in control groups. In a study by Pratzel (1998), similar levels of change in PPT were accompanied by significant improvements in VAS scores of patient reported pain intensity. A double blind, randomised, placebo controlled trial was used to investigate the analgesic effect of a standard physical therapy programme and repeated sulphur bath treatments (bath additives contained polysulfide and huminic acid). Twenty patients with rheumatic disease, showed an average increase of 1.1 Kg/cm 2 (9.9 N) in the mean PPT value of 16 anatomical sites measured in each patient. This compared with an increase of 0.4 Kg/cm 2 reported in placebo groups (placebo bath additives contained huminic acids only and baths could not be distinguished by smell or colour). In the same study, the single point defined by each patient as giving maximum pain was recorded separately. In this instance, an average increase of 1.5 Kg/cm 2 in mean PPT was shown in treatment groups compared with controls (standard physical therapy programme only). Although these examples represent changes in PPT due to pathology or in response to a therapeutic intervention, and are not gender specific, a difference in the level of PPT of greater than 1 Kg/cm 2 has typically implied clinically relevant changes. It is suggested by Price et al. (1986) that clinical and experimental pain are reduced by similar levels in response to therapeutic intervention (specifically to opiate intervention). Therefore, one might conclude that, the mean gender difference in PPT seen in this study i.e. 12.2 N (1.2 Kg/cm 2), is likely to be above the implied level of clinically relevant change identified, and thus has important implications for experimental research and clinical practice. However, we accept that results using a single anatomical measure will only provide an indication of potential gender differences in other PPT measures. Therefore the recommendations that can be made based on these results are limited to sample selection and analysis techniques. The results suggest that it is prudent to use designs that incorporate either single gender groups, or where analysis requires ‘within-subject’ comparisons (and gender will not confound results), samples should have equal gender mix within intervention groups. Additionally the generalisation of results across genders would seem inappropriate in experimental studies and further investigations are required to establish clinically relevant changes in PPT for both gender groups. It is also important to note that the relevance of gender dependent differences in experimental pain compared with clinical pain remains speculative and further research is required (Fillingim, 2000). Indeed, the literature widely suggests that gender is only one factor
that may influence the experience of pain and, although the underlying reasons for gender differences have been extensively investigated, the precise physiological and psychological mechanisms underlying the difference remain unclear. Other proposals have included; the notion of gender role expectancy, age, personality, familial influence, cultural and hormonal factors (Isselee et al., 2001; Rollman and Lautenbacher, 2001; Fillingim, 2000; Fillingim et al., 2000; Fillingim and Ness, 2000; Fillingim et al., 1998; Helme and Gibson, 1997; Thomas and Rose 1991; Zatzick and Dimsdale 1990; Otto and Dougher 1985; Keele 1972). In experimental designs, the gender of the subject in relation to the experimenter is suggested to influence responses (Levine and De Simone, 1991), while anxiety and fear have also been reported to reduce PPT (Buchanan and Midgley, 1987). Due to the sheer number of variables, Lautenbacher (1997) suggests that it is impossible to account for all relevant characteristics, which may contribute to apparent differences in gender reports of pain and indeed these factors (with the exception of age) have not been considered in this analysis, which is an obvious limitation. Within the second experiment of this study, results showed a post hoc observed power of 0.76. However, due to the relatively small sample size (n ¼ 30) and known heterogeneity in PPT measures, it would be prudent to consider the conclusions to be indicative of a response and again further large studies, which include more anatomical measurement sites, would be beneficial. Nevertheless, the indication is that the use of repeated measures applied in this way produces a stable response over a 1 h period within both gender groups and also reflects the reliability of the measurement technique. Results from two quick and successive measurements in experiment 1 (n ¼ 240) support this notion of reliability with greater statistical power. Even so, experimental designs should consider the use of standardising heterogeneous baseline PPT measures to reflect change against the standard, rather than using absolute levels of measured PPT. This will reduce the effect of gender differences, and other potentially confounding variables, which have been associated with the PPT measurement, for example age (Edwards and Fillingim, 1999; Jensen et al., 1992; Brennum et al., 1989). In conclusion, the results from this study show that there is a significant difference between genders in the mean PPT measured at the first interosseous muscle of at least 12.2 N (1.23 Kg/cm 2), with females showing lower thresholds. The magnitude of this difference was largely unaffected by 14 repeated measurements (seven trains of two repeated stimuli) over a 1 h period and PPT measured in this way is shown to be stable, independent of gender. Nevertheless the magnitude of the observed differences between genders is likely to be at a clinically relevant level. It is therefore recommended that, in order to reduce potential bias in experimental protocols, single gender samples are used or, gender is matched across all experimental groups.
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