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Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation
International Journal of Psychophysiology 27 Ž1997. 161]166
Short communication
Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation Michelle Pfleeger a , Patricia A. Stranevaa , Roger B. Fillingimb , William Maixner c , Susan S. Girdler a,U a
Departments of Psychiatry and Psychology, Medical Research Building A, Uni®ersity of North Carolina, Chapel Hill, NC 27599-7175, USA b Department of Psychology, Uni®ersity of Alabama, Birmingham, AL, USA c Endodontics Department, Uni®ersity of North Carolina, Chapel Hill, NC, USA Received 25 March 1997; revised 20 May 1997; accepted 1 July 1997
Abstract Eleven women were tested twice for ischemic pain sensitivity; once during their follicular phase ŽDays 4]9. and once during their mid-late luteal phase Ž5]10 days after ovulation. of a confirmed ovulatory cycle. Additionally, in order to examine blood pressure-related hypoalgesic effects, each had 3]4 clinic blood pressures determined during an initial screening interview and each also completed a daily symptom calendar for one complete menstrual cycle prior to testing in order to investigate relationships between ‘real-life’ symptomatology and laboratory-induced pain sensitivity. Results revealed significantly shorter pain tolerance times and marginally shorter pain threshold times in the luteal vs. follicular phase, while verbal descriptors of pain intensity Žsensory. and pain unpleasantness Žaffective. did not vary with cycle phase. Clinic blood pressures were positively correlated with pain threshold and tolerance times assessed during both cycle phases. Real-life physical symptom ratings were predictive of laboratory pain intensity ratings during the follicular phase and tended to predict unpleasantness ratings during both phases. These results not only confirm recent reports of greater sensitivity to ischemic pain in women during the luteal phase of their cycle, but extend the literature by demonstrating pressure-related hypoalgesic effects in women during both cycle phases. Q 1997 Elsevier Science B.V. Keywords: Menstrual cycle; Blood pressure; Ischemic pain sensitivity
U
Corresponding author.
0167-8760r97r$17.00 Q 1997 Published by Elsevier Science B.V. All rights reserved. PII S0167-8760Ž97. 00058-5
162
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
Both clinical Že.g. Bush et al., 1993; Eggen, 1993; Honkasalo et al., 1993. and experimental Že.g. Fillingim and Maixner, 1995. evidence indicate that women are more sensitive to pain than men. While animal studies suggest that female sex hormones may contribute to this increased sensitivity Že.g. Drury and Gold, 1977; Ryan and Maier, 1988; Frye et al., 1992, 1993., studies examining sensitivity to pain at different points in the female menstrual cycle have yielded mixed results Že.g. Tedford et al., 1977; Goolkasian, 1983; Veith et al., 1984; Hapidou and De Catanzaro, 1988.. These contradictory findings are likely attributable to methodological issues, especially differences in pain induction methods and reliance on calendar method for determining cycle phase. Recently, Fillingim et al. Ž1997. attempted to address these issues by testing women for both thermal and ischemic pain sensitivity at three points in confirmed ovulatory cycles. While they found no cycle effects on thermal pain sensitivity, they did find that the luteal phase of the cycle, when both estrogens and progesterone are elevated, was associated with greater sensitivity to ischemic pain than the follicular, low hormone, phase. Another pain modulatory mechanism which has been well documented concerns arterial blood pressure ŽBP.. Inverse relationships between BP and pain sensitivity have been observed in both hypertensive Že.g. Rosa et al., 1986; Sheps et al., 1992. and normotensive humans Že.g. Bruehl et al., 1992; McCubbin and Bruehl, 1994.. However, only a small handful of studies have examined pressure-related hypoalgesia in women, yielding mixed results ŽMaixner and Humphrey, 1993; Fillingim and Maixner, 1996; Bragdon et al., 1997.. Thus, the purpose of this study was to reconfirm the findings of greater ischemic pain sensitivity in the luteal vs. follicular phase of ovulatory cycles, but also to extend the previous literature on pressure-related algesia by examining the relationship between clinic blood pressure and pain sensitivity in women. Informed consent was obtained from 11 women at an initial screening visit Ž6]8 weeks prior to testing., after which a health questionnaire was completed and 3]4 clinic blood pressures were
taken by a research nurse, using the subject’s non-dominant arm, spaced at 1 min intervals. The average of these measures constituted clinic blood pressures and were also used to derive mean arterial pressure ŽMAP., based on the standard formula: MAP s ŽSBP y DBP.r3 q DBP. All women were normotensive, reported themselves to be in good health and not taking prescription medication, including oral contraceptives. The women were, on average, 33 years of age Ž29]44., of average height Ž165.8 cm. and weight Ž66.3 kg. and all but one ŽAsian American. were European American. Three women were cigarette smokers, none reported greater than social use of alcohol and three indicated that one or more of their biological parents were hypertensive. Prior to testing, each was asked to complete the Prospective Record of the Impact and Severity of Menstrual Symptoms ŽPRISM. calendar ŽReid, 1985. on a daily basis for one menstrual cycle prior to testing. This calendar allows for the quantification of the severity of a variety of physical Že.g. headache, bloating. and emotional symptoms Že.g. depressed, anxious. during the menstrual cycle, using a 0]3 numerical scale. The PRISM calendar was employed to confirm average menstrual cycle length and to exclude from participation any woman with chronic affective or physical symptomatology, or with severe premenstrual syndrome. Once entered into protocol, the PRISM calendar data served as a measure with which to assess the relationship between experimental pain sensitivity and ‘real-life’ symptomatology. Each subject was tested twice, once during her early follicular phase ŽDays 4]9. and once during her mid-to-late luteal phase Ž5]10 days after ovulation., counterbalancing order of testing. Ovulation was confirmed with the One-Step Clearplan Easy W ovulation test, which detects urinary luteinizing hormone surge occurring 24]36 h prior to ovulation. Each subject returned her positive test stick to verify the result. Testing involved an initial 15 min, supine rest period, followed by the submaximal effort tourniquet test Žsee Maixner et al., 1990.. Briefly, this procedure induces ischemic arm pain by occluding the arm with a standard blood pressure cuff,
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
inflated to 200 mmHg, and having the subjects perform 20 hand grip exercises at 30% of their maximum. Subjects were asked to indicate ischemic pain onset ŽIPO. and the point at which they were no longer willing or able to tolerate pain ŽIschemic Pain Tolerance, IPT.. The procedure was terminated at tolerance or after 20 min, whichever came first. At IPT, but before deflating the cuff, the subjects were asked to rate their arm pain using standardized verbal descriptors ŽGracely and Dubner, 1987., relating both to the sensory Žintensity . and affective Žunpleasantness . component of their arm pain. A post-task questionnaire, administered after deflation of the tourniquet, assessed task-related anger, tension, confusion, fatigue, ability to concentrate, inadequacy, feelings of helplessness, satisfaction with performance, task fairness and amount of effort exerted during the task. To examine menstrual cycle effects on dependent measures, a series of within-subjects, paired t-tests was conducted. Owing to our well defined a priori hypothesis regarding direction of menstrual cycle effects for IPO and IPT Ži.e. luteal phase follicular phase., combined with our relatively small sample size, t-tests for cycle effects on these dependent measures employed one-tailed tests of
163
significance. All other cycle phase effects were examined using two-tailed tests. PRISM calendar symptoms were divided into eight physical and 12 emotional symptoms, and analyses used average symptom severity during 6-day blocks corresponding to the follicular phase ŽDays 4]9. and to the luteal phase Žthe 6 days preceding menses.. Pearson Product Moment Correlational analyses were used in order to examine predictive relationships involving menstrual symptomatology, blood pressure and pain sensitivity. As expected, even in healthy women without a menstrually-related disorder, the daily calendars revealed significantly more physical Ž8.4 vs. 19.1, t s 5.4, P- 0.001. and emotional symptomatology Ž8.8 vs. 22.7; t s 5.6, P- 0.001. in the luteal compared with the follicular phase. The menstrual cycle also exerted a significant effect on laboratory-induced ischemic pain sensitivity ŽFig. 1.. Ischemic pain tolerance ŽIPT. was significantly shorter during the luteal phase Ž t s 2.14, P- 0.03, one-tailed. and a similar trend was observed for pain threshold ŽIPO; t s 1.82, Ps 0.05, onetailed.. There were, however, no cycle effects on task-related moods or effort, or on verbal descriptors of pain intensity Ž9.5 vs. 9.6. or unpleasantness Ž6.8 vs. 6.6..
Fig. 1. Ischemic pain sensitivity in women Ž n s 11. as a function of menstrual cycle phase.
164
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
The strongest relationships between blood pressure and pain sensitivity were observed in the luteal phase and these were between IPT and clinic DBP and MAP Ž r s 0.71, P- 0.01; see Fig. 2.. Luteal phase IPO and clinic DBP and MAP exhibited similarly significant positive correlations Ž r s 0.59 and 0.60, respectively, P- 0.05.. In the follicular phase, only SBP and MAP significantly related to IPT Ž r s 0.62 and 0.63, respectively, P- 0.05., although clinic SBP and MAP tended to relate to IPO Ž r s 0.56 and 0.54, respectively, P- 0.10.. Blood pressure did not relate, however, to self-reported intensity or unpleasantness of ischemic pain in either cycle phase. In addition to blood pressure, perceived unpleasantness of ischemic pain was a significant predictor of pain onset, being negatively related to IPO during both the luteal Ž r s y0.63, P- 0.05. and follicular phases Ž r s y0.55, P- 0.10.. Verbal reports of pain intensity did not predict IPO or IPT during either phase. Contrary to expectations, relationships between daily, real-life symptom ratings and IPO and IPT were uniformly low and non-significant for both cycle phases. There was some evidence, however, that these daily ratings related more strongly to
the verbal descriptors of ischemic pain. Specifically, physical symptom severity was significantly related to pain intensity Ž r s 0.60, P- 0.05. during the follicular phase and tended to relate to pain unpleasantness in both phases Ž r s 0.52, P0.10.. The results of the present study suggest that the luteal phase of the menstrual cycle is associated with greater sensitivity to ischemic pain, replicating the recent work of Fillingim et al. Ž1997.. Additionally, we obtained some of the first evidence for BP-related hypoalgesia in women. Although this study was based on a relatively small sample size, strengths of our study include confirmation of ovulatory cycles and systematic assessment of blood pressure, thereby strengthening the validity of these results. Although sex hormone levels were not assessed in this study, evidence suggests that they may modulate cycle-related differences in pain sensitivity. For example, in both primate ŽFerin, 1984. and human females ŽCohen et al., 1981; Facchinetti et al., 1983., there is endogenous opioid control of gonadotropins. Also, estrogen levels in human females are related to thermal pain sensitivity ŽFillingim et al., 1997., with higher lev-
Fig. 2. Relationship between blood pressure and pain sensitivity in the luteal phase.
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
els predicting reduced thermal pain thresholds. Finally, in ovulatory cycles, 5]10 days post-ovulation, the time employed for luteal phase testing in the present study, is associated with high levels of estradiol relative to other segments of the menstrual cycle. Thus, changes in the female sex hormone milieu associated with different cycle phases may act directly, or indirectly via interactions with endogenous opioids, to modulate pain sensitivity in women, and this may account for greater ischemic pain sensitivity in the luteal phase. In addition to demonstrating cycle-related differences in ischemic pain sensitivity, this study is among the first to document significant relationships between arterial BP and pain sensitivity in women. Only three studies of which we are aware have directly examined pressure-related hypoalgesia in women ŽMaixner and Humphrey, 1993; Fillingim and Maixner, 1996; Bragdon et al., 1997. and only that of Bragdon et al. Ž1997. have reported significant relationships, especially involving stress-induced BP. The inconsistent findings across these studies may relate to several factors, including differences in pain induction methods and differences in the conditions under which BP was assessed Žrest or stress .. While speculative, the possibility exists that for women, owing to their generally lower resting pressures, pressurerelated analgesia may be more readily observed under conditions of stress-induced BP elevations than under basal conditions. While the conditions under which clinic BP was taken in the present study were not specifically designed to be stressful, they were obtained during the subject’s first visit to a novel environment and by a professional clinical research nurse. Although BPs were entirely within normotensive ranges, it is possible that the strong relationships that we observed between clinic blood pressures and ischemic pain threshold and tolerance reflect, in part, a ‘white coat’ stress effect ŽBernardy et al., 1995.. Future studies in larger groups of ovulatory women, assessing both sex hormone levels and blood pressures at different cycle phases and under a variety of rest and stress conditions, will be needed not only to confirm these results but also to examine the independent or interactive pain modulatory
165
effects of sex hormone and blood pressure mechanisms for women. Acknowledgements This work was supported by grants from the National Institutes of Health ŽMH-51246, MH33127 and DE-07509.. The authors are grateful to Whitehall Laboratories, Madison, NJ for their generous donation of the Clearplan Easy W ovulation prediction kits and to Dot Faulkner for manuscript preparation. References Bernardy, N.C., Everson, S.A., al’Absi, M., Schott, H., Lovallo, W.R., 1995. Risk for hypertension predicts the ‘White Coat’ effect in young men. Psychol. Beitr. 35, 26]31. Bragdon, E.E., Light, K.C., Girdler, S.S., Maixner, W., 1997. Blood pressure, gender and parental hypertension are factors in baseline and post stress pain sensitivity in normotensive adults. Int. J. Behav. Med. Žin press. pp. 25. Bruehl, S., Carlson, C.R., McCubbin, J.A., 1992. The relationship between pain sensitivity and blood pressure in normotensives. Pain 48, 463]467. Bush, F.M., Harkins, S.W., Harrington, W.G., Price, D.D., 1993. Analysis of gender effects on pain perception and symptom presentation in temporomandibular joint pain. Pain 53, 73]80. Cohen, M.R., Cohen, R.M., Pickar, D., Weingartner, H., Murphy, D.L., Bunney, W.E., 1981. Behavioral effects after high dose naloxone administration to normal volunteers. Lancet 2, 1110. Drury, R.A., Gold, R.M., 1977. Differential effects of ovarian hormones on reactivity to foot-shock in rats. Physiol. Behav. 20, 187]191. Eggen, A.E., 1993. The Tromso Study: Frequency and predicting factors of analgesic drug use in a free-living population Ž12]56 years.. J. Clin. Epidemiol. 46, 1297]1304. Facchinetti, F., Nappi, G., Petraglia, F., Volpe, A., Genazzani, A.R., 1983. Oestradiolrprogesterone imbalance and the premenstrual syndrome. Lancet 2, 1302. Ferin, M., 1984. Endogenous opioid peptides and the menstrual cycle. Trends in Neurosciences 7, 194]196. Fillingim, R.B., Maixner, W., 1995. Gender differences in response to noxious stimuli. Pain Forum 4, 209]221. Fillingim, R.B., Maixner, W., 1996. The influence of resting blood pressure and gender on pain responses. Psychosom. Med. 58, 326]332. Fillingim, R.B., Maixner, W., Girdler, S.S., Light, K.C., Sheps, D.S., Mason, G.A., 1997. Ischemic but not thermal pain sensitivity varies across the menstrual cycle. Psychosom. Med. Žin press. pp. 27.
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Frye, C.A., Bock, B.C., Kanarek, R.B., 1992. Hormonal milieu affects tailflick latency in female rats and may be attenuated by access to sucrose. Physiol. Behav. 52, 699]706. Frye, C.A., Cuevas, C.A., Kanarek, R.B., 1993. Die and estrous cycle influence pain sensitivity in rats. Pharmacol. Biochem. Behav. 45, 255]260. Goolkasian, P., 1983. An ROC analysis of pain reactions in dysmenorrheic and nondysmenorrheic women. Percept. Psychophys. 34, 381]386. Gracely, R.H., Dubner, R., 1987. Reliability and validity of verbal descriptor scales of painfulness. Pain 29, 175]185. Hapidou, E.G., De Catanzaro, D., 1988. Sensitivity to cold pressor pain in dysmenorrheic and non-dysmenorrheic women as a function of menstrual cycle phase. Pain 34, 277]283. Honkasalo, M.L., Kaprio, J., Heikkila, K., Sillanpaa, M., Koskenvuo, M., 1993. A population-based survey of headache and migraine in 22,809 adults. Headache 33, 403]412. Maixner, W., Gracely, R.H., Zuniga, J.R., Humphrey, C.B., Bloodworth, G.R., 1990. Cardiovascular and sensory responses to forearm ischemia and dynamic hand exercise. Am. J. Physiol. 259, R1156]R1163. Maixner, W., Humphrey, C., 1993. Gender differences in pain and cardiovascular responses to forearm ischemia. Clin. J. Pain 8, 16]25.
McCubbin, J.A., Bruehl, S., 1994. Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives?. Pain 57, 63]67. Reid, R.L., 1985. Premenstrual syndrome. In: Leventhal, J.M., Hoffman, J.J., Keith L.G., Taylor P.J. ŽEds., Obstetrics, Gynecology, and Fertility. Year Blood Medical, Chicago. Rosa, C., Ghione, S., Panattoni, E., Mezzasalma, L., Giuliane, G., 1986. Comparison of pain perception in normotensives and borderline hypertensives by means of a tooth pulpstimulation test. J. Cardiovasc. Pharmacol. 8, S125]S127. Ryan, S.M., Maier, S.F., 1988. The estrous cycle and estrogen modulate stress-induced analgesia. Behav. Neurosci. 102, 371]380. Sheps, D.S., Bragdon, E.E., Gray, T.F., et al., 1992. Relation between system hypertension and pain perception. Am. J. Cardiol. 70, 3F]5F. Tedford, W.H., Warren, D.E.J., Flynn, W.E., 1977. Alteration of shock aversion thresholds during the menstrual cycle. Percept. Psychophys. 21, 193]196. Veith, J.L., Anderson, J., Slade, S.A., Thompson, P., Laugel, G.R., Getzlaf, S., 1984. Plasma beta-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physiol. Behav. 32, 31]34.
Short communication
Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation Michelle Pfleeger a , Patricia A. Stranevaa , Roger B. Fillingimb , William Maixner c , Susan S. Girdler a,U a
Departments of Psychiatry and Psychology, Medical Research Building A, Uni®ersity of North Carolina, Chapel Hill, NC 27599-7175, USA b Department of Psychology, Uni®ersity of Alabama, Birmingham, AL, USA c Endodontics Department, Uni®ersity of North Carolina, Chapel Hill, NC, USA Received 25 March 1997; revised 20 May 1997; accepted 1 July 1997
Abstract Eleven women were tested twice for ischemic pain sensitivity; once during their follicular phase ŽDays 4]9. and once during their mid-late luteal phase Ž5]10 days after ovulation. of a confirmed ovulatory cycle. Additionally, in order to examine blood pressure-related hypoalgesic effects, each had 3]4 clinic blood pressures determined during an initial screening interview and each also completed a daily symptom calendar for one complete menstrual cycle prior to testing in order to investigate relationships between ‘real-life’ symptomatology and laboratory-induced pain sensitivity. Results revealed significantly shorter pain tolerance times and marginally shorter pain threshold times in the luteal vs. follicular phase, while verbal descriptors of pain intensity Žsensory. and pain unpleasantness Žaffective. did not vary with cycle phase. Clinic blood pressures were positively correlated with pain threshold and tolerance times assessed during both cycle phases. Real-life physical symptom ratings were predictive of laboratory pain intensity ratings during the follicular phase and tended to predict unpleasantness ratings during both phases. These results not only confirm recent reports of greater sensitivity to ischemic pain in women during the luteal phase of their cycle, but extend the literature by demonstrating pressure-related hypoalgesic effects in women during both cycle phases. Q 1997 Elsevier Science B.V. Keywords: Menstrual cycle; Blood pressure; Ischemic pain sensitivity
U
Corresponding author.
0167-8760r97r$17.00 Q 1997 Published by Elsevier Science B.V. All rights reserved. PII S0167-8760Ž97. 00058-5
162
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
Both clinical Že.g. Bush et al., 1993; Eggen, 1993; Honkasalo et al., 1993. and experimental Že.g. Fillingim and Maixner, 1995. evidence indicate that women are more sensitive to pain than men. While animal studies suggest that female sex hormones may contribute to this increased sensitivity Že.g. Drury and Gold, 1977; Ryan and Maier, 1988; Frye et al., 1992, 1993., studies examining sensitivity to pain at different points in the female menstrual cycle have yielded mixed results Že.g. Tedford et al., 1977; Goolkasian, 1983; Veith et al., 1984; Hapidou and De Catanzaro, 1988.. These contradictory findings are likely attributable to methodological issues, especially differences in pain induction methods and reliance on calendar method for determining cycle phase. Recently, Fillingim et al. Ž1997. attempted to address these issues by testing women for both thermal and ischemic pain sensitivity at three points in confirmed ovulatory cycles. While they found no cycle effects on thermal pain sensitivity, they did find that the luteal phase of the cycle, when both estrogens and progesterone are elevated, was associated with greater sensitivity to ischemic pain than the follicular, low hormone, phase. Another pain modulatory mechanism which has been well documented concerns arterial blood pressure ŽBP.. Inverse relationships between BP and pain sensitivity have been observed in both hypertensive Že.g. Rosa et al., 1986; Sheps et al., 1992. and normotensive humans Že.g. Bruehl et al., 1992; McCubbin and Bruehl, 1994.. However, only a small handful of studies have examined pressure-related hypoalgesia in women, yielding mixed results ŽMaixner and Humphrey, 1993; Fillingim and Maixner, 1996; Bragdon et al., 1997.. Thus, the purpose of this study was to reconfirm the findings of greater ischemic pain sensitivity in the luteal vs. follicular phase of ovulatory cycles, but also to extend the previous literature on pressure-related algesia by examining the relationship between clinic blood pressure and pain sensitivity in women. Informed consent was obtained from 11 women at an initial screening visit Ž6]8 weeks prior to testing., after which a health questionnaire was completed and 3]4 clinic blood pressures were
taken by a research nurse, using the subject’s non-dominant arm, spaced at 1 min intervals. The average of these measures constituted clinic blood pressures and were also used to derive mean arterial pressure ŽMAP., based on the standard formula: MAP s ŽSBP y DBP.r3 q DBP. All women were normotensive, reported themselves to be in good health and not taking prescription medication, including oral contraceptives. The women were, on average, 33 years of age Ž29]44., of average height Ž165.8 cm. and weight Ž66.3 kg. and all but one ŽAsian American. were European American. Three women were cigarette smokers, none reported greater than social use of alcohol and three indicated that one or more of their biological parents were hypertensive. Prior to testing, each was asked to complete the Prospective Record of the Impact and Severity of Menstrual Symptoms ŽPRISM. calendar ŽReid, 1985. on a daily basis for one menstrual cycle prior to testing. This calendar allows for the quantification of the severity of a variety of physical Že.g. headache, bloating. and emotional symptoms Že.g. depressed, anxious. during the menstrual cycle, using a 0]3 numerical scale. The PRISM calendar was employed to confirm average menstrual cycle length and to exclude from participation any woman with chronic affective or physical symptomatology, or with severe premenstrual syndrome. Once entered into protocol, the PRISM calendar data served as a measure with which to assess the relationship between experimental pain sensitivity and ‘real-life’ symptomatology. Each subject was tested twice, once during her early follicular phase ŽDays 4]9. and once during her mid-to-late luteal phase Ž5]10 days after ovulation., counterbalancing order of testing. Ovulation was confirmed with the One-Step Clearplan Easy W ovulation test, which detects urinary luteinizing hormone surge occurring 24]36 h prior to ovulation. Each subject returned her positive test stick to verify the result. Testing involved an initial 15 min, supine rest period, followed by the submaximal effort tourniquet test Žsee Maixner et al., 1990.. Briefly, this procedure induces ischemic arm pain by occluding the arm with a standard blood pressure cuff,
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
inflated to 200 mmHg, and having the subjects perform 20 hand grip exercises at 30% of their maximum. Subjects were asked to indicate ischemic pain onset ŽIPO. and the point at which they were no longer willing or able to tolerate pain ŽIschemic Pain Tolerance, IPT.. The procedure was terminated at tolerance or after 20 min, whichever came first. At IPT, but before deflating the cuff, the subjects were asked to rate their arm pain using standardized verbal descriptors ŽGracely and Dubner, 1987., relating both to the sensory Žintensity . and affective Žunpleasantness . component of their arm pain. A post-task questionnaire, administered after deflation of the tourniquet, assessed task-related anger, tension, confusion, fatigue, ability to concentrate, inadequacy, feelings of helplessness, satisfaction with performance, task fairness and amount of effort exerted during the task. To examine menstrual cycle effects on dependent measures, a series of within-subjects, paired t-tests was conducted. Owing to our well defined a priori hypothesis regarding direction of menstrual cycle effects for IPO and IPT Ži.e. luteal phase follicular phase., combined with our relatively small sample size, t-tests for cycle effects on these dependent measures employed one-tailed tests of
163
significance. All other cycle phase effects were examined using two-tailed tests. PRISM calendar symptoms were divided into eight physical and 12 emotional symptoms, and analyses used average symptom severity during 6-day blocks corresponding to the follicular phase ŽDays 4]9. and to the luteal phase Žthe 6 days preceding menses.. Pearson Product Moment Correlational analyses were used in order to examine predictive relationships involving menstrual symptomatology, blood pressure and pain sensitivity. As expected, even in healthy women without a menstrually-related disorder, the daily calendars revealed significantly more physical Ž8.4 vs. 19.1, t s 5.4, P- 0.001. and emotional symptomatology Ž8.8 vs. 22.7; t s 5.6, P- 0.001. in the luteal compared with the follicular phase. The menstrual cycle also exerted a significant effect on laboratory-induced ischemic pain sensitivity ŽFig. 1.. Ischemic pain tolerance ŽIPT. was significantly shorter during the luteal phase Ž t s 2.14, P- 0.03, one-tailed. and a similar trend was observed for pain threshold ŽIPO; t s 1.82, Ps 0.05, onetailed.. There were, however, no cycle effects on task-related moods or effort, or on verbal descriptors of pain intensity Ž9.5 vs. 9.6. or unpleasantness Ž6.8 vs. 6.6..
Fig. 1. Ischemic pain sensitivity in women Ž n s 11. as a function of menstrual cycle phase.
164
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
The strongest relationships between blood pressure and pain sensitivity were observed in the luteal phase and these were between IPT and clinic DBP and MAP Ž r s 0.71, P- 0.01; see Fig. 2.. Luteal phase IPO and clinic DBP and MAP exhibited similarly significant positive correlations Ž r s 0.59 and 0.60, respectively, P- 0.05.. In the follicular phase, only SBP and MAP significantly related to IPT Ž r s 0.62 and 0.63, respectively, P- 0.05., although clinic SBP and MAP tended to relate to IPO Ž r s 0.56 and 0.54, respectively, P- 0.10.. Blood pressure did not relate, however, to self-reported intensity or unpleasantness of ischemic pain in either cycle phase. In addition to blood pressure, perceived unpleasantness of ischemic pain was a significant predictor of pain onset, being negatively related to IPO during both the luteal Ž r s y0.63, P- 0.05. and follicular phases Ž r s y0.55, P- 0.10.. Verbal reports of pain intensity did not predict IPO or IPT during either phase. Contrary to expectations, relationships between daily, real-life symptom ratings and IPO and IPT were uniformly low and non-significant for both cycle phases. There was some evidence, however, that these daily ratings related more strongly to
the verbal descriptors of ischemic pain. Specifically, physical symptom severity was significantly related to pain intensity Ž r s 0.60, P- 0.05. during the follicular phase and tended to relate to pain unpleasantness in both phases Ž r s 0.52, P0.10.. The results of the present study suggest that the luteal phase of the menstrual cycle is associated with greater sensitivity to ischemic pain, replicating the recent work of Fillingim et al. Ž1997.. Additionally, we obtained some of the first evidence for BP-related hypoalgesia in women. Although this study was based on a relatively small sample size, strengths of our study include confirmation of ovulatory cycles and systematic assessment of blood pressure, thereby strengthening the validity of these results. Although sex hormone levels were not assessed in this study, evidence suggests that they may modulate cycle-related differences in pain sensitivity. For example, in both primate ŽFerin, 1984. and human females ŽCohen et al., 1981; Facchinetti et al., 1983., there is endogenous opioid control of gonadotropins. Also, estrogen levels in human females are related to thermal pain sensitivity ŽFillingim et al., 1997., with higher lev-
Fig. 2. Relationship between blood pressure and pain sensitivity in the luteal phase.
M. Pfleeger et al. r International Journal of Psychophysiology 27 (1997) 161]166
els predicting reduced thermal pain thresholds. Finally, in ovulatory cycles, 5]10 days post-ovulation, the time employed for luteal phase testing in the present study, is associated with high levels of estradiol relative to other segments of the menstrual cycle. Thus, changes in the female sex hormone milieu associated with different cycle phases may act directly, or indirectly via interactions with endogenous opioids, to modulate pain sensitivity in women, and this may account for greater ischemic pain sensitivity in the luteal phase. In addition to demonstrating cycle-related differences in ischemic pain sensitivity, this study is among the first to document significant relationships between arterial BP and pain sensitivity in women. Only three studies of which we are aware have directly examined pressure-related hypoalgesia in women ŽMaixner and Humphrey, 1993; Fillingim and Maixner, 1996; Bragdon et al., 1997. and only that of Bragdon et al. Ž1997. have reported significant relationships, especially involving stress-induced BP. The inconsistent findings across these studies may relate to several factors, including differences in pain induction methods and differences in the conditions under which BP was assessed Žrest or stress .. While speculative, the possibility exists that for women, owing to their generally lower resting pressures, pressurerelated analgesia may be more readily observed under conditions of stress-induced BP elevations than under basal conditions. While the conditions under which clinic BP was taken in the present study were not specifically designed to be stressful, they were obtained during the subject’s first visit to a novel environment and by a professional clinical research nurse. Although BPs were entirely within normotensive ranges, it is possible that the strong relationships that we observed between clinic blood pressures and ischemic pain threshold and tolerance reflect, in part, a ‘white coat’ stress effect ŽBernardy et al., 1995.. Future studies in larger groups of ovulatory women, assessing both sex hormone levels and blood pressures at different cycle phases and under a variety of rest and stress conditions, will be needed not only to confirm these results but also to examine the independent or interactive pain modulatory
165
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