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The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults
Pain 114 (2005) 358–363 www.elsevier.com/locate/pain
The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults Douglas J. Frencha,*, Christopher R. Franceb, Janis L. Franceb, Lori F. Arnottb a´
Ecole de psychologie, Universite´ de Moncton, 507 Taillon, Moncton, NB, Canada E1A 3E9 b Department of Psychology, Ohio University, Columbus, OH, USA
Received 3 August 2004; received in revised form 9 December 2004; accepted 28 December 2004
Abstract The nociceptive flexion reflex (NFR) is a polysynaptic withdrawal reflex that occurs in response to painful stimulation. In human studies, NFR responsiveness has been used as a direct measure of nociception as well as an indirect measure of supraspinal modulation of nociceptive transmission. Previous studies have suggested that anxiety may influence NFR responding, and therefore it has been recommended that anxiety be reduced by familiarizing participants with assessment methodology prior to formal NFR assessment. The present study was designed to assess the influence of anxiety on NFR threshold. Using a repeated measures design, 40 men and women completed an NFR threshold assessment twice within session one, and twice again during a second session conducted 24 h later. Within each assessment session, state anxiety was measured at the beginning of the session and immediately following each NFR threshold assessment. Results indicated that although anxiety increased in response to NFR threshold assessment and was positively related to subjective pain reports, anxiety was not related to observed NFR threshold levels. These findings suggest that individual differences in anxiety do not significantly affect NFR threshold level determinations under standard testing conditions. q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Nociceptive flexion reflex; Anxiety; Assessment; Reliability
1. Introduction The nociceptive flexion reflex (NFR) is polysynaptic withdrawal reflex that is widely used in experimental and clinical pain studies (for a review, Skljarevski and Ramadan, 2002). From a research perspective, a primary advantage of the NFR threshold is that it is an objective physiological correlate of nociception that is normally highly correlated with subjective pain threshold. NFR threshold levels have also been used to examine differences in central nervous system modulation of nociceptive transmission both between groups and within individuals. For example, clinical studies have shown that NFR threshold is often lower in individuals with pain disorders as compared to healthy controls (Banic et al., 2004; * Corresponding author. Tel.: C1 506 858 4201; fax: C1 506 858 4768. E-mail address: [email protected] (D.J. French).
Boureau et al., 1977; Desmeules et al., 2003; Langemark et al., 1993; Leroux et al., 1995; Sandrini et al., 2000) and laboratory studies have demonstrated that NFR thresholds are responsive to both pharmacologic and non-pharmacologic analgesic manipulations (Danziger et al., 1998; Kiernan et al., 1995; Petersen-Felix et al., 1994; PetersenFelix et al., 1996; Piguet et al., 1998; Sandrini et al., 1993; Willer and Bathien, 1977; Willer and Ernst, 1986; Willer et al., 1989). In a series of studies on supraspinal modulation of NFR threshold, Willer and colleagues (1983, 1979, 1980a,b) demonstrated that anticipation of very intense electrical shocks (i.e. seven to eight times pain threshold) was associated with increased central hyperexcitability as indexed by a lowering of NFR thresholds. Based in part upon these findings, many investigators subsequently implemented procedures to acquaint participants with the NFR procedures prior to formal threshold assessment to
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.2004.12.034
D.J. French et al. / Pain 114 (2005) 358–363
minimize the potential confounding effects of acute anxiety. Sandrini and colleagues (1993) make this an explicit recommendation in their review of NFR studies and assessment methodology, in which they state “.to reduce emotional stress and strain, the subjects should be clearly informed about the procedure. If possible, a preliminary trial session should be held at least a few hours prior to recording.” Although NFR responding may be altered under conditions of high anxiety, individual differences in acute anxiety on NFR threshold levels under normal testing circumstances has not been tested empirically. Accordingly, the purpose of the present study was to provide a direct assessment of the influence of individual differences in naturally occurring anxiety on NFR threshold in healthy young adults. Using a repeated measures design, participants completed an NFR threshold assessment twice within session one, and twice again during a second session conducted 24 h later. This design allowed us to examine changes in state anxiety related to NFR assessment, the relationship between anxiety and NFR thresholds, and the stability of NFR thresholds over time. Despite the fact that the NFR paradigm has been used in many studies to date, there is presently little published data on reliability of measurement. Therefore, the present study also provides important information on within session and 24 h test–retest reliability of NFR threshold levels.
2. Methods 2.1. Participants The sample included 40 young adult men (nZ20) and women (nZ20) recruited from introductory psychology classes at Ohio University.1 All participants received course credit in return for their participation. 2.2. Scheduling and informed consent Participants were scheduled for two laboratory sessions: days 1 and 2 (24 h later); sessions were scheduled to begin at approximately the same time each day (G1 h). Participants were instructed to refrain from caffeine, nicotine, alcohol, and strenuous exercise for at least 4 h, and from analgesic medication for 24 h before testing. Upon arriving at the laboratory for the first session, informed consent was obtained and then height and weight were measured and recorded. The remainder of the laboratory protocol did not vary between the two testing sessions. 1 The initial subject pool included 53 participants. Out of a total of 212 reflex assessments (53 participants!4 NFR threshold assessments), we recorded a total of 194 NFR thresholds for an overall reflex detection rate of 91.5%. However, to permit analyses to be carried out on consistent sample of participants with detectable reflexes on all four NFR assessments, the final sample had to be reduced to 40 participants.
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2.3. Laboratory testing procedure During each laboratory session, participants completed two assessments of their nociceptive flexion reflex (NFR) thresholds. To begin, participants completed a brief questionnaire to assess adherence to the requested dietary, exercise, and medication restrictions. This was followed by a 10-min seated resting baseline, during which blood pressure and heart rate readings were obtained using a Critikon Dinamap Pro100 blood pressure monitor and an appropriately sized cuff attached to the participants’ non-dominant arm. During the resting baseline, participants completed a State Anxiety Inventory (Spielberger, 1983). The NFR stimulation and recording sites were then prepared and the required electrodes were attached (see details below). Prior to the first NFR threshold assessment, participants rated the level of pain that they anticipated during testing using a 0 (no pain) to 100 (maximum tolerable pain) Verbal Rating Scale. Participants then received a series of four electrocutaneous stimulations of increasing intensity (0, 2, 4, and 6 mA) to acclimatize them to the stimulation that would be used to assess the NFR threshold. After acclimatization participants were again asked to rate their anticipated pain for the upcoming procedure. The first NFR assessment was then carried out (see details below), followed by completion of the McGill Pain Questionnaire-Short Form (MPQ; Melzack, 1987) and a second State Anxiety Inventory. After a 10-min rest period participants completed a second NFR assessment, MPQ, and State Anxiety Inventory. Upon completion of both NFR threshold assessments, the electrodes were removed and, as appropriate, the date and time of the next testing session was confirmed. 2.3.1. Electrode attachment NFR recording and stimulation electrode sites were cleaned and abraded with Omni Prep electrode paste. Electromyographic (EMG) activity was recorded using a DelSys, Bagnoli-2 differential EMG amplifier. For the NFR recording, the active electrode was placed over the left biceps femoris muscle 10 cm superior to the popliteal fossa, with a reference electrode attached over the lateral epicondyle of the femur. EMG was recorded and processed using a CED Micro1401 analog-to-digital converter and Spike2 software. To elicit the NFR, a Nicolet bar electrode (anode inferior) was attached to the left leg over the retromalleolar pathway of the sural nerve. Electrical stimulation was delivered using a Digitimer, DS7A constant-current stimulator. 2.3.2. Nociceptive flexion reflex (NFR) assessment To assess the NFR threshold, participants were seated in a Hi-Seat rehabilitation chair (model 2000) with the left leg rest adjusted to maintain knee flexion at 60G58 from horizontal. Each stimulation trial consisted of a volley of five 1 ms rectangular pulses with a 3 ms interpulse interval (total durationZ17 ms). Using an up–down staircase method (Levitt, 1971), stimulation intensity was increased in 4 mA increments until an NFR was detected (or a maximum intensity of 40 mA was reached) and then was decreased in 2 mA increments until a reflex was no longer detected. Continuing from this intensity, the procedure was then repeated using 1 mA increments until the reflex appeared and disappeared two more times. The NFR threshold (in mA) was defined as the average of the peaks during the last two ascending sequences (current intensity that elicited a reflex) and troughs
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during the last two descending sequences (current intensity that no longer elicited a reflex). NFR occurrence was defined as a mean EMG response in the 90–150 ms post-stimulation interval that exceeded mean EMG activity during the 60 ms pre-stimulation baseline (K65 to K5 ms) interval by at least 1.5 SD. As in previous studies conducted in our laboratory (France and Suchowiecki, 2001; France et al., 2002a,b; Page and France, 1997), the 90–150 ms interval was chosen because it avoids possible contamination by the low-threshold cutaneous flexor reflex, startle reactions, and voluntary movements. During the NFR threshold assessments participants rated the perceived intensity of each stimulation using a Verbal Rating Scale (VRS) with anchors of 1 (sensory threshold), 25 (uncomfortable), 50 (painful), 75 (very painful), and 100 (maximum tolerable). In the event that a participant provided a rating of 100, the procedure was discontinued. Electrical stimulation of the sural nerve was triggered following each VRS rating using a variable interval of 6 s (range 4–8 s) to decrease the likelihood of stimulus predictability. 2.3.3. Questionnaires 2.3.3.1. State anxiety inventory. The Spielberger State Anxiety Inventory (Spielberger, 1983) assesses transitory subjective feelings of apprehension and tension using 20 short statements reflecting how participants feel at the moment. Respondents rate each statement on a four-point scale, from 1 (not at all) to 4 (very much so). This scale is widely used as a research tool and has demonstrated acceptable internal consistency, test–retest reliability, and construct validity (Spielberger, 1983). In the present study, state anxiety scores were found to be normally distributed, with obtained values ranging from 21 to 65. 2.3.3.2. McGill pain questionnaire—short form (MPQ). The MPQ allows quantitative, multidimensional pain ratings to be obtained in a brief period of time (Melzack, 1987). Respondents rate 15 pain descriptors on a scale from 0 (none) to 3 (severe). A sum of all ratings is then used to compute a total pain rating index score. The MPQ is a reliable and valid instrument commonly employed in clinical and research applications (Melzack, 1987). 2.3.3.3. Verbal rating scale (VRS). This scale comprises a vertical line graphic labelled with intensity-denoting adjectives and numbers. Starting from the bottom of the graphic, the scale is labelled 1 (sensory threshold), 25 (uncomfortable), 50 (painful), 75 (very painful), and 100 (maximum tolerable). Verbal rating scales are widely used measures of subjective pain and have been shown to possess adequate reliability and validity (Jensen and Karoly, 1992).
3. Results 3.1. Characteristics of participants Study participants had an average age of 19.2 years (SDZ1.3) and an average body mass index of 23.2 kg/m2 (SDZ3.1). Average resting blood pressure, assessed in the pre-NFR baseline phase of session 1, was 114.1 mmHg
(SDZ10.5) and 65.1 mmHg (SDZ6.4) for systolic and diastolic blood pressure, respectively. 3.2. Changes in anxiety, subjective pain and NFR threshold State anxiety scores, subjective pain ratings and NFR threshold values are presented in Table 1. To examine changes in participant anxiety levels from baseline to the first and second NFR threshold assessments, a 3 Period (preNFR, post-NFR1, post-NFR2)!2 Day (day 1, day 2) multivariate analysis of variance (MANOVA) approach to repeated measures analysis was conducted. Results of this analysis revealed a significant main effect of Period, F(2,38)Z14.0, P!0.01, h2Z0.42, indicating that significant changes in state anxiety occurred within each of the testing sessions. Anxiety scores did not differ across days, F(1,39)Z1.7, PZ0.20, h2Z0.04, nor was there a significant interaction effect, F(2,38)Z1.9, PZ0.16. h2Z0.09. Follow-up analyses on the significant main effect of Period were conducted using paired comparisons of state anxiety scores for each of the three anxiety assessment periods. These analyses revealed that anxiety increased significantly above baseline levels following the first NFR assessment, t(39)Z5.0, P!0.01. State anxiety then decreased significantly following the second NFR assessment, t(39)Z3.8, P!0.01, but remained elevated when compared to initial baseline levels, t(39)Z2.7, P!0.01. Changes in subjective pain ratings reported following the two NFR assessments conducted each testing day were explored using a 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA on both VRS and MPQ ratings. A significant main effect for Day was found for VRS ratings of pain, F(1,39)Z12.6, P!0.01, h2Z0.24 indicating that participants rated the NFR procedure as significantly more painful on day 1. VRS pain ratings provided for the two NFR assessments conducted within each day did not differ significantly, F(1,39)Z1.0, PZ0.32, h 2Z0.03, nor was there Table 1 Means and standard deviations observed for the State Anxiety Inventory (STAI), pain ratings on the McGill Pain Questionnaire (MPQ) and the Verbal Rating Scale (VRS) and NFR thresholds
Session 1 STAI MPQ VRS Pain NFR threshold (mA) Session 2 STAI MPQ VRS Pain NFR threshold (mA)
Baseline
NFR 1
NFR 2
M(SD)
M(SD)
M(SD)
32.4(8.3)
39.0(9.5) 10.4(5.9) 55.2(28.7) 18.9(10.1)
35.9(9.4) 10.1(6.8) 53.8(27.3) 19.9(9.9)
32.8(8.4)
36.6(10.3) 9.6(6.7) 46.2(27.3) 18.9(9.6)
34.8(8.8) 9.8(6.8) 44.1(25.1) 20.4(10.3)
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Table 2 Correlations between State Anxiety Inventory (STAI) scores obtained at baseline and after each NFR assessment with pain ratings and NFR thresholds MPQ
Day 1 STAI-baseline STAI-NFR1 STAI-NFR2 Day 2 STAI-baseline STAI-NFR1 STAI-NFR2
VRS
NFR Threshold
NFR1
NFR2
NFR1
NFR2
NFR1
NFR2
K0.04 0.62** –
K0.02 – 0.64**
K0.02 0.43** –
0.12 – 0.52**
0.03 0.09 –
0.13 – 0.17
0.47** 0.60** –
0.33* – 0.60**
0.34* 0.57** –
0.29 – 0.69**
0.09 0.29 –
K0.05 – 0.20
MPQ, McGill Pain Questionnaire; VRS, Verbal Rating Scale; * P!0.05; ** P!0.01.
a significant interaction effect, F(2,38)Z0.03, PZ0.87, h2Z0.00. A similar 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA conducted on MPQ ratings revealed no significant main effects for Day, F(1,39)Z0.81, PZ0.37, h2Z0.14, Period, F(1,39)Z 0.02, PZ0.90, h2Z0.00, and no significant interaction effect, F(1,39)Z0.34, PZ0.56, h2Z0.01. These results indicate that retrospective evaluations of NFR procedural pain did not change significantly from one day to the other or within testing day. A 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA on NFR threshold revealed that the levels of stimulation required to elicit the reflex were not significantly different when examined both within each testing session, F(1,39)Z3.5, PZ0.07, h2Z0.08 and across testing days, F(1,39)Z0.06, PZ0.81, h2Z0.00. There was no significant interaction effect, F(1,39)Z2.33, PZ0.63, h2Z0.01. Taken together these results suggest that NFR thresholds are stable over time. 3.3. Correlational analyses Pearson correlational analyses were used to examine the degree of association between measures of anxiety, self-reported pain and NFR responding. These analyses were conducted using both baseline (i.e. pre-NFR) anxiety measures, as well as the ratings of anxiety obtained immediately after each NFR threshold assessment. As shown in Table 2, anxiety scores were significantly related to subjective pain ratings during NFR assessment (VRS) as well as retrospective pain ratings (MPQ), but were not significantly related to NFR thresholds. This was also true of baseline anxiety ratings on day 2 but not day 1. Further analyses revealed that within-subject changes in anxiety were not significantly correlated with within-subject changes in NFR. To assess the relationship between resting blood pressure and nociceptive responses, correlations were conducted between baseline systolic blood pressure levels recorded on day 1 and NFR thresholds and pain ratings obtained each day. Results indicated that higher systolic blood pressure was associated with higher NFR thresholds on
day 1 (rZ0.37 and 0.43, P!0.05) and day 2 (rZ0.34 and 0.38, P!0.05). However, resting blood pressure was not significantly related to the procedural pain ratings on either day (rsZ0.02–0.15). Finally, correlational analyses were conducted to examine the stability of NFR thresholds both within and across sessions. Results indicated that within-session NFR thresholds were reliable on day 1, rZ0.83, P!0.001, and day 2, rZ0.80, P!0.001. Reliability of NFR thresholds across testing days was assessed by examining the correlation between average threshold values calculated for day 1 (MZ19.4; SDZ9.6) and day 2 (MZ19.6; SDZ9.4). These mean session thresholds were also positively correlated (rZ0.73, P!0.001), indicating stability over a 24 h interval.
4. Discussion The primary goal of the present study was to investigate the influence of individual differences in self-reported anxiety on NFR responding. Previous studies have suggested that high levels of state anxiety may increase central hyperexcitability as indexed by a lowering of NFR thresholds (Willer et al., 1979; 1980a,b). These early findings prompted the recommendation that routine efforts be made to minimize anxiety prior to NFR testing to reduce undesirable variability (Sandrini et al., 1993). The results of the present study suggest that state anxiety fluctuated during NFR testing and was related to subjective ratings of pain within each of the testing sessions. However, state anxiety was not related to NFR threshold values. Previous studies that have reported a significant relationship between anxiety and lowered NFR thresholds were specifically designed to evoke high levels of arousal by having participants anticipate extremely painful electrocutaneous shocks that were seven to eight times pain threshold (Willer et al., 1979, 1980a,b). In contrast, the present data suggest that under standard NFR assessment conditions it may not be necessary to control for naturally occurring individual differences in state anxiety levels. As noted above, concern over the potential effects of acute anxiety have also led researchers to ensure participant
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familiarization with the NFR equipment and procedures, often in a separate laboratory session conducted prior to actual testing of the reflex. Our findings suggest that this may not be necessary to permit a reliable assessment of NFR threshold. Specifically, our repeated NFR assessments revealed that threshold levels did not change significantly from the first to the second day of testing, suggesting that prior exposure does not affect the observed threshold levels on the second day of testing. Further, although anxiety showed modest increases within each testing session, results indicated that anxiety levels did not differ significantly between the first and second day of testing. Thus, prior exposure to the procedures 24 h earlier does not appear to reduce baseline anxiety levels or attenuate the observed changes in anxiety during the second day of testing. In sum, it appears that NFR thresholds are robust to modest levels of state anxiety. However, it must be noted that similar evidence will need to be developed and reported in the various pain and non-pain patient populations that have been assessed using the NFR paradigm. Similarly, the present findings may not extend to individuals with high levels of clinical or experimental levels of anxiety. A potentially important contribution of the present study is that it highlights the fact that NFR threshold does not necessarily respond to the same factors that influence pain. Although NFR has been widely used in pain research because it tends to be positively correlated with reported pain, NFR is a measure of nociceptive responding and not the subjective experience of pain. Thus, similar nociceptive input may produce different levels of subjective pain across individuals (and within individuals over time) due to a variety of psychosocial factors; however, it does not necessarily follow that there must be a corresponding change in descending modulation of nociceptive transmission through spinal gating mechanisms. In the case of the present study, it is conceivable that elevated anxiety may contribute to a heightened pain experience without affecting descending modulation. Studies of pain catastrophizing (e.g. France et al., 2002a; 2004) have shown that those who perceive electrocutaneous stimulation as more threatening and/or who are less able to distract themselves during NFR assessment report higher levels of NFR procedural pain independent of NFR responding. Similarly, in the present study higher anxiety was associated with higher pain reports but not lower NFR thresholds. While state anxiety did not relate to NFR responding in the present study, it is nonetheless desirable to conduct the NFR assessment procedures in such a way as to help minimize participant anxiety during testing. Specifically, because anxiety is related to the participant’s subjective reports of electrocutaneous pain, efforts to minimize anxiety may increase participants’ ability or willingness to reach the subjectively painful levels of stimulation that are at times necessary to elicit the NFR response. A secondary goal of the present study was to examine both short-term (within-session) and longer term (24 h)
NFR threshold reliability data. Despite the fact that the NFR threshold has been widely used in clinical and experimental studies of pain, to our knowledge there are no existing reports on the test–retest reliability of NFR thresholds within and across sessions. In the present study, NFR thresholds demonstrated test–retest reliability of 0.80–0.83 within the same testing session, and 0.73 across a 24-h interval. This evidence of temporal stability has important implications for studies employing pharmacological agents or other interventions designed to modulate nociceptive responding. If within-subject changes in NFR threshold are to be attributed to a given manipulation, it is important that data are available showing that NFR thresholds remain stable over time. The present findings thus provide important empirical support for the temporal stability of NFR thresholds. There is still a need for additional information on the long-term stability of NFR thresholds over weeks to months so that this paradigm can be applied with confidence in studies that examine the impact of medication or other manipulations that require more than 24 h to produce antinociceptive effects (e.g. SSRIs). Finally, given existing evidence of a positive relationship between blood pressure and hypoalgesia (France, 1999), we examined our current data for evidence of a relationship between resting blood pressure and NFR threshold and subjective pain ratings. Consistent with prior evidence from our laboratory (France et al., 2002b; Page and France, 1997), higher resting systolic blood pressure was significantly related to higher NFR threshold levels. Interestingly, blood pressure was not significantly related to pain ratings, which is similar to the findings that we obtained in our most recent study after controlling for sex differences in pain ratings (France et al., 2002b). The goals of the present study were to examine the influence of anxiety on NFR responding and to provide test– retest reliability data for NFR thresholds. Overall, the present findings suggest that, unlike subjective reports of pain which are positively associated with anxiety, NFR responding is unaffected by modest fluctuations in state anxiety. Accordingly, previously recommended efforts to reduce participant anxiety by prior familiarization with the NFR procedure may not be necessary. NFR thresholds also demonstrated good short-term and 24-h test–retest reliability. Taken together, these findings contribute additional support for the use of NFR thresholds as a reliable measure of nociception in humans.
Acknowledgements This work was supported by a grant from the Canadian Institutes of Health Research awarded to Douglas French (IDG-52125) and a grant from the National Institutes of Health awarded to Christopher France (NHLBI R01 HL64794).
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The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults Douglas J. Frencha,*, Christopher R. Franceb, Janis L. Franceb, Lori F. Arnottb a´
Ecole de psychologie, Universite´ de Moncton, 507 Taillon, Moncton, NB, Canada E1A 3E9 b Department of Psychology, Ohio University, Columbus, OH, USA
Received 3 August 2004; received in revised form 9 December 2004; accepted 28 December 2004
Abstract The nociceptive flexion reflex (NFR) is a polysynaptic withdrawal reflex that occurs in response to painful stimulation. In human studies, NFR responsiveness has been used as a direct measure of nociception as well as an indirect measure of supraspinal modulation of nociceptive transmission. Previous studies have suggested that anxiety may influence NFR responding, and therefore it has been recommended that anxiety be reduced by familiarizing participants with assessment methodology prior to formal NFR assessment. The present study was designed to assess the influence of anxiety on NFR threshold. Using a repeated measures design, 40 men and women completed an NFR threshold assessment twice within session one, and twice again during a second session conducted 24 h later. Within each assessment session, state anxiety was measured at the beginning of the session and immediately following each NFR threshold assessment. Results indicated that although anxiety increased in response to NFR threshold assessment and was positively related to subjective pain reports, anxiety was not related to observed NFR threshold levels. These findings suggest that individual differences in anxiety do not significantly affect NFR threshold level determinations under standard testing conditions. q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Nociceptive flexion reflex; Anxiety; Assessment; Reliability
1. Introduction The nociceptive flexion reflex (NFR) is polysynaptic withdrawal reflex that is widely used in experimental and clinical pain studies (for a review, Skljarevski and Ramadan, 2002). From a research perspective, a primary advantage of the NFR threshold is that it is an objective physiological correlate of nociception that is normally highly correlated with subjective pain threshold. NFR threshold levels have also been used to examine differences in central nervous system modulation of nociceptive transmission both between groups and within individuals. For example, clinical studies have shown that NFR threshold is often lower in individuals with pain disorders as compared to healthy controls (Banic et al., 2004; * Corresponding author. Tel.: C1 506 858 4201; fax: C1 506 858 4768. E-mail address: [email protected] (D.J. French).
Boureau et al., 1977; Desmeules et al., 2003; Langemark et al., 1993; Leroux et al., 1995; Sandrini et al., 2000) and laboratory studies have demonstrated that NFR thresholds are responsive to both pharmacologic and non-pharmacologic analgesic manipulations (Danziger et al., 1998; Kiernan et al., 1995; Petersen-Felix et al., 1994; PetersenFelix et al., 1996; Piguet et al., 1998; Sandrini et al., 1993; Willer and Bathien, 1977; Willer and Ernst, 1986; Willer et al., 1989). In a series of studies on supraspinal modulation of NFR threshold, Willer and colleagues (1983, 1979, 1980a,b) demonstrated that anticipation of very intense electrical shocks (i.e. seven to eight times pain threshold) was associated with increased central hyperexcitability as indexed by a lowering of NFR thresholds. Based in part upon these findings, many investigators subsequently implemented procedures to acquaint participants with the NFR procedures prior to formal threshold assessment to
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.2004.12.034
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minimize the potential confounding effects of acute anxiety. Sandrini and colleagues (1993) make this an explicit recommendation in their review of NFR studies and assessment methodology, in which they state “.to reduce emotional stress and strain, the subjects should be clearly informed about the procedure. If possible, a preliminary trial session should be held at least a few hours prior to recording.” Although NFR responding may be altered under conditions of high anxiety, individual differences in acute anxiety on NFR threshold levels under normal testing circumstances has not been tested empirically. Accordingly, the purpose of the present study was to provide a direct assessment of the influence of individual differences in naturally occurring anxiety on NFR threshold in healthy young adults. Using a repeated measures design, participants completed an NFR threshold assessment twice within session one, and twice again during a second session conducted 24 h later. This design allowed us to examine changes in state anxiety related to NFR assessment, the relationship between anxiety and NFR thresholds, and the stability of NFR thresholds over time. Despite the fact that the NFR paradigm has been used in many studies to date, there is presently little published data on reliability of measurement. Therefore, the present study also provides important information on within session and 24 h test–retest reliability of NFR threshold levels.
2. Methods 2.1. Participants The sample included 40 young adult men (nZ20) and women (nZ20) recruited from introductory psychology classes at Ohio University.1 All participants received course credit in return for their participation. 2.2. Scheduling and informed consent Participants were scheduled for two laboratory sessions: days 1 and 2 (24 h later); sessions were scheduled to begin at approximately the same time each day (G1 h). Participants were instructed to refrain from caffeine, nicotine, alcohol, and strenuous exercise for at least 4 h, and from analgesic medication for 24 h before testing. Upon arriving at the laboratory for the first session, informed consent was obtained and then height and weight were measured and recorded. The remainder of the laboratory protocol did not vary between the two testing sessions. 1 The initial subject pool included 53 participants. Out of a total of 212 reflex assessments (53 participants!4 NFR threshold assessments), we recorded a total of 194 NFR thresholds for an overall reflex detection rate of 91.5%. However, to permit analyses to be carried out on consistent sample of participants with detectable reflexes on all four NFR assessments, the final sample had to be reduced to 40 participants.
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2.3. Laboratory testing procedure During each laboratory session, participants completed two assessments of their nociceptive flexion reflex (NFR) thresholds. To begin, participants completed a brief questionnaire to assess adherence to the requested dietary, exercise, and medication restrictions. This was followed by a 10-min seated resting baseline, during which blood pressure and heart rate readings were obtained using a Critikon Dinamap Pro100 blood pressure monitor and an appropriately sized cuff attached to the participants’ non-dominant arm. During the resting baseline, participants completed a State Anxiety Inventory (Spielberger, 1983). The NFR stimulation and recording sites were then prepared and the required electrodes were attached (see details below). Prior to the first NFR threshold assessment, participants rated the level of pain that they anticipated during testing using a 0 (no pain) to 100 (maximum tolerable pain) Verbal Rating Scale. Participants then received a series of four electrocutaneous stimulations of increasing intensity (0, 2, 4, and 6 mA) to acclimatize them to the stimulation that would be used to assess the NFR threshold. After acclimatization participants were again asked to rate their anticipated pain for the upcoming procedure. The first NFR assessment was then carried out (see details below), followed by completion of the McGill Pain Questionnaire-Short Form (MPQ; Melzack, 1987) and a second State Anxiety Inventory. After a 10-min rest period participants completed a second NFR assessment, MPQ, and State Anxiety Inventory. Upon completion of both NFR threshold assessments, the electrodes were removed and, as appropriate, the date and time of the next testing session was confirmed. 2.3.1. Electrode attachment NFR recording and stimulation electrode sites were cleaned and abraded with Omni Prep electrode paste. Electromyographic (EMG) activity was recorded using a DelSys, Bagnoli-2 differential EMG amplifier. For the NFR recording, the active electrode was placed over the left biceps femoris muscle 10 cm superior to the popliteal fossa, with a reference electrode attached over the lateral epicondyle of the femur. EMG was recorded and processed using a CED Micro1401 analog-to-digital converter and Spike2 software. To elicit the NFR, a Nicolet bar electrode (anode inferior) was attached to the left leg over the retromalleolar pathway of the sural nerve. Electrical stimulation was delivered using a Digitimer, DS7A constant-current stimulator. 2.3.2. Nociceptive flexion reflex (NFR) assessment To assess the NFR threshold, participants were seated in a Hi-Seat rehabilitation chair (model 2000) with the left leg rest adjusted to maintain knee flexion at 60G58 from horizontal. Each stimulation trial consisted of a volley of five 1 ms rectangular pulses with a 3 ms interpulse interval (total durationZ17 ms). Using an up–down staircase method (Levitt, 1971), stimulation intensity was increased in 4 mA increments until an NFR was detected (or a maximum intensity of 40 mA was reached) and then was decreased in 2 mA increments until a reflex was no longer detected. Continuing from this intensity, the procedure was then repeated using 1 mA increments until the reflex appeared and disappeared two more times. The NFR threshold (in mA) was defined as the average of the peaks during the last two ascending sequences (current intensity that elicited a reflex) and troughs
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during the last two descending sequences (current intensity that no longer elicited a reflex). NFR occurrence was defined as a mean EMG response in the 90–150 ms post-stimulation interval that exceeded mean EMG activity during the 60 ms pre-stimulation baseline (K65 to K5 ms) interval by at least 1.5 SD. As in previous studies conducted in our laboratory (France and Suchowiecki, 2001; France et al., 2002a,b; Page and France, 1997), the 90–150 ms interval was chosen because it avoids possible contamination by the low-threshold cutaneous flexor reflex, startle reactions, and voluntary movements. During the NFR threshold assessments participants rated the perceived intensity of each stimulation using a Verbal Rating Scale (VRS) with anchors of 1 (sensory threshold), 25 (uncomfortable), 50 (painful), 75 (very painful), and 100 (maximum tolerable). In the event that a participant provided a rating of 100, the procedure was discontinued. Electrical stimulation of the sural nerve was triggered following each VRS rating using a variable interval of 6 s (range 4–8 s) to decrease the likelihood of stimulus predictability. 2.3.3. Questionnaires 2.3.3.1. State anxiety inventory. The Spielberger State Anxiety Inventory (Spielberger, 1983) assesses transitory subjective feelings of apprehension and tension using 20 short statements reflecting how participants feel at the moment. Respondents rate each statement on a four-point scale, from 1 (not at all) to 4 (very much so). This scale is widely used as a research tool and has demonstrated acceptable internal consistency, test–retest reliability, and construct validity (Spielberger, 1983). In the present study, state anxiety scores were found to be normally distributed, with obtained values ranging from 21 to 65. 2.3.3.2. McGill pain questionnaire—short form (MPQ). The MPQ allows quantitative, multidimensional pain ratings to be obtained in a brief period of time (Melzack, 1987). Respondents rate 15 pain descriptors on a scale from 0 (none) to 3 (severe). A sum of all ratings is then used to compute a total pain rating index score. The MPQ is a reliable and valid instrument commonly employed in clinical and research applications (Melzack, 1987). 2.3.3.3. Verbal rating scale (VRS). This scale comprises a vertical line graphic labelled with intensity-denoting adjectives and numbers. Starting from the bottom of the graphic, the scale is labelled 1 (sensory threshold), 25 (uncomfortable), 50 (painful), 75 (very painful), and 100 (maximum tolerable). Verbal rating scales are widely used measures of subjective pain and have been shown to possess adequate reliability and validity (Jensen and Karoly, 1992).
3. Results 3.1. Characteristics of participants Study participants had an average age of 19.2 years (SDZ1.3) and an average body mass index of 23.2 kg/m2 (SDZ3.1). Average resting blood pressure, assessed in the pre-NFR baseline phase of session 1, was 114.1 mmHg
(SDZ10.5) and 65.1 mmHg (SDZ6.4) for systolic and diastolic blood pressure, respectively. 3.2. Changes in anxiety, subjective pain and NFR threshold State anxiety scores, subjective pain ratings and NFR threshold values are presented in Table 1. To examine changes in participant anxiety levels from baseline to the first and second NFR threshold assessments, a 3 Period (preNFR, post-NFR1, post-NFR2)!2 Day (day 1, day 2) multivariate analysis of variance (MANOVA) approach to repeated measures analysis was conducted. Results of this analysis revealed a significant main effect of Period, F(2,38)Z14.0, P!0.01, h2Z0.42, indicating that significant changes in state anxiety occurred within each of the testing sessions. Anxiety scores did not differ across days, F(1,39)Z1.7, PZ0.20, h2Z0.04, nor was there a significant interaction effect, F(2,38)Z1.9, PZ0.16. h2Z0.09. Follow-up analyses on the significant main effect of Period were conducted using paired comparisons of state anxiety scores for each of the three anxiety assessment periods. These analyses revealed that anxiety increased significantly above baseline levels following the first NFR assessment, t(39)Z5.0, P!0.01. State anxiety then decreased significantly following the second NFR assessment, t(39)Z3.8, P!0.01, but remained elevated when compared to initial baseline levels, t(39)Z2.7, P!0.01. Changes in subjective pain ratings reported following the two NFR assessments conducted each testing day were explored using a 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA on both VRS and MPQ ratings. A significant main effect for Day was found for VRS ratings of pain, F(1,39)Z12.6, P!0.01, h2Z0.24 indicating that participants rated the NFR procedure as significantly more painful on day 1. VRS pain ratings provided for the two NFR assessments conducted within each day did not differ significantly, F(1,39)Z1.0, PZ0.32, h 2Z0.03, nor was there Table 1 Means and standard deviations observed for the State Anxiety Inventory (STAI), pain ratings on the McGill Pain Questionnaire (MPQ) and the Verbal Rating Scale (VRS) and NFR thresholds
Session 1 STAI MPQ VRS Pain NFR threshold (mA) Session 2 STAI MPQ VRS Pain NFR threshold (mA)
Baseline
NFR 1
NFR 2
M(SD)
M(SD)
M(SD)
32.4(8.3)
39.0(9.5) 10.4(5.9) 55.2(28.7) 18.9(10.1)
35.9(9.4) 10.1(6.8) 53.8(27.3) 19.9(9.9)
32.8(8.4)
36.6(10.3) 9.6(6.7) 46.2(27.3) 18.9(9.6)
34.8(8.8) 9.8(6.8) 44.1(25.1) 20.4(10.3)
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Table 2 Correlations between State Anxiety Inventory (STAI) scores obtained at baseline and after each NFR assessment with pain ratings and NFR thresholds MPQ
Day 1 STAI-baseline STAI-NFR1 STAI-NFR2 Day 2 STAI-baseline STAI-NFR1 STAI-NFR2
VRS
NFR Threshold
NFR1
NFR2
NFR1
NFR2
NFR1
NFR2
K0.04 0.62** –
K0.02 – 0.64**
K0.02 0.43** –
0.12 – 0.52**
0.03 0.09 –
0.13 – 0.17
0.47** 0.60** –
0.33* – 0.60**
0.34* 0.57** –
0.29 – 0.69**
0.09 0.29 –
K0.05 – 0.20
MPQ, McGill Pain Questionnaire; VRS, Verbal Rating Scale; * P!0.05; ** P!0.01.
a significant interaction effect, F(2,38)Z0.03, PZ0.87, h2Z0.00. A similar 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA conducted on MPQ ratings revealed no significant main effects for Day, F(1,39)Z0.81, PZ0.37, h2Z0.14, Period, F(1,39)Z 0.02, PZ0.90, h2Z0.00, and no significant interaction effect, F(1,39)Z0.34, PZ0.56, h2Z0.01. These results indicate that retrospective evaluations of NFR procedural pain did not change significantly from one day to the other or within testing day. A 2 Period (post-NFR1, post-NFR2)!2 Day (day 1, day 2) repeated measures MANOVA on NFR threshold revealed that the levels of stimulation required to elicit the reflex were not significantly different when examined both within each testing session, F(1,39)Z3.5, PZ0.07, h2Z0.08 and across testing days, F(1,39)Z0.06, PZ0.81, h2Z0.00. There was no significant interaction effect, F(1,39)Z2.33, PZ0.63, h2Z0.01. Taken together these results suggest that NFR thresholds are stable over time. 3.3. Correlational analyses Pearson correlational analyses were used to examine the degree of association between measures of anxiety, self-reported pain and NFR responding. These analyses were conducted using both baseline (i.e. pre-NFR) anxiety measures, as well as the ratings of anxiety obtained immediately after each NFR threshold assessment. As shown in Table 2, anxiety scores were significantly related to subjective pain ratings during NFR assessment (VRS) as well as retrospective pain ratings (MPQ), but were not significantly related to NFR thresholds. This was also true of baseline anxiety ratings on day 2 but not day 1. Further analyses revealed that within-subject changes in anxiety were not significantly correlated with within-subject changes in NFR. To assess the relationship between resting blood pressure and nociceptive responses, correlations were conducted between baseline systolic blood pressure levels recorded on day 1 and NFR thresholds and pain ratings obtained each day. Results indicated that higher systolic blood pressure was associated with higher NFR thresholds on
day 1 (rZ0.37 and 0.43, P!0.05) and day 2 (rZ0.34 and 0.38, P!0.05). However, resting blood pressure was not significantly related to the procedural pain ratings on either day (rsZ0.02–0.15). Finally, correlational analyses were conducted to examine the stability of NFR thresholds both within and across sessions. Results indicated that within-session NFR thresholds were reliable on day 1, rZ0.83, P!0.001, and day 2, rZ0.80, P!0.001. Reliability of NFR thresholds across testing days was assessed by examining the correlation between average threshold values calculated for day 1 (MZ19.4; SDZ9.6) and day 2 (MZ19.6; SDZ9.4). These mean session thresholds were also positively correlated (rZ0.73, P!0.001), indicating stability over a 24 h interval.
4. Discussion The primary goal of the present study was to investigate the influence of individual differences in self-reported anxiety on NFR responding. Previous studies have suggested that high levels of state anxiety may increase central hyperexcitability as indexed by a lowering of NFR thresholds (Willer et al., 1979; 1980a,b). These early findings prompted the recommendation that routine efforts be made to minimize anxiety prior to NFR testing to reduce undesirable variability (Sandrini et al., 1993). The results of the present study suggest that state anxiety fluctuated during NFR testing and was related to subjective ratings of pain within each of the testing sessions. However, state anxiety was not related to NFR threshold values. Previous studies that have reported a significant relationship between anxiety and lowered NFR thresholds were specifically designed to evoke high levels of arousal by having participants anticipate extremely painful electrocutaneous shocks that were seven to eight times pain threshold (Willer et al., 1979, 1980a,b). In contrast, the present data suggest that under standard NFR assessment conditions it may not be necessary to control for naturally occurring individual differences in state anxiety levels. As noted above, concern over the potential effects of acute anxiety have also led researchers to ensure participant
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familiarization with the NFR equipment and procedures, often in a separate laboratory session conducted prior to actual testing of the reflex. Our findings suggest that this may not be necessary to permit a reliable assessment of NFR threshold. Specifically, our repeated NFR assessments revealed that threshold levels did not change significantly from the first to the second day of testing, suggesting that prior exposure does not affect the observed threshold levels on the second day of testing. Further, although anxiety showed modest increases within each testing session, results indicated that anxiety levels did not differ significantly between the first and second day of testing. Thus, prior exposure to the procedures 24 h earlier does not appear to reduce baseline anxiety levels or attenuate the observed changes in anxiety during the second day of testing. In sum, it appears that NFR thresholds are robust to modest levels of state anxiety. However, it must be noted that similar evidence will need to be developed and reported in the various pain and non-pain patient populations that have been assessed using the NFR paradigm. Similarly, the present findings may not extend to individuals with high levels of clinical or experimental levels of anxiety. A potentially important contribution of the present study is that it highlights the fact that NFR threshold does not necessarily respond to the same factors that influence pain. Although NFR has been widely used in pain research because it tends to be positively correlated with reported pain, NFR is a measure of nociceptive responding and not the subjective experience of pain. Thus, similar nociceptive input may produce different levels of subjective pain across individuals (and within individuals over time) due to a variety of psychosocial factors; however, it does not necessarily follow that there must be a corresponding change in descending modulation of nociceptive transmission through spinal gating mechanisms. In the case of the present study, it is conceivable that elevated anxiety may contribute to a heightened pain experience without affecting descending modulation. Studies of pain catastrophizing (e.g. France et al., 2002a; 2004) have shown that those who perceive electrocutaneous stimulation as more threatening and/or who are less able to distract themselves during NFR assessment report higher levels of NFR procedural pain independent of NFR responding. Similarly, in the present study higher anxiety was associated with higher pain reports but not lower NFR thresholds. While state anxiety did not relate to NFR responding in the present study, it is nonetheless desirable to conduct the NFR assessment procedures in such a way as to help minimize participant anxiety during testing. Specifically, because anxiety is related to the participant’s subjective reports of electrocutaneous pain, efforts to minimize anxiety may increase participants’ ability or willingness to reach the subjectively painful levels of stimulation that are at times necessary to elicit the NFR response. A secondary goal of the present study was to examine both short-term (within-session) and longer term (24 h)
NFR threshold reliability data. Despite the fact that the NFR threshold has been widely used in clinical and experimental studies of pain, to our knowledge there are no existing reports on the test–retest reliability of NFR thresholds within and across sessions. In the present study, NFR thresholds demonstrated test–retest reliability of 0.80–0.83 within the same testing session, and 0.73 across a 24-h interval. This evidence of temporal stability has important implications for studies employing pharmacological agents or other interventions designed to modulate nociceptive responding. If within-subject changes in NFR threshold are to be attributed to a given manipulation, it is important that data are available showing that NFR thresholds remain stable over time. The present findings thus provide important empirical support for the temporal stability of NFR thresholds. There is still a need for additional information on the long-term stability of NFR thresholds over weeks to months so that this paradigm can be applied with confidence in studies that examine the impact of medication or other manipulations that require more than 24 h to produce antinociceptive effects (e.g. SSRIs). Finally, given existing evidence of a positive relationship between blood pressure and hypoalgesia (France, 1999), we examined our current data for evidence of a relationship between resting blood pressure and NFR threshold and subjective pain ratings. Consistent with prior evidence from our laboratory (France et al., 2002b; Page and France, 1997), higher resting systolic blood pressure was significantly related to higher NFR threshold levels. Interestingly, blood pressure was not significantly related to pain ratings, which is similar to the findings that we obtained in our most recent study after controlling for sex differences in pain ratings (France et al., 2002b). The goals of the present study were to examine the influence of anxiety on NFR responding and to provide test– retest reliability data for NFR thresholds. Overall, the present findings suggest that, unlike subjective reports of pain which are positively associated with anxiety, NFR responding is unaffected by modest fluctuations in state anxiety. Accordingly, previously recommended efforts to reduce participant anxiety by prior familiarization with the NFR procedure may not be necessary. NFR thresholds also demonstrated good short-term and 24-h test–retest reliability. Taken together, these findings contribute additional support for the use of NFR thresholds as a reliable measure of nociception in humans.
Acknowledgements This work was supported by a grant from the Canadian Institutes of Health Research awarded to Douglas French (IDG-52125) and a grant from the National Institutes of Health awarded to Christopher France (NHLBI R01 HL64794).
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