Heart rate variability and pain: associations of two interrelated homeostatic processes

Between-person variability in pain sensitivity remains poorly understood. Given a conceptualization of pain as a homeostatic emotion, we hypothesized inverse associations between measures of resting heart rate variability (HRV), an index of autonomic regulation of heart rate that has been linked to emotionality, and sensitivity to subsequently administered thermal pain. Resting electrocardiography was collected, and frequency-domain measures of HRV were derived through spectral analysis. Fifty-nine right-handed participants provided ratings of pain intensity and unpleasantness following exposure to 4 degrees C thermal pain stimulation, and indicated their thresholds for barely noticeable and moderate pain during three exposures to decreasing temperature. Greater low-frequency HRV was associated with lower ratings of 4 degrees C pain unpleasantness and higher thresholds for barely noticeable and moderate pain. High-frequency HRV was unrelated to measures of pain sensitivity. Findings suggest pain sensitivity is influenced by characteristics of a central homeostatic system also involved in emotion.     

The relationship between resting blood pressure and acute pain sensitivity: effects of chronic pain and alpha-2 adrenergic blockade

This study tested for alpha-2 adrenergic mediation of the inverse relationship between resting blood pressure and acute pain sensitivity in healthy individuals. It also replicated limited prior work suggesting this inverse blood pressure/pain association is altered in chronic pain, and provided the first test of whether chronic pain-related changes in alpha-2 adrenergic function contribute to these alterations. Resting blood pressure was assessed in 32 healthy controls and 24 chronic low back pain participants prior to receiving placebo or an intravenous alpha-2 adrenergic receptor antagonist (yohimbine hydrochloride, 0.4 mg/kg) in a randomized crossover design. Participants experienced three acute pain tasks during both sessions. A significant Systolic Blood Pressure × Participant Type × Drug interaction on finger pressure McGill Pain Questionnaire-Sensory ratings (P < .05) reflected significant hyperalgesic effects of yohimbine in chronic pain participants with lower systolic blood pressures (P < .05) but not those with higher systolic pressures, and no significant effects of yohimbine in controls regardless of blood pressure level. A Drug × Systolic Blood Pressure interaction on finger pressure visual analog scale unpleasantness indicated the inverse blood pressure/pain association was significantly stronger under yohimbine relative to placebo (P < .05). Significant Participant Type × Systolic Blood Pressure interactions (P’s < .05) were noted for finger pressure visual analog scale pain intensity and unpleasantness, ischemic pain threshold, and heat pain threshold, reflecting absence or reversal of inverse blood pressure/pain associations in chronic pain participants. Results suggest that blood pressure-related hypoalgesia can occur even when alpha-2 adrenergic systems are blocked. The possibility of upregulated alpha-2 adrenergic inhibitory function in chronic pain patients with lower blood pressure warrants further evaluation.     

Pain sensitivity in offspring of hypertensives at rest and during baroreflex stimulation

Healthy males with a parental history of hypertension (PH+) showed reduced pain sensitivity to a constrictive thigh-cuff pressure stimulus as compared to individuals without a parental history of hypertension. The protocol included eight trials in which a thigh-cuff was inflated until the subject reported the stimulus to be painful. The PH+ group exhibited significantly lower pain sensitivity as indicated by (1) higher levels of constrictive pressure when pain was first reported and (2) lower subjective pain ratings at maximum constrictive pressure. To assess the role of baroreflex stimulation on pain sensitivity in these groups, four trials were administered concurrently with external carotid pressure stimulation. There were no significant differences in pain sensitivity in each group as a function of baroreflex stimulation. The results suggest that the hypoalgesia observed in hypertensives may predate the development of sustained elevations in blood pressure.     

Ethnic differences in thermal pain responses.

OBJECTIVE: Although numerous studies have reported ethnic differences in the prevalence and severity of clinical pain, little is known about how these differences affect the perception of experimental pain. The present experiment examined the effects of ethnicity (African American vs. white) on thermal pain responses in a healthy undergraduate population. METHODS: Thirty white subjects (16 women and 14 men) and 18 African Americans (10 women and 8 men) participated in the study. Thermal testing included evaluation of the following: warmth thresholds, thermal pain thresholds, thermal pain tolerances, and magnitude estimates of both the intensity and unpleasantness of thermal pain (at 46 degrees, 47 degrees, 48 degrees, and 49 degrees C). RESULTS: Although no group differences emerged for warmth thresholds, thermal pain thresholds, or pain intensity ratings, African Americans demonstrated lower thermal pain tolerances than whites. In addition, African Americans had smaller slopes and larger intercepts than whites for ratings of pain unpleasantness. Additional analyses suggested that these findings were a consequence of group differences in thermal pain unpleasantness ratings at the lowest temperatures assessed (46 degrees and 47 degrees C); at these temperatures, African Americans rated the stimuli as more unpleasant than whites. Finally, group differences in thermal pain tolerance and thermal pain unpleasantness ratings seemed to partially account for greater self-reported daily pain symptoms among African Americans. CONCLUSIONS: Collectively, these findings seem to suggest ethnic differences in the perception of the affective-motivational dimension of thermal pain.     

Relationship between baroreceptor cardiac reflex sensitivity and pain experience in normotensive individuals.

In the present study, the relationship between cardiac baroreceptor function and the perception of acute pain was investigated in 60 normotensive subjects. Baroreceptor reflex sensitivity was determined using the sequence method based on continuous blood pressure recordings. A cold pressor test was used for pain induction. Visual analogue scales and a questionnaire were applied in order to quantify sensory and affective pain experience. Moderated multiple regression analysis revealed an inverse relationship between baroreceptor reflex sensitivity assessed during painful stimulation and the intensity of experienced pain. This relationship was moderated by resting blood pressure, with decreasing blood pressure being accompanied by a decrease in the magnitude of the association. Furthermore, resting blood pressure was inversely related to pain intensity. The inverse association between baroreceptor reflex sensitivity and pain experience is discussed as reflecting the well-established pain-inhibiting effect of baroreceptor activity. The finding that this relationship was less pronounced in the case of lower blood pressure suggests that baroreceptor-mediated pain attenuation is reduced in this population.     

EEG responses to tonic heat pain

The aim of the present study was to characterize the EEG response pattern specific for tonic pain which is an experimental pain model resembling clinical pain more closely than phasic pain. Tonic experimental pain was produced by a series of heat pulses 1°C above pain threshold over 10 min. A series of heat pulses 0.3°C below pain threshold and a constant temperature of 37°C served as non-painful heat control and as baseline condition, respectively. The level of attention was experimentally manipulated by instruction and by a distraction task. Twenty male, pain-free subjects had to rate the sensation intensity and sensation unpleasantness during thermal stimulation. Furthermore, a German version of the McGill Pain Questionnaire was to be filled out after tonic painful heat stimulation. The EEG was recorded via 10 leads according to 10/20 convention. Power density was calculated for the usual frequency bands. The ratings showed that tonic painful heat was experienced clearly distinct from tonic non-painful heat. An EEG response pattern emerged characterized by a rather generalized increased delta² activity, a left-biased fronto-temporally diminished theta activity, a fronto-temporal decrease in the alpha¹ activity and a left-sided temporal increase in the beta¹ activity. This observation agrees well with the findings of others. However, there was no evidence in our data that these EEG changes are specific to tonic heat pain as opposed to changes observed during tonic non-painful heat stimulation. Accordingly, the repeatedly reported EEG patterns are also likely to be produced by other forms of strong somatosensory stimuli and to be not specific for pain.     

Reduced tolerance and cardiovascular response to ischemic pain in minor depression

BACKGROUND: A paradoxical association between a higher prevalence of clinical pain and a reduced sensitivity to brief experimental pain seems to exist during depression. METHODS: We assessed the responses to sustained ischemic pain produced by a maximal effort tourniquet procedure in 32 controls and 11 individuals with minor depression (Zung autoscale > or =50). Stethoscopic blood pressures and heart rates were monitored throughout the procedure. RESULTS: Measures of pain threshold, and measures of pain intensity and pain unpleasantness during the ischemic procedure were similar in depressed and control subjects. Yet, the overall numerical ratings of ischemic pain during the procedure was 28% higher and pain tolerance was 44% lower in depressed compared to control subjects. Clinical pain complaints were reported by 91% of depressed but only by 41% of control subjects (P = 0.01). Sustained ischemic pain induced significant elevations of systolic and mean arterial blood pressures in controls but not in depressed subjects. LIMITATIONS: The main limitation of the present study was the preponderance of females in the depressed group. Yet, we did not find significant gender differences in the sensory-affective and autonomic responses to ischemic pain in our sample. CONCLUSIONS: These findings suggest alterations in the sensory and autonomic nervous systems during minor depression.     

Race and sex differences in cutaneous pain perception

OBJECTIVE: The purpose of this study was to determine race and sex differences in cutaneous pain perception. METHODS: Pain perception was measured using a suprathreshold evaluation of pain intensity and pain unpleasantness to a series of thermal stimuli in 27 whites (14 men and 13 women) and 24 African Americans (12 men and 12 women). Blood pressure, depressive symptoms, anxiety state levels, and negative mood were assessed before pain testing to examine whether they might account for any sex or race differences in pain perception that emerged. RESULTS: African Americans rated the stimuli as more unpleasant and showed a tendency to rate it as more intense than whites. Women showed a tendency to rate the stimuli as more unpleasant and more intense than men. In addition, systolic blood pressure was inversely related to pain intensity. After statistically adjusting for systolic blood pressure, sex differences in pain unpleasantness were reduced and sex differences in pain intensity were abolished; race differences were unaltered. CONCLUSIONS: These differences in pain perception may be associated with different pain mechanisms: in the ease of sex, differences in opioid activity and baroreceptor-regulated pain systems; in the case of race, unmeasured psychological characteristics are suggested by the larger differences in ratings of pain unpleasantness than pain intensity.     

Cardiovascular responses after brisk finger movement and their dependency on the "eigenfrequency" of the baroreflex loop

The ‘thermal grill illusion’ refers to paradoxical sensations of heat and pain, resulting from simultaneous application of interlaced warm and cold stimuli to the skin. It provides an interesting model of integrative mechanisms in the nervous system, supposed to be relevant in explaining the hypersensitivity found in chronic pain of unclear etiology. The aim of this study is to investigate the perceptual qualities elicited by a reconstruction of the original grill stimulator and to compare these qualities with those elicited by a single temperature thermode of identical dimensions. Healthy participants performed these comparisons by choosing adjectives describing the perceived sensory qualities. We hypothesized that the thermal grill would be perceived as different from a single temperature hot stimulus near pain threshold because of varying sensory qualities. Moreover, the qualities elicited by the grill were expected to be different from the qualities elicited by its single component temperatures. The thermal grill elicited a complex percept, which was distinguished almost perfect from a hot stimulus. The pattern of perceived qualities of the thermal grill differed from single temperature warm and hot stimuli. Pain-related sensations were less present in the grill percept than in a single hot stimulus near pain threshold. The spectrum of qualities of the grill stimulus changed marginally with stimulus duration by decrease of a cold component and concurrent increase of a heat component. In conclusion, the percept of the thermal grill is not simply pain - it can be understood as a metaesthetic percept at the transition from heat to pain.     

Blood pressure and pain sensitivity in children and adolescents

Elevated blood pressure is associated with diminished pain sensitivity. While this finding is well established in adults, it is less clear when the relation between blood pressure and pain sensitivity emerges across the life course. Evidence suggests this phenomenon may exist during childhood. Children (N = 309; 56% boys) aged 10–15 years and their parents participated. Blood pressure readings were taken during a resting baseline. Maximum pain intensity was rated using a visual analogue scale (rated 0–10) in response to a finger prick pain induction. Parent‐measured resting blood pressure was inversely associated with boys' pain ratings only. Cross‐sectionally, lower pain ratings were related to higher SBP, univariately. Longitudinally, pain ratings predicted higher DBP, even after controlling for covariates. Determining when and how the relation between blood pressure and pain sensitivity emerges may elucidate the pathophysiology of hypertension.     

Spatial summation of heat-induced pain: influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness

1. Psychophysical experiments were initiated to determine the possible influence of increasing stimulus size on perceived pain intensity. Six trained human subjects (5 male, 1 female) made visual analogue scale (VAS) ratings for pain-sensation intensity and unpleasantness in response to nociceptive thermal stimuli. Test stimuli consisted of 5-s duration heat pulses (45-50 degrees C in 1 degrees increments) delivered by one, two, or three contact thermal probes (1 cm2 each) applied to the medial aspect of the anterior forearm. 2. The area of skin receiving noxious thermal stimuli was changed by randomly varying the number of thermodes activated. The effects of varying the distance between the thermal probes also were evaluated. In the first series of experiments, thermal-probe separation was kept close to 0; in subsequent experimental series, the thermodes were separated by either 5 or 10 cm. 3. In each experimental series, considerable spatial summation occurred in both pain-sensation intensity and unpleasantness dimensions of pain. This summation occurred throughout the nociceptive thermal range of 45-50 degrees C and was larger at suprathreshold temperatures (greater than or equal to 47 degrees C) than those near threshold (less than or equal to 46 degrees C). Unlike spatial summation of perceived warmth, that of pain was not characterized by systematic changes in power-function exponents but as approximately upward parallel displacements in double-logarithmic coordinates. 4. Thermal-probe separation over a range of 0-10 cm had no effects on spatial summation of pain-sensation intensity or pain unpleasantness. In contrast, increasing thermal-probe separation increased the subjects' ability to discriminate differences in stimulus size and their ability to detect correctly the number of thermal probes activated. 5. Because affective VAS ratings of unpleasantness were linearly related to, but distinctly and systematically less than, VAS ratings of pain-sensation intensity, it was clear that subjects responded quite differently to these two pain dimensions. Affective judgements were not additionally influenced by thermal probe separation and hence by the ability to perceive stimulus size or number of thermal probes activated. 6. The results indicate that powerful spatial-summation mechanisms exist for heat-induced pain. Spatial summation of pain is likely to be subserved both by local integration mechanisms at the level of single spinothalamic-tract neurons and by recruitment of central nociceptive neurons, because spatial summation of pain occurred to approximately equal extents under conditions of thermode separations over a distance of at least 20 cm.     

Effects of artificial and natural baroreceptor stimulation on nociceptive responding and pain

The arterial baroreflex may mediate hypertensive hypoalgesia. Carotid baroreceptors can be artificially stimulated by neck suction and inhibited by compression. Effects of brief neck suction and compression on nociceptive responding and pain were studied in 25 normotensive adults. The sural nerve was electrocutaneously stimulated at threshold intensity during systole or diastole combined with neck suction, neck compression, or no pressure. Nociceptive responding was indexed by electromyographic activity elicited in the biceps femoris. Participants rated the intensity of sural stimulation. Although artificial baroreceptor stimulation (suction) did not affect nociceptive responding, baroreceptor inhibition (compression) reduced pain ratings. In contrast, natural baroreceptor stimulation during systole reduced nociceptive responding compared to diastole, but did not affect pain ratings. The data provide partial support for baroreflex modulation of pain.     

Attenuation of sensory and affective responses to heat pain: evidence for contralateral mechanisms

Attenuation of responses to repeated sensory events has been thoroughly studied in many modalities; however, attenuation of pain perception has not yet benefitted from such extensive investigation. Described here are two psychophysical studies that examined the effects of repeated exposure to thermal stimuli, assessing potential attenuation of the perception of pain and its possible spatial specificity. Twenty-two subjects were presented thermal stimuli to the volar surface of the right and left forearms. Twelve subjects in study 1 received the same stimuli and conditions on each of five daily experimental sessions, whereas 10 subjects in study 2 received thermal stimuli, which were restricted to one side for four daily sessions and then applied to the other side on the fifth session. Ratings of warmth intensity, pain intensity, and pain unpleasantness were recorded while the subjects performed a thermal sensory discrimination task. Results of study 1 demonstrate that repeated stimulation with noxious heat can lead to long-term attenuation of pain perception; results of study 2 extend these findings of attenuation to both pain intensity and unpleasantness and show that this effect is highly specific to the exposed body side for both aspects of the pain experience. We suggest that the functional plasticity underlying this attenuation effect lies in brain areas with a strong contralateral pattern of pain-related activation.     

Effects of cardiopulmonary baroreceptor activation on pain may be moderated by risk for hypertension

Cardiopulmonary baroreceptor stimulation may modulate pain, though the literature is much smaller than research showing that sinoaortic baroreceptor stimulation can buffer pain. To examine the possibility that risk for established high blood pressure may moderate the effects of cardiopulmonary baroreceptor stimulation on pain, 22 borderline hypertensive and 18 normotensive men participated in a laboratory experiment. Group differences in blood pressure were documented by 24-h ambulatory blood pressure recording. Ratings of the intensity of acute heat pain were influenced by both group membership and leg position. Passive elevation of the legs, a technique that stimulates cardiopulmonary baroreceptors, reduced ratings of heat pain though only among borderline hypertensives. Alteration of pain sensitivity may reflect the development of the hypertensive process.     

The behavioral impact of baroreflex function: A review

The baroreflex consists of a negative feedback loop adjusting heart activity to blood pressure fluctuations. This review is concerned with interactions between baroreflex function and behavior. In addition to changes in baroreflex cardiac control subject to behavioral manipulations, interindividual differences in reflex function predicted psychological and central nervous features. The sensitivity of the reflex was inversely related to cognitive performance, evoked potential amplitudes, experimental pain sensitivity, and the severity of clinical pain. Possible variables moderating the strength of the associations are tonic blood pressure, gender, and psychiatric disease. It is suggested that these observations reflect inhibition of higher brain function by baroreceptor afferents. While in many cases increased baroreflex function implies stronger inhibition, individual and situational factors modulate the behavioral impact of cardiac regulation.     

Effects of PRES baroreceptor stimulation on thermal and mechanical pain threshold in borderline hypertensives and normotensives

Prior studies have noted a pain relieving effect of baroreceptor stimulation and of higher tonic blood pressure in animals and humans. The present study used a new technique for the controlled, noninvasive stimulation of human carotid baroreceptors (PRES). PRES baroreceptor manipulation was delivered to both normotensive subjects (n= 11) and medication-free labile hypertensive subjects (n= 10) during both thermal and mechanical pain. Consistent with prior research, hypertensives had a higher threshold for thermal pain than did normotensives. PRES baroreceptor manipulation had no significant effect on thermal pain threshold for either group. For the mechanical pain model, the opposite results were obtained; group pain threshold did not differ, but there was a significant PRES baroreceptor stimulation effect of increasing pain threshold for both groups. Results are discussed in terms of specific features of the stimuli, dampening of pain in hypertensives, and adaptation to pain.     

Why look in the brain for answers to temporomandibular disorder pain?

Temporomandibular disorder (TMD) patients often exhibit widespread clinical pain, as well as greater sensitivity to experimental pain than pain-free controls, suggesting a role of central pathophysiologic mechanisms in TMD. Moreover, TMD is more prevalent among women, which may be related to the higher sensitivity of women to experimental pain. Women also exhibit greater temporal summation of heat pain compared to men. Temporal summation, the increase in pain intensity upon repetitive noxious stimulation of constant intensity, at a high frequency is centrally mediated. Thus, greater temporal summation in women indicates that their central nociceptive processing is upregulated compared to men. Recent studies in our research center sought further evidence for upregulation of central nociceptive processing in females compared to males and in TMD patients compared to healthy controls, assessing group differences in temporal summation of mechanically evoked pain, and aftersensations following repetitive noxious stimulation. Sixteen series of 10 repetitive, sharp, mechanical stimuli were applied to the fingers of 25 female TMD patients, 25 healthy women, and 25 healthy men, with a computer-controlled small probe. All subjects rated the pain intensity or the unpleasantness evoked by the 1st, 5th and 10th stimulus in the series, and the aftersensations 15 s and 1 min after the last stimulus on visual-analog scales. TMD patients exhibited greater temporal summation of pain and unpleasantness, stronger aftersensations, and more frequent painful aftersensations than controls. Healthy females showed greater temporal summation of pain intensity and unpleasantness, higher intensity and unpleasantness of aftersensations, and more frequent painful aftersensations than males. Greater temporal summation of pain and aftersensations from digital stimulation of TMD patients than controls suggest a generalized hyperexcitability of the central nociceptive system in this patient group. Such hyperexcitability may contribute to the development and/or maintenance of chronic TMD pain. Moreover, greater temporal summation of pain and aftersensations in healthy females than males indicate that their central processing of nociceptive input may be more easily upregulated into pathological hyperexcitability, possibly accounting for the predominance of TMD among women.     

Differential cerebral responses to aversive auditory arousal versus muscle pain: specific EEG patterns are associated with human pain processing

The specificity of electroencephalogram (EEG) activity in relation to processing of human pain needs further elucidation. This study was designed to determine if nociceptive input and general arousal responses to external stimulation exert different effects on EEG activity. Continuous aversive auditory stimuli (90 dB for 2 min) and painful injection of hypertonic saline (5.8%, 0.2 ml) into the left brachioradialis muscle were administered to 12 male subjects during separate sessions in a counterbalanced design. Intensity, arousal and unpleasantness were assessed during the muscle pain and auditory stimulation using a visual analogue scale and arousal-affective scales. The EEG data (32 channels) was acquired before, during and after application of painful and aversive auditory stimuli. Aversive auditory stimulation and intramuscular injection of hypertonic saline induced similar degrees of arousal and unpleasantness associated with a similarity of intensity of sensation of pain and auditory sensation. However, muscle pain induced a significant decrease of alpha-1 activity (8–14 Hz) at T6, PC2, PC6, Pz, P4, O2 and POz sites compared to the baseline, but aversive auditory stimulation did not produce any significant changes in alpah-1 activity compared to baseline. The alpha-1 EEG powers at P3, Pz, P4, PC1, PC2 and POz, and alpha-2 at Pz and POz sites were significantly decreased during muscle pain when compared with aversive noise stimulation. These results indicate that specific EEG patterns are associated with human pain processing. Electronic Publication     

Quantification of cardiac baroreflex function at rest and during autonomic stimulation

The cardiac baroreflex constitutes an important mechanism mediating autonomic control of heart activity. Its function can be quantified by applying sequence analysis based on continuous recordings of blood pressure and heart rate. In this study, several indices derived from this method were compared regarding their suitability to estimate baroreflex function at rest and during autonomic stimulation. A cold pressor test was used to induce vagal withdrawal. Changes in the following indices evoked by this procedure were examined: baroreflex sensitivity (the extent of changes in heart period following blood pressure fluctuations), baroreflex effectiveness (the relative frequency in which the reflex responds to blood pressure fluctuations), and baroreflex power (the reflex operations in a defined period). The values of all indices decreased during autonomic stimulation. The strongest and most consistent effect, however, was observed for baroreflex sensitivity, suggesting that this parameter is the most sensitive to changes in parasympathetic tone among the three parameters. Baroreflex sensitivity also proved to differentiate between individuals with higher and lower resting blood pressure. Therefore, this index may best reflect the well-known involvement of the baroreflex in the long-term setting of blood pressure. Midrange correlations between the indices of baroreflex function suggest that they quantify similar, though not identical, aspects of baroreflex function. This study supports the use of sequence analysis as a reliable tool for the quantification of parasympathetic cardiac control. The sensitivity index must be considered the most relevant to quantify baroreflex function among the three parameters.