Lincoln M. Tracy

Meta-analytic evidence for decreased heart rate variability in chronic pain implicating parasympathetic nervous system dysregulation.

Abstract Both sympathetic and parasympathetic nervous systems are involved in regulating pain states. The activity of these systems seems to become disturbed in states of chronic pain. This disruption in autonomic balance can be measured through the assessment of heart rate variability (HRV), that is, the variability of the interval between consecutive heart beats. However, there is yet to be a systematic evaluation of the body of literature concerning HRV across several chronic pain conditions. Moreover, modern meta-analytical techniques have never been used to validate and consolidate the extent to which HRV may be decreased in chronic pain. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines, this study systematically evaluated and critically appraised the literature concerning HRV in people living with chronic pain. After screening 17,350 sources, 51 studies evaluating HRV in a chronic pain group met the inclusion criteria. Twenty-six moderate–high quality studies were included in quantitative meta-analyses. On average, the quality of studies was moderate. There were 6 frequency-domain and time-domain measures of HRV across a broad range of chronic pain conditions. High heterogeneity aside, pooled results from the meta-analyses reflected a consistent, moderate-to-large effect of decreased high-frequency HRV in chronic pain, implicating a decrease in parasympathetic activation. These effects were heavily influenced by fibromyalgia studies. Future research would benefit from wider use of standardised definitions of measurement, and also investigating the synergistic changes in pain state and HRV throughout the development and implementation of mechanism-based treatments for chronic pain.

Oxytocin and the modulation of pain experience: Implications for chronic pain management

In an acute environment pain has potential protective benefits. However when pain becomes chronic this protective effect is lost and the pain becomes an encumbrance. Previously unheralded substances are being investigated in an attempt to alleviate the burden of living with chronic pain. Oxytocin, a neuropeptide hormone, is one prospective pharmacotherapeutic agent gaining popularity. Oxytocin has the potential to modulate the pain experience due to its ubiquitous involvement in central and peripheral psychological and physiological processes, and thus offers promise as a therapeutic agent. In this review, we discuss previous effective applications of oxytocin in pain-free clinical populations and its potential use in the modulation of pain experience. We also address the slowly growing body of literature investigating the administration of oxytocin in clinical and experimentally induced pain in order to investigate the potential mechanisms of its reported analgesic actions. We conclude that oxytocin offers a potential novel avenue for modulating the experience of pain, and that further research into this area is required to map its therapeutic benefit.

Location, location, location: Variation in sensitivity to pain across the body

There is evidence that sensitivity to noxious stimuli differs between the sexes and across the body, but few studies have investigated differences in the perception and experience of acute pain stimuli across the body in healthy individuals.

Sex-specific effects of intranasal oxytocin on thermal pain perception: A randomised, double-blind, placebo-controlled cross-over study

Chronic neck and shoulder pain (CNSP) is a common musculoskeletal disorder in adults, which is linked to hypersensitivity to noxious stimuli. The hormone oxytocin has been implicated as a potential therapeutic for the management of chronic pain disorders, and has been suggested to have sex-specific effects on the salience of threatening stimuli. This study investigated the influence of intranasal oxytocin on the perception of noxious thermal stimuli. Participants were 24 individuals with CNSP lasting >12months (eight women), and 24 age- and sex-matched healthy, pain-free controls. In a randomised double-blind, placebo-controlled, cross-over study, participants attended two sessions, self-administering intranasal oxytocin (24 IU) in one session, and placebo in another. Participants rated intensity and unpleasantness of thermal heat stimuli at three body sites: the cervical spine, deltoid, and tibialis anterior, on 11-point numerical rating scales. Compared with placebo, intranasal oxytocin increased the perceived intensity of noxious heat stimuli in women with CNSP (Cohens d=0.71), but not in men with CNSP, or healthy, pain-free controls. Men and women displayed divergent sensitivity across target sites for ratings of pain intensity (partial eta squared=0.12) and pain unpleasantness (partial eta squared=0.24), irrespective of drug condition. Men were more sensitive at the cervical spine and deltoid, whereas women were more sensitive at the tibialis. These findings suggest that oxytocin and endogenous sex hormones may interact to influence the salience of noxious stimuli. The hyperalgesic effects of oxytocin in women suggest that caution should be taken when considering oxytocin in the management of chronic pain. TRIAL REGISTRATION CT-2016-CTN-01313-1; ACTRN12616000532404.

Sex differences in empathy for pain: What is the role of autonomic regulation?

Empathy involves both affective and cognitive components whereby we understand, and express concerns for, the experiences of others. Women typically have superior trait empathy compared with men, which seems to have a neurological basis with sex differences in the structure and function of neural networks involved in empathy. This study investigated sex differences in empathy for pain using the Empathy for Pain Scale, and examined whether these trait differences were associated with disruptions in autonomic regulation, specifically via the parasympathetic nervous system (measured through the square root of the mean squared differences of successive R-R intervals; RMSSD) both at rest and during a socioevaluative stress task (i.e., the serial sevens task). Compared with men, women reported higher empathic concern (Cohens r = .25) and affective distress (Cohens d = 0.65) toward another in pain. In both men and women, there was a decrease in lnRMSSD in the stress task compared to rest. Sex moderated the relationship between resting lnRMSSD and self-reported empathic concern. Specifically, there was no clear association between empathic concern and lnRMSSD in men whereas in women there was a negative relationship, with lower resting lnRMSSD associated with higher empathic concern, and higher lnRMSSD associated with lower levels of empathic concern that were similar to men. These findings suggest that empathic feelings may result from poorer psychophysiological regulation, and concur with previous research displaying sex-specific relationships between resting heart rate variability and emotion regulation abilities.

Heart Rate Variability and Sensitivity to Experimentally Induced Pain: A Replication

To the Editor, The neural systems involved in autonomic control and perception of pain are closely coupled, and extensive interactions between these sets of neural structures can be observed. The functional interaction of these systems is an important component of the pain regulatory process. Blood pressure and heart rate are both products of autonomic reactivity, and have been studied to specify the relationship between pain stimuli and autonomic reactions. Heart rate variability (HRV), by contrast, attempts to tease out the relative contributions of sympathetic and parasympathetic activity underlying autonomic reactivity, and therefore bears great potential to study autonomic nervous system (re)activity in experimental pain research. However, while several experimental studies have explored the effect of experimentally induced pain on HRV, only 2 previous studies have treated resting HRV as an independent variable, to investigate interindividual differences in pain sensitivity. Appelhans and Luecken found that HRV was associated with ratings of pain unpleasantness but not pain intensity in subjects receiving painful cold stimulation. In a recent study published in Pain Practice, NahmanAverbuch et al. found that the relationships between parasympathetic function, pain perception, and pain modulation were prominent only in individuals with higher anxiety, where higher parasympathetic arousal was associated with higher ratings of tonic heat pain and a more efficient conditioned pain modulation capacity (ie, a decrease in sensitivity to pain). In this letter, we aimed to replicate previous findings by Appelhans and Luecken to further elucidate the association of pain sensitivity and resting autonomic function. Data for this analysis was taken from the first session of a previous study investigating the 2-week test-retest reliability of the cold pressor task (CPT). Healthy undergraduate students were recruited at the SRH University Heidelberg from September 2012 through January 2013. Participants provided written informed consent and completed several questionnaires. Self-rated health (S-RH) was measured using the question “How do you rate your current health status?” on a 0 (“very bad”) to 6 (“excellent”) scale. Only subjects indicating an S-RH of ≥ 3 (“fair”) were included in the trial. The sample of participants included in this analysis consisted of 28 female and 6 male, healthy undergraduate students. The age range was 20 to 31 years (mean 22.85 years, SD = 2.46). Each participant was given a day of the week (Monday through Friday) and a time (between 9:00 am and 6:00 pm) when assessments would be made. Date and time of measurements were recorded by a protocol. Before the CPT, HRV was measured. Sociodemographic variables were assessed using a self-developed questionnaire. All participants received class credits or an allowance of 20€ for completion of the study. Heart rate variability was measured for 5 minutes in a sitting position immediately before hand immersion into cold water. A Polar RS800CX portable device (Polar Electro Inc., Bethpage, NY, U.S.A.) using a transmitter consisting of a stable polyamide case with electrodes attached to an elastic belt fixed to the chest of the subjects was used to record interbeat intervals (IBIs) at a sampling frequency of 1,000 Hz, providing a temporal resolution of 1 millisecond for each R–R interval. Device-specific software (Polar ProTrainer 5) was used to transfer recordings to a PC. IBI data (.txt files) were exported and analyzed using Kubios HRV (Biosignal Analysis and Medical Imaging Group, University Kuopio, Finland, Version 2.0). In line with the previous study, an autoregressive model was fitted to the RR-interval series, and the area under the power spectral density function within the low-frequency (LF; 0.04 to 0.15 Hz) and high-frequency bands (HF; 0.15 to 0.4 Hz) was derived, and underwent natural log transformation. The peak frequency of HRV power within the HF band was used as an estimate of respiratory rate. Cold pain sensitivity was assessed by immersing the nondominant hand up to the wrist in an acrylic glass tank with circulating water to prevent local warming. Water temperature was controlled constantly at 4°C (mean = 4.32°C; SD = 0.25°C) with a chilling device, and water pump, and measured with 3 digital thermometers at different spots. Subjects were told to keep their hands open rather than closed in a fist while they were immersed in the water. Before the immersion the subject was told to keep his or her hand in the water until the pain became intolerable, with a cutoff time of 4 minutes. The latencies to the first pain sensation (pain threshold) and to the intolerable pain (pain tolerance) were measured with a stopwatch in seconds. The

Effects of explicit cueing and ambiguity on the anticipation and experience of a painful thermal stimulus

Many factors can influence the way in which we perceive painful events and noxious stimuli, but less is known about how pain perception is altered by explicit knowledge about the impending sensation. This study aimed to investigate the impact of explicit cueing on anxiety, arousal, and pain experience during the anticipation and delivery of noxious thermal heat stimulations. Fifty-two healthy volunteers were randomised to receive explicit instructions about visual cue-stimulus temperature pairings, or no explicit instructions about the cue-stimulus pairs. A pain anxiety task was used to investigate the effects of explicit cueing on anticipatory anxiety, pain experience and electrophysiological responses. Participants who received explicit instructions about the cue-stimulus pairs (i.e., the relationship between the colour of the cue and the temperature of the associated stimuli) reported significantly higher subjective anxiety prior to the delivery of the thermal heat stimuli (p = .025, partial eta squared = .10). There were no effects of explicit cueing on subsequent pain intensity, unpleasantness, or the electrophysiological response to stimulus delivery. The perceived intensity and unpleasantness of the stimuli decreased across the blocks of the paradigm. In both groups anticipating the ambiguous cue elicited the largest change in electrophysiological arousal, indicating that not knowing the impending stimulus temperature led to increased arousal, compared to being certain of receiving a high temperature thermal stimulus (both p < .001). Perceived stimulus intensity varied between ambiguous and non-ambiguous cues, depending on the temperature of the stimulus. Together these findings highlight the impact and importance of explicit cueing and uncertainty in experimental pain studies, and how these factors influence the way healthy individuals perceive and react to noxious and innocuous thermal stimuli.

The effects of propranolol on heart rate variability and quantitative, mechanistic, pain profiling: a randomized placebo-controlled crossover study

Abstract Background and aims The autonomic nervous system (ANS) is capable of modulating pain. Aberrations in heart rate variability (HRV), reflective of ANS activity, are associated with experimental pain sensitivity, chronic pain, and more recently, pain modulatory mechanisms but the underlying mechanisms are still unclear. HRV is lowered during experimental pain as well as in chronic pain conditions and HRV can be increased by propranolol, which is a non-selective β-blocker. Sensitization of central pain pathways have been observed in several chronic pain conditions and human mechanistic pain biomarkers for these central pain pathways include temporal summation of pain (TSP) and conditioned pain modulation (CPM). The current study aimed to investigate the effect of the β-blocker propranolol, and subsequently assessing the response to standardized, quantitative, mechanistic pain biomarkers. Methods In this placebo-controlled, double-blinded, randomized crossover study, 25 healthy male volunteers (mean age 25.6 years) were randomized to receive 40 mg propranolol and 40 mg placebo. Heart rate, blood pressure, and HRV were assessed before and during experimental pain tests. Cuff pressure pain stimulation was used for assessment of pain detection (cPDTs) and pain tolerance (cPTTs) thresholds, TSP, and CPM. Offset analgesia (OA) was assessed using heat stimulation. Results Propranolol significantly reduced heart rate (p<0.001), blood pressure (p<0.02) and increased HRV (p<0.01) compared with placebo. No significant differences were found comparing cPDT (p>0.70), cPTT (p>0.93), TSP (p>0.70), OA-effect (p>0.87) or CPM (p>0.65) between propranolol and placebo. Conclusions The current study demonstrated that propranolol increased HRV, but did not affect pressure pain sensitivity or any pain facilitatory or modulatory outcomes. Implications Analgesic effects of propranolol have been reported in clinical pain populations and the results from the current study could indicate that increased HRV from propranolol is not associated with peripheral and central pain pathways in healthy male subjects.

Intranasal oxytocin reduces heart rate variability during a mental arithmetic task: A randomised, double-blind, placebo-controlled cross-over study

&NA; Heart rate variability (HRV) refers to variation in the interval between successive heart beats. Low HRV is an indicator of potential autonomic nervous system dysfunction. People with chronic pain often display autonomic dysregulation, especially in the parasympathetic nervous system. The hormone oxytocin has been shown to increase HRV in non‐clinical samples, but its potential impact on HRV in persons with chronic pain is unknown. This study investigated the impact of intranasal oxytocin on HRV in persons with chronic neck and shoulder pain. Participants included 24 individuals with chronic neck and shoulder pain lasting >12 months and 24 age‐ and sex‐matched pain‐free controls. In a randomised double‐blind, placebo‐controlled, cross‐over study, participants self‐administered intranasal oxytocin (24 IU) in one session, and placebo in another, before HRV was recorded at rest and during a mental arithmetic task. Intranasal oxytocin did not influence HRV at rest. However, compared to placebo, intranasal oxytocin elicited small decreases in low‐frequency and high‐frequency HRV in both groups during the mental arithmetic task. These results suggest that intranasal oxytocin may enhance the salience of the mental arithmetic task, leading to reduced engagement of the parasympathetic nervous system when completing the task. Further investigation and replication of these findings are required to improve our understanding of the effects of intranasal oxytocin on autonomic functioning both at rest and under cognitive stress. HighlightsHeart rate variability (HRV) is an index of autonomic regulation.People with chronic pain typically have low HRV.HRV was measured at rest, and during a mental arithmetic task.Oxytocin decreased HRV during the mental arithmetic task.Oxytocin may modulate salience of threatening stimuli.

Heart rate variability is associated with thermal heat pain threshold in males, but not females

Previous research has suggested that heart rate variability (HRV; the variability in the interval between successive heartbeats) can predict the perception of experimentally-induced pain (i.e., pain sensitivity). However, little research has sought to investigate sex-specific associations between HRV and pain sensitivity. This is an important consideration, given that sex differences in resting HRV have been observed, and there has been extensive debate about sex differences in sensitivity to experimentally-induced pain. We examined whether the association between resting HRV and sensitivity to experimentally-induced pain differed in men and women. Fifty-one pain free individuals (26 women, mean age = 21.9 years) participated. Resting electrocardiography (ECG) was collected during a paced breathing task (15 cycles per minute), and measures of HRV were extracted via Fast Fourier Transformation. Thermal heat pain threshold (i.e., the point at which the sensation was first perceived as painful, rather than warm) was measured with a Medoc Pathway Pain and Sensory Evaluation System. There were no sex differences in resting HRV or thermal heat pain threshold, nor did sex moderate the relationship between HRV and thermal heat pain threshold. However, there were significant positive relationships between thermal heat pain threshold and LF-HRV (r = 0.47), and HF-HRV (r = 0.43) in men, but not in women. The results suggest that higher pain threshold appears to be related to greater engagement of the inhibitory parasympathetic nervous system in men only, and that other biopsychosocial mechanisms may contribute to experimental pain experience in women. Future research is needed to study these mechanisms further, accounting for other factors known to influence nociceptive and cardiovascular regulatory processes (e.g., ethnicity, hormones).