Blood pressure and the perception of illusive pain

Numerous studies have documented an inverse relationship between blood pressure and sensitivity to experimental nociceptive stimulation. The present study aimed to investigate possible associations between blood pressure and the occurrence and intensity of paradoxical pain induced by the thermal grill paradigm. Thirty‐one healthy subjects were stimulated three times for 1 min with the nonnoxious temperatures of 15°C and 41°C set at the interlaced cold and warm bars of a water bath‐driven thermal grill. Blood pressure and heart rate were recorded concomitantly. On account of previous observations of an association between the sensitivity of the cardiac baroreflex and pain perception, this parameter was additionally obtained. Numerical rating scales were used to quantify subjective pain intensity and pain unpleasantness; subjects were classified as responders and nonresponders to thermal grill stimulation based on pain intensity ratings. Responders exhibited lower systolic and diastolic blood pressure than nonresponders, and inverse linear associations arose between blood pressure and pain intensity and unpleasantness. Baroreflex sensitivity was unrelated to pain ratings. The findings confirmed the hypothesis of a blood pressure dependence of paradoxical pain and support the notion that the cardiovascular and pain regulatory systems interact not only in the processing of pain elicited by noxious input, but also in nonnoxiously generated illusive pain. While this finding is not consistent with the assumption of an involvement of the baroreflex system in mediating the observed interaction, psychological traits and neurochemical factors are alternatively considered.     

Trait anger and blood pressure recovery following acute pain: evidence for opioid-mediated effects

Previous work has suggested that positive associations between trait anger (TRANG) and pain sensitivity are due to dysfunctional endogenous opioid analgesic systems. In this study, we examined whether TRANG is associated with impaired opioid modulation of blood pressure (BP) recovery. A total of 46 pain-free normotensive controls and 69 normotensive chronic low back pain (LBP) sufferers received opioid blockade (8mg naloxone IV) or placebo in randomized, counterbalanced order in separate sessions. During each, participants underwent a 1-min finger pressure pain task followed by an ischemic forearm pain task. Opioid blockade impaired post-pain BP recovery in controls but not LBP participants (ps < .001). In controls, low TRANG was associated with blockade-induced recovery impairments, with no blockade effect in high TRANG participants. In LBP participants, blockade did not alter recovery regardless of TRANG (interaction ps < .05). Results support dysfunctional opioid modulation of BP recovery in healthy high TRANG controls and further suggest chronic pain-related impairments in opioid-mediated cardiovascular recovery.     

Effects of alpha2-adrenoceptor blockade and thyrotropin-releasing hormone (TRH) on the cardiovascular system in the rabbit

The effects of two different doses of thyrotropin-releasing hormone on regional blood flows were studied in urethane-anaesthetized rabbits pretreated with the α₂ adrenergic antagonists yohimbine and idazoxan. The effects of yohimbine were also studied using unanaesthetized rabbits. Blood flow measurements were performed using the tracer microsphere method. Thyrotropin-releasing hormone was injected i. v. at a dose of either 0.1 mg kg^-1 or 2.0 mg kg^-1. Yohimbine and idazoxan did not modify the effect of thyrotropin-releasing hormone on mean arterial blood pressure. In the anaesthetized animals, blockade of the α₂ adrenoceptors resulted in a vasoconstriction in several peripheral organs and the vasoconstriction increased after thyrotropin-releasing hormone administration. Pretreatment with yohimbine reduced total cerebral blood flow moderately and in such animals thyrotropin-releasing hormone elicited only minor cerebral blood flow effects. Pretreatment with idazoxan did not reduce the total cerebral blood flow and in such animals it increased from 53± 1 to 75±4 g min^-1 100 g^-1 (P < 0.01) after the administration of the lower dose of thyrotropin-releasing hormone and from 64±5 to 112±17 g min^-1 100 g^-1 (P < 0.01) after the higher dose. In the conscious animals, yohimbine caused an increase in mean arterial blood pressure and heart rate. Vascular resistance increased in several organs. The cerebral blood flow decreased in white matter (P <0.05) and the caudate nucleus (P < 0.05). The results indicate that there is a yohimbine-sensitive mechanism involved in the cerebrovasodilating effect of thyrotropin-releasing hormone in anaesthetized rabbits. There is also an activation of the sympathetic nervous system by thyrotropin-releasing hormone which results in increased vascular resistance and mean arterial blood pressure. Its effect on the vascular resistance may be enhanced by α₂ adrenoceptor blockade. In conscious animals, there seems to be a yohimbine-sensitive mechanism involved in the control of cerebral blood flow.     

Altered cardiovascular/pain regulatory relationships in chronic pain

In healthy individuals, there is an inverse relationship between resting blood pressure (BP) and pain sensitivity. This study examined possible dysregulation of this adaptive relation in chronic pain patients, and tested whether the extent of this dysregulation is a function of pain duration, Continuous resting BP_s were assessed for 5 min after a 5-min rest period in 121 chronic benign pain patients. Unlike the inverse relationship observed previously in normals, mean resting diastolic BP_s during the assessment period were correlated positively with ratings of pain severity. A Pain Duration x Systolic BP i nteraction emerged (p > .05) such that the magnitude of the BP-pain relation was greatest in patients with the longest duration of pain, r(38) = .50, p > .001. A hypothesized progressive alteration in endogenous pain regulatory systems in chronic pain patients was supported. A possible role of endogenous opioid dysfunction in accounting for these alterations is discussed. This investigation was supported by Grant BRSG S07 RR05366-28. awarded to John W. Burns by the Biomedical Research Grant Program, Division of Research Resources, National Institutes of Health. We thank Kathleen Kiselica and Ronald Pawl for allowing access to their patients at the Center for Rehabilitation at Lake Forest Hospital in Lake Forest, IL.     

Hypoalgesia associated with elevated resting blood pressure: evidence for endogenous opioid involvement

This study used a placebo-controlled, between-subjects opioid blockade design to evaluate endogenous opioid involvement in the hypoalgesia associated with elevated resting blood pressure (BP) in 163 healthy individuals. Participants were randomly assigned to Drug condition (placebo, naltrexone) and Task Order (computerized maze task with harassment followed by an ischemic pain task or vice versa). Resting BP was assessed, followed by drug administration, and then the pain and maze tasks. A significant Drug × Systolic BP (SBP) interaction was observed on McGill Pain Questionnaire-Affective pain ratings (P < .01), indicating that BP-related hypoalgesia observed under placebo was absent under opioid blockade. A significant Gender × Drug × SBP × Task Order interaction was observed for VAS pain intensity (P < .02). Examination of simple effects comprising this interaction suggested that BP-related hypoalgesia occurred only in male participants who experienced the pain task in the absence of emotional arousal, and indicated that this hypoalgesia occurred under placebo but not under opioid-blockade. Results suggest that under some circumstance, BP-related hypoalgesia may have an endogenous opioid-mediated component in healthy individuals, particularly men.     

Suppression of pain-related thoughts and feelings during pain-induction: sex differences in delayed pain responses

Women tend to report greater acute and chronic pain intensity than men, and various mechanisms have been proposed to account for these sex differences. Suppression has been related to amplified pain intensity, and thus we examined whether sex differences in the use of suppression partly explained the discrepancy between men and women on pain report. Participants (N = 222; women: 55%) underwent a cold pressor, during which half the sample was randomly assigned to suppress pain-related thoughts and feelings and the other half was not. A 2-min recovery period followed the cold pressor. Ten min later, all participants were exposed to another physical stimulus (a massage device). Significant condition × Sex interactions were found for pain intensity, sensory ratings from the McGill Pain Questionnaire and unpleasantness ratings for the massage device, such that: (a) men in the No Suppression condition reported lower pain and unpleasantness than women in the same condition; (b) men in Suppression condition reported greater pain and unpleasantness then men in No Suppression condition, but equivalent pain and unpleasantness to women in No Suppression condition; (c) differences between men and women on pain in No Suppression condition were partly mediated by women’s report of greater spontaneous use of avoidance/suppression during the cold pressor. Results using an “addition” paradigm (i.e., manipulating use of suppression) and a “take away” (i.e., mediation) paradigm converge to suggest that women spontaneously use suppression to regulate pain more than men, and that the differential use of suppression partly explains the tendency for women to report greater pain intensity than men.     

Chest pain is inversely associated with blood pressure during exercise among individuals being assessed for coronary heart disease

Acute and chronic increases in blood pressure have been related to decreases in pain perception. This phenomenon has been studied primarily using acute experimental pain stimuli. To extend the literature to naturalistic pain and in particular the problem of silent cardiac ischemia, this study examined the relationship between blood pressure and chest pain during exercise stress testing. Nine hundred seven (425 men, 482 women) individuals undergoing exercise stress testing for diagnosis of possible myocardial ischemia completed the McGill Pain Questionnaire (MPQ) immediately afterward and other questionnaires before and after testing. Blood pressure was measured before, during, and after exercise. Systolic blood pressure at the end of exercise was inversely related to a number of measures of pain such as total score on the MPQ. The relationship could not be explained by individual differences in exercise duration, medication use, sex, or other measured variable. In sum, the inverse relationship between blood pressure and sensitivity to pain that has been observed in other populations in experimental and naturalistic conditions was observed for chest pain during exercise. Blood pressure may contribute to episodes of silent ischemia.     

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.     

Blood pressure, gender, and parental hypertension are factors in baseline and poststress pain sensitivity in normotensive adults

We studied 38 men and 36 women to learn whether a brief speech stressor reduced normotensive humans thermal pain sensitivity, whether baseline and poststress pain threshold and tolerance varied with blood pressure (BP) and hemodynamic measures, and whether these relations differed by gender and parental hypertension (PH). PH-women with low resting BPs had lower baseline pain tolerance than did all other groups (ps < .05), and this group alone exhibited stress-induced analgesia (ps = .008). In women, pre- and poststress pain tolerance varied directly with rest and stress BP (ps < .05). In men, BP and pain measures were not related, but high cardiac index during stress was associated with low baseline pain tolerance (p < .01). The present findings support the hypothesis that pain sensitivity and cardiac stress response share a common mechanism, but they yield little support for the hypothesis that analgesic responses to acute stress contribute to hypertension etiology via an instrumental learning process. We are grateful to Robin Campbell for her technical assistance and to Dr. Alan L. Hinderliter for his assistance in screening volunteers for participation in this study. This research was supported by Grant R01-HL3t533 from the National Health, Lung, and Blood Institute, Bethesda, MD     

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.     

Glutamate and capsaicin-induced pain,hyperalgesia and modulatory interactions in human tendon tissue

Experimental glutamate and capsaicin-induced pain has not been described in tendon tissue despite the implications of addressing these receptors in pain management strategies. This study investigated pain induction and modulatory interactions by injecting glutamate (0.5 ml, 1 M) and capsaicin (0.5 ml, 5 μg, 33 μM) to human tendon tissue. Following the initial glutamate or capsaicin injection, a second injection of either glutamate (following capsaicin), capsaicin (following glutamate) or hypertonic saline (after both glutamate and capsaicin) was given. Twelve male volunteers participated. Subjects had four sequences of injections to tibialis anterior tendon over two sessions 1 week apart. Pain intensity responses were scored on a visual analogue scale (VAS). Pressure pain thresholds (PPTs) were assessed before, during and after pain induction. Capsaicin caused significantly higher peak pain scores compared to glutamate (P < 0.003) whilst glutamate pain was of significantly longer duration (P < 0.0003). Capsaicin following glutamate resulted in significantly higher average VAS scores 180–450 s after injection compared to capsaicin as primary injection (P < 0.05). PPTs were significantly reduced during capsaicin pain (72 ± 5 and 80 ± 6% of pre-pain values at the injection site and 2 cm proximal, P < 0.002). Following capsaicin, hypertonic saline and glutamate showed significant reductions in PPT at the same sites and to a similar degree compared to baseline (P < 0.002). The results indicate in tendon tissue a facilitation of response to capsaicin injection following glutamate injection. PPTs were only reliably reduced by capsaicin injection. These results emphasize the possible importance of peripheral glutamate receptor antagonists in pain management in musculoskeletal conditions.     

Muscle trigger points and pressure pain hyperalgesia in the shoulder muscles in patients with unilateral shoulder impingement: a blinded, controlled study

Our aim was to describe the differences in the presence of trigger points (TrPs) in the shoulder muscles and to investigate the presence of mechanical hypersensitivity in patients with unilateral shoulder impingement and healthy controls. Twelve patients with strictly unilateral shoulder impingement and 10 matched controls were recruited. TrPs in the levator scapula, supraspinatus, infraspinatus, subscapularis, pectoralis major, and biceps brachii muscles were explored. TrPs were considered active if the local and referred pain reproduced the pain symptoms and the patient recognized the pain as a familiar pain. Pressure pain thresholds (PPT) were assessed over the levator scapulae, supraspinatus, infraspinatus, pectoralis major, biceps brachii, and tibialis anterior muscles. Both explorations were randomly done by an assessor blinded to the subjects’ condition. Patients with shoulder impingement have a greater number of active (mean ± SD: 2.5 ± 1; P < 0.001) and latent (mean ± SD: 2 ± 1; P = 0.003) TrPs when compared to controls (only latent TrPs, mean ± SD: 1 ± 1). Active TrPs in the supraspinatus (67%), infraspinatus (42%), and subscapularis (42%) muscles were the most prevalent in the patient group. Patients showed a significant lower PPT in all muscles when compared to controls (P < 0.001). Within the patient group a significant positive correlation between the number of TrPs and pain intensity (r _s = 0.578; P = 0.045) was found. Active TrPs in some muscles were associated to greater pain intensity and lower PPTs when compared to those with latent TrPs in the same muscles (P < 0.05). Significant negative correlations between pain intensity and PPT levels were found. Patients with shoulder impingement showed widespread pressure hypersensitivity and active TrPs in the shoulder muscles, which reproduce their clinical pain symptoms. Our results suggest both peripheral and central sensitisation mechanisms in patients with shoulder impingement syndrome.     

Pain-induced inhibition of gastric motility is mediated by adrenergic and vagal non-adrenergic reflexes in the rat.

Painful stimuli have been shown to inhibit gastric motility in animal experiments and delay gastric emptying in humans. The aim of the present study was to investigate in detail mechanisms involved in pain-induced gastric inhibition. Pain stimulation by exerting pressure on a testicle induced a prompt gastric relaxation which lasted throughout the period of stimulation. Pain-induced gastric relaxation was significantly reduced by the selective alpha-1 blocker, prazosin, and by the non-selective beta-blocker, propranolol. Similarly pain-induced inhibition of gastric tone was significantly reduced by bilateral cervical vagotomy. In contrast, gastric relaxation following pain stimulation was significantly potentiated by the selective adrenergic alpha-2 blocker, yohimbine. Combined administration of prazosin and propranolol followed by bilateral cervical vagotomy abolished gastric relaxation in response to pain stimulation. In conclusion, gastric relaxation in response to painful stimulation was found to be reflex-mediated via sympathetic neurons acting on alpha-1 and beta receptors and possibly also via vagal non-adrenergic fibres. Pain-induced inhibition of gastric tone was significantly increased by yohimbine. It is suggested that yohimbine by blocking presynaptic inhibitory receptors on adrenergic neurons facilitates the release of noradrenaline in response to pain stimulation.     

Resting blood pressure differentially predicts time course in a tonic pain experiment

Resting blood pressure (BP) shows a negative relationship with pain sensitivity (BP‐related hypoalgesia). In chronic pain conditions, this relationship is inverted. The precise mechanisms responsible for the inversion are unknown. Using a tonic pain protocol, we report findings closely resembling this inversion in healthy participants. Resting BP and state measures of anxiety and mood were assessed from 33 participants (21 female). Participants then immersed their dominant hand in painfully hot water (47 °C) for five trials of 1‐min duration, with 30‐s intertrial intervals. Throughout the trials, participants continually registered their pain. After a 35‐min intermission, the trial sequence was repeated. A disassociation of the negative relationship of resting systolic BP (as per Trial 1) was found using hierarchical linear modeling (p < .001, R² = .07). The disassociation unfolds over each consecutive trial, with an increasingly positive relationship. In Sequence 2, the initially negative relationship is almost completely absent. Furthermore, the association of BP and pain was found to be moderated by anxiety, such that only persons with low anxiety exhibited BP hypoalgesia. Our findings expand the existing literature by incorporating anxiety as a moderator of BP hypoalgesia. Furthermore, the protocol emulates the changing relationship between BP and pain observed in chronic pain patients. The protocol has potential as a model for chronic pain; however, future research should determine if similar physiological systems are involved. The finding holds potential diagnostic or prognostic relevance for certain clinical pain conditions, especially those involving dysfunction of the descending modulation of pain.     

Influence of oral contraceptives on endogenous pain control in healthy women

This study investigated the influence of oral contraceptives (OC) on diffuse noxious inhibitory control (DNIC) in healthy women. Fifteen women taking OC and 17 normally menstruating women (No-OC) were tested during high and low endogenous estrogens sessions. Saliva was sampled for analysis of endogenous estradiol level. Mechanical pressure (test stimuli) was applied to the masseter muscle and finger. The pain induced by this pressure was assessed on a 0–10 numerical rating scale (NRS) before, during, and after immersion of the contralateral hand in ice-cold water (cold pressor test, CPT) to induce DNIC. For all subjects, pain induced by the test stimuli decreased significantly during the CPT (P < 0.001). The decrease in general was larger in the No-OC group, with a significant difference between groups in the masseter muscle in the low session (P < 0.027). There were no significant differences between groups or sessions in estradiol levels. These results indicate that endogenous pain modulation may be less effective in OC users.     

Expectations contribute to reduced pain levels during prayer in highly religious participants

Although the use of prayer as a religious coping strategy is widespread and often claimed to have positive effects on physical disorders including pain, it has never been tested in a controlled experimental setting whether prayer has a pain relieving effect. Religious beliefs and practices are complex phenomena and the use of prayer may be mediated by general psychological factors known to be related to the pain experience, such as expectations, desire for pain relief, and anxiety. Twenty religious and twenty non-religious healthy volunteers were exposed to painful electrical stimulation during internal prayer to God, a secular contrast condition, and a pain-only control condition. Subjects rated expected pain intensity levels, desire for pain relief, and anxiety before each trial and pain intensity and pain unpleasantness immediately after on mechanical visual analogue scales. Autonomic and cardiovascular measures provided continuous non-invasive objective means for assessing the potential analgesic effects of prayer. Prayer reduced pain intensity by 34 % and pain unpleasantness by 38 % for religious participants, but not for non-religious participants. For religious participants, expectancy and desire predicted 56–64 % of the variance in pain intensity scores, but for non-religious participants, only expectancy was significantly predictive of pain intensity (65–73 %). Conversely, prayer-induced reduction in pain intensity and pain unpleasantness were not followed by autonomic and cardiovascular changes.     

Hypervolemic hyperalgesia in healthy young adults

A cardiopulmonary baroreflex mechanism may be implicated in hypertensive hypoalgesia. Previous research in animals and humans has noted that manipulations that stimulate the vagus nerve are associated with predominantly anti-nociceptive effects. This study examined the effects of cardiopulmonary baroreceptor stimulation on venipuncture and intraveneous catherization pain during euvolemic and hypervolemic conditions while participants lay supine. In the euvolemic condition, participants maintained their normal diet whereas in the hypervolemic condition, they consumed additional water containing sodium citrate. As expected, blood volume was higher (P < .05) during the hypervolemic condition than the hypovolemic condition. Pain ratings were higher (P < .05) during hypervolemia compared to euvolemia. These findings suggest that increased cardiopulmonary baroreceptor activation during hypervolemia can be associated with increased sensitivity to noxious stimulation. In agreement with previously reported pro-nociceptive effects of vagus nerve stimulation, the current hyperalgesia finding provides further evidence that the cardiovascular system can influence the pain system.     

Treatment effect and mechanism of Fu's subcutaneous needling among patients with shoulder pain: A retrospective pilot study

Fu's subcutaneous needling (FSN) is a new acupuncture therapy developed from acupuncture and Traditional Chinese Medicine models. The aim of this study was to investigate the effect of FSN on shoulder pain. In this retrospective comparative study, patient case files with shoulder pain (Group A) treated with FSN were analyzed and compared with the same number of patients with shoulder pain (Group B) treated with conventional acupuncture and physical therapy. Motion-related pain (MRP), pain under pressure (PUP), and Range of motion (ROM) were collected before and after intervention. In the 68 patients, there were 39 males and 29 females, aged 21–53 years old (mean ± SD = 36.4 ± 8.15) with onset time ranging from 1 day to 7 days (mean ± SD = 3.15 ± 1.73). MRP, PUP, and ROM scores were improved after FSN intervention (p < .05). There were significant differences between group A and group B in MRP, PUP, and ROM scores after FSN intervention and 1 week follow-up (p < .05). No adverse events, such as fainting and sharp pain, occurred during the treatment process. FSN can be an effective rehabilitation intervention for improving shoulder pain and shoulder range of motion.     

Possible involvement of supraspinal opioid and GABA receptors in CDP-choline-induced antinociception in acute pain models in rats

Cytidine-5'-diphosphate choline (CDP-choline; citicoline) is an essential endogenous compound normally produced by the organism and is a source of cytidine and choline. Our recent studies on acute pain models demonstrate that intracerebroventricularly administered CDP-choline produces antinociception via supraspinal alpha-7 nicotinic acetylcholine receptors-mediated mechanism in rats. However, it remains to be elucidated which other supraspinal mechanisms are involved in the antinociceptive effect of CDP-choline. In this study, we investigated the role of the supraspinal opioidergic, GABAergic, alpha-adrenergic and serotonergic receptors in CDP-choline-induced antinociception. The antinociceptive effect of CDP-choline was evoked by the intracerebroventricular (i.c.v.) administration. Two different pain models were utilized: thermal paw withdrawal test and mechanical paw pressure test. The i.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 micromol) produced dose-dependent antinociception. Non-specific opioid receptor antagonist naloxone (10 microg; i.c.v.) and GABA(B) receptor antagonist CGP-35348 (20 microg; i.c.v.) pretreatments inhibited the antinociceptive effects of CDP-choline (1.0 micromol; i.c.v.). In contrast, the alpha-1 adrenergic receptor antagonist prazosin (20 microg; i.c.v.), alpha-2 adrenergic receptor antagonist yohimbine (30 microg; i.c.v.) and non-specific serotonin receptor antagonist methysergide (20 microg; i.c.v.) pretreatments had no effect on CDP-choline-induced antinociception in the thermal paw withdrawal test and in the mechanical paw pressure test. Therefore, it can be postulated that i.c.v. administered CDP-choline exerts antinociceptive effect mediated by supraspinal opioid and GABA(B) receptors in acute pain models. Furthermore, supraspinal alpha-adrenergic and serotonergic receptors do not appear to be involved in the antinociceptive effect of CDP-choline.