Sex-Related Effects of Adrenergic Drugs on Conditioned Pain Modulation: A Randomized Controlled Cross-Over Double-Blind Trial.

Objective: Endogenous pain inhibition can be investigated using conditioned pain modulation (CPM). CPM efficacy has been reported to be influenced by various factors, such as gender and cardiovascular (autonomic) activity. The aim of this study is to describe the effect of pharmacological manipulations of autonomic activity on CPM efficacy. Methods: Thirty healthy participants were enrolled to assess CPM efficacy in 4 experimental sessions. The first session consisted of the determination of baseline CPM effectiveness. The three following sessions were performed in a randomized order and consisted of the injection of (1) esmolol, (2) ephedrine, or (3) placebo, before the conditioning stimulus. Pain intensity induced by using a contact heat stimulation thermode was compared before and after a cold-pressure conditioning stimulus to evaluate CPM effectiveness. Results: Our results show that inhibiting sympathetic nervous activity with esmolol did not have a significant effect on CPM. Conversely, enhancing sympathetic nervous activity with ephedrine increased CPM effectiveness in healthy women but decreased it in men. Conclusions: Increasing sympathetic activity with adrenergic agonists, such as ephedrine, could improve CPM effectiveness in women. It will be interesting to verify if the same results are present in patients suffering from chronic pain and if adrenergic agonists could have better therapeutic effects in women showing reduced CPM effectiveness.

Beneficial Effects of Regular Physical Activity on Exercise-Induced Analgesia in Adolescent Males.

PURPOSE: To evaluate exercise-induced analgesia (EIA) effectiveness in healthy adolescent males and to investigate possible associations between EIA and physiological/psychological variables. METHODS: Twenty-eight healthy adolescent males (14-17 y) participated in this study. EIA was evaluated by comparing perceptions of heat pain stimulations before and after an increasing maximal load test on a cycle ergometer (VO2max). RESULTS: Pain intensity for mild and strong heat pain stimulations significantly decreased following physical exercise (mild: EIA = 28.6%; 95% confidence interval, 0.9-1.9; P < .001 and strong: EIA = 11.3%; 95% confidence interval, 0.3-1.4; P = .002). The number of physical activity hours per week was positively correlated with the effectiveness of EIA for mild and strong pain intensity (r = .41, P = .03 and r = .43, P = .02, respectively). CONCLUSIONS: Intense physical exercise decreases perception of intensity of experimental heat pain in healthy adolescent males. The least physically active adolescents have reduced EIA effectiveness to experimental heat pain stimulations compared with physically active ones. Adolescents adopting an active lifestyle have more endogenous pain inhibition and could, therefore, potentially be less disposed to suffer from chronic pain later in life.

Reduced endogenous pain inhibition in adolescent girls with chronic pain.

Background and aims Chronic pain is affecting a growing number of individuals including adolescents. Different endogenous pain inhibitory systems could confer protection against development of chronic pain. Decreased pain perception can be observed following intense pain (i.e. conditioned pain modulation - CPM) or after physical exercise (i.e. exercise-induced analgesia - EIA). Reduced effectiveness of pain inhibitory mechanisms have been reported in several chronic pain conditions. However, the extent of these dysfunctions has not been thoroughly investigated in adolescents suffering from chronic pain. Our hypothesis was that adolescents suffering from chronic pain have less effective CPM and EIA than pain-free teenagers. Methods Twenty-five healthy adolescent girls and 16 teenage girls with chronic pain participated in this study. Only girls were included in this investigation, since chronic pain is more prevalent in females. The effectiveness of CPM was assessed by comparing heat pain stimulations (individually adapted to induce mild pain intensity) performed with a thermode before and after a cold pressor test (CPT; 2 min, 10 °C). EIA was evaluated by comparing pain intensity produced by an ice cube placed on the forearm before and after a graded exercise test on a cycle ergometer. Results Pain intensity produced by heat pain stimulations decreased following CPT in healthy (p<0.05), but not in chronic pain adolescent girls (p=0.4). Pain intensity induced by the ice cube was reduced after exercise in healthy (p<0.05), but not in chronic pain adolescents (p=0.9). The effectiveness of CPM and EIA was inferior in teenage girls suffering from chronic pain compared to healthy participants (p<0.05). Conclusions Endogenous pain inhibitory mechanisms triggered by intense pain or by physical exercise are effective in healthy adolescent girls. Teenage girls living with chronic pain do not show diminished pain perception after a CPT or a graded exercise test. These results suggest that pain inhibitory mechanisms such as CPM and EIA are ineffective in adolescent girls suffering from chronic pain. Implications In a wider context, the findings of the present research could help understand better the mechanisms involved in the development of chronic pain. Improved comprehension of this subject might help prevent chronic pain conditions and thus, reduce the negative impacts of this burden.

Increased spinal pain sensitization in major depressive disorder: A pilot study.

Although patients suffering from major depressive disorder (MDD) often complain from painful symptoms, the relationship between experimental pain processes and depression has yet to be clearly characterized. Only recently have studies employing temporal summation (TS) paradigms offered preliminary insight into the co-occurrence of pain and depression. This study sets out to evaluate the contribution of spinal and supraspinal processes in pain sensitization in MDD using a TS paradigm. Thirteen volunteers with no psychiatric disorders (controls) and fourteen MDD subjects were included in the analysis. Low-(0.14Hz) and high-(1Hz) frequency intermittent stimulations of the sural nerve were used to induce TS. Spinal pain sensitization was quantified by measuring the change in the amplitude of the nociceptive-specific flexion reflex (NFR) response, and supraspinal pain sensitization was obtained by measuring change in subjective pain rating, from the low- to high-frequency stimulation condition. We found an increased sensitization in the NFR response (p<0.05) in MDD subjects in the high-frequency condition, which did not translate into an increase of their subjective responses. However, we found a positive association between spinal sensitization and painful somatic symptoms in MDD subjects. Together, these results suggest increased spinal pain sensitization in MDD, which might explain the high prevalence of painful somatic symptoms in these patients.

Altered autonomic nervous system reactivity to pain in trigeminal neuralgia.

BACKGROUND: In the past two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. METHODS: Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. RESULTS: At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p values >0.05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared with healthy controls (all p values <0.05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r=-.58, p<0.05). CONCLUSIONS: These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain.

The role of cardiovascular activity in fibromyalgia and conditioned pain modulation.

Fibromyalgia (FM) is a chronic widespread pain condition of unknown origin. Reduced endogenous pain inhibition could be related to high pain sensitivity in FM. Associations between conditioned pain modulation (CPM) and cardiovascular responses to pain have been observed in healthy subjects (HS). Because reduced cardiovascular reactivity to various stressors has been reported in FM patients, we investigated relationships between CPM and cardiovascular response to the cold pressor test (CPT) in 22 FM patients and 25 HS. CPM was evaluated by comparing pain intensity produced by a 120-second heat test stimulus (HTS) before and after a CPT (2minutes, 12°C). The CPT, used to activate CPM, produced greater pain intensity in FM patients. Patients with FM had higher heart rates than HS at baseline and during CPT. Higher heart rate was related with higher pain intensity during the CPT. Blood pressure increments during CPT were weaker in the FM group. CPM was less effective in FM patients than in HS. Importantly, systolic blood pressure responses during CPT were positively related to CPM effectiveness, suggesting that reduced blood pressure response during the conditioning stimulus could be involved in CPM dysfunction in the FM group. Higher heart rate could be implicated in the greater sensitivity to cold pain in FM. Patients with FM have reduced blood pressure response to a painful CPT. Reduced cardiovascular reactivity to pain could have important involvement in diminished endogenous pain inhibition efficacy and FM pathophysiology.

Cardiovascular influences on conditioned pain modulation.

Conditioned pain modulation (CPM) (ie, diffuse noxious inhibitory controls) is characterized by reduced perception of pain caused by intense pain in a remote body area. The conditioning stimuli used to trigger CPM causes pain, but also important cardiovascular responses. Higher blood pressure has been associated with reduced pain sensitivity. Descending pain inhibitory mechanisms such as CPM could be involved in this relationship. We investigated the associations between CPM and cardiovascular responses during the cold-pressor test (CPT). Heat pain threshold and tolerance were evaluated in 26 (13 men, 13 women) healthy subjects. CPM was evaluated by comparing pain intensity produced by a 120-second heat stimulation before and after a CPT (5 minutes, 7°C). Heart rate, blood pressure, and baroreflex sensitivity were monitored at rest and during CPT to evaluate cardiovascular responses. We observed a positive relationship between resting blood pressure and heat pain tolerance. The CPT caused important heart rate and blood pressure increases. CPT also reduced pain intensity during the subsequent heat pain-stimulus, indicating effective CPM. A significant positive association was observed between CPM magnitude and the increase in blood pressure during the CPT. These results show that resting blood pressure values are related to acute pain tolerance, while descending pain inhibition is associated with increases in blood pressure. The rise in blood pressure caused by the conditioning stimulus is an important factor predicting the extent of endogenous pain inhibition in healthy subjects.

Comparing pain modulation and autonomic responses in fibromyalgia and irritable bowel syndrome patients.

OBJECTIVES: Past studies confirm that patients with fibromyalgia (FM) and irritable bowel syndrome (IBS) show similar pain processing dysfunctions, such as reduced pain inhibition and aberrant autonomic nervous system (ANS) responses. However, patients with FM and IBS have rarely been investigated in the same study. The aim of the present study, therefore, was to compare descending pain inhibition, pain sensitivity, and ANS reactivity to pain in FM, IBS, and healthy controls (HC). METHODS: Female patients with FM (n=10), IBS (n=13), and HCs (n=10) were exposed to multiple cold water (12°C) immersions to study pain sensitivity and descending pain inhibition. Heart rate variability was also assessed during immersions. RESULTS: Pain intensity scores were highest in FM, intermediate in IBS, and smallest in HCs. In contrast, pain inhibition was absent in FM, intermediate in IBS, and strongest in HCs. Importantly, controlling for differences in pain inhibition abolished group differences in pain sensitivity. Heart rate variability analyses confirmed that, in response to mild levels of pain, patients with FM showed greater sympathetic activity whereas HCs showed greater parasympathetic activity. Patients with IBS showed intermediate ANS responses. DISCUSSION: Our results confirm the presence of graded levels of somatic hyperalgesia across patients with IBS and FM. A similar pattern of result was observed for pain inhibitory dysfunctions. These pain processing changes were accompanied by abnormal autonomic responses, which maintained patients (principally patients with FM) in a state of sympathetic hyperactivity. Results suggest that patients with IBS and FM may present common, but graded, pain processing and autonomic dysfunctions.

Sex differences in perceived pain are affected by an anxious brain.

Decades of research confirm that women have greater pain sensitivity than men. Women also show greater overall anxiety sensitivity than men. Given these differences, we hypothesized that sex differences in anxiety would explain sex differences in experienced pain and physiological responses to pain (at both spinal and cortical levels). By measuring subjective pain, state/trait anxiety, nociceptive flexion reflexes, and somatosensory evoked potentials (SEPs), it was possible to test the effects of anxiety on the processing of painful drives at different levels of the neuraxis while also documenting the role played by anxiety on sex differences in experienced pain. Results confirm that women are indeed more sensitive to pain than men. Importantly, this difference was accompanied by a significant sex difference in cortical activity (SEP amplitude) but not spinal nociceptive activity, suggesting that much of the sex difference in experienced pain is attributable to variations in thalamocortical processing and to ensuing changes in the appraisal of and/or emotional response to noxious insult. In support of this claim, we found that sex differences in cortical activity and subjective pain disappeared when trait anxiety was controlled for. This means that stable predispositions to respond with heightened apprehension contribute to baseline pain sensitivity differences between the sexes. These results indicate that the modulatory effect of affect on pain-related brain processes may explain why men and women experience painful shocks so differently. In our study, the mediating role of anxiety on sex differences in pain was tested and confirmed using path analysis.

Respiratory effects on experimental heat pain and cardiac activity.

OBJECTIVE: Slow deep breathing has been proposed as an effective method to decrease pain. However, experimental studies conducted to validate this claim have not been carried out. DESIGN: We measured thermal pain threshold and tolerance scores from 20 healthy adults during five different conditions, namely, during natural breathing (baseline), slow deep breathing (6 breaths/minute), rapid breathing (16 breaths/minute), distraction (video game), and heart rate (HR) biofeedback. We measured respiration (rate and depth) and HR variability from the electrocardiogram (ECG) output and analyzed the effects of respiration on pain and HR variability using time and frequency domain measures of the ECG. RESULTS: Compared with baseline, thermal pain threshold was significantly higher during slow deep breathing (P = 0.002), HR biofeedback (P < 0.001), and distraction (P = 0.006), whereas thermal pain tolerance was significantly higher during slow deep breathing (P = 0.003) and HR biofeedback (P < 0.001). Compared with baseline, only slow deep breathing and HR biofeedback conditions had an effect on cardiac activity. These conditions increased the amplitude of vagal cardiac markers (peak-to-valley, P < 0.001) as well as low frequency power (P < 0.001). CONCLUSION: Slow deep breathing and HR biofeedback had analgesic effects and increased vagal cardiac activity. Distraction also produced analgesia; however, these effects were not accompanied by concomitant changes in cardiac activity. This suggests that the neurobiology underlying respiratory-induced analgesia and distraction are different. Clinical implications are discussed, as are the possible cardiorespiratory processes responsible for mediating breathing-induced analgesia.