Reduced Pain Ratings Research Articles

Increased Sympathetic Outflow Induces Adaptation to Acute Experimental Pain.

There are interrelationships between the autonomic nervous system and pain. This study aims to explore the effect of different autonomic manipulations on pain perception and modulation. Twenty healthy subjects (10 men and 10 women, mean age 25 ± 3 years) participated in this single-blinded, semi-randomized, controlled study, which included 2 study visits. Warm detection thresholds, heat pain thresholds, conditioned pain modulation (CPM), and pain adaptation were tested before and after administration of phenylephrine, clonidine, yohimbine, and saline. Changes in heart rate and blood pressure were found after all the pharmacological interventions. The only effect on pain measures was that yohimbine enhanced pain adaptation capacity while phenylephrine reduced it (P = 0.032). Several significant correlations were found between autonomic and pain parameters; greater decreases in heart rate after phenylephrine were associated with reduced pain ratings (r2 = 0.288, P = 0.018). In addition, enhanced pain adaptation was associated with higher total vascular resistance (r2 = 0.442, P = 0.01). Different effects of acute autonomic manipulations on experimental pain were found: an increase in sympathetic tone induced by yohimbine led to reduced pain sensitivity; a decrease in sympathetic tone with no effect on vagal-parasympathetic tone induced by phenylephrine led to reduction in pain adaptation capacity; and a decrease in sympathetic tone and increase in vagal parasympathetic tone by clonidine led to no change in pain adaptation capacity. While increased sympathetic outflow does facilitate pain adaptation, activation of either the sympathetic or parasympathetic limbs of the autonomic nervous system does not affect pain thresholds or CPM. Finally, a correlation exists between nociception and cardiovascular parameters only due to baroreflex activation.

A Prospective Safety Study of Autologous Adipose-Derived Stromal Vascular Fraction Using a Specialized Surgical Processing System

Autologous adipose-derived stromal vascular fraction (SVF) has been proposed as a remedy for a number of inflammatory, autoimmune, and degenerative conditions. This procedure had mainly been evaluated in veterinary medicine and outside the United States when this study was initiated. This study looks at adverse events to evaluate safety as its primary objective and secondarily follows efficacy of SVF as deployed through intra-articular injections and intravenous infusions for a variety of orthopedic and non-orthopedic conditions. We hypothesized that autologous SVF deployment using a specialized surgical processing system (the CSN Time Machine® system, trademark name for the MediKhan Lipokit/Maxstem system; MediKhan, Los Angeles, California) was safe (ie, minimally acceptable adverse events) and that clinical efficacy could be demonstrated. This was a prospective case series. After institutional review board approval, 1698 SVF deployment procedures were performed between 2011 and 2016 by us and other affiliates with our same system trained by us as a nearly closed sterile surgical lipotransfer procedure on 1524 patients with various degenerative, inflammatory, and autoimmune conditions with a majority involving the musculoskeletal system. All outcome test data were collected in an online database over a 5-year period. Our study shows a very low number of reported adverse events and a reduction in pain ratings after 6 months or more across a variety of musculoskeletal diseases and improvements in a variety of other degenerative conditions. Our system for producing adipose-derived SVF therapy for our patients was safe and benefits could be measured for a long time after SVF deployment. Further controlled long-term studies for specific disease conditions with large patient populations are necessary to further investigate the benefits observed.

Alpha-range visual and auditory stimulation reduces the perception of pain.

Alpha power is believed to have an inverse relationship with the perception of pain. Increasing alpha power through an external stimulus may, therefore, induce an analgesic effect. Here, we attempt to modulate the perception of a moderately painful acute laser stimulus by separately entraining three frequencies across the alpha band: 8, 10 and 12Hz. Participants were exposed to either visual or auditory stimulation at three frequencies in the alpha-band range and a control frequency. We collected verbal pain ratings of laser stimuli from participants following 10 minutes of flashing LED goggle stimulation and 10 minutes of binaural beat stimulation across the alpha range. Alterations in sleepiness, anxiety and negative mood were recorded following each auditory or visual alpha-rhythm stimulation session. A significant reduction in pain ratings was found after both the visual and the auditory stimulation across all three frequencies compared with the control condition. In the visual group, a significantly larger reduction was recorded following the 10-Hz stimulation than succeeding the 8- and 12-Hz conditions. This study suggests that a short presentation of auditory and visual stimuli, oscillating in the alpha range, have an analgesic effect on acute laser pain, with the largest effect following the 10-Hz visual stimulation. Pain reductions following stimulation in the alpha range are independent of sleepiness, anxiety, and negative moods. This study provides new behavioural evidence showing that visual and auditory entrainment of frequencies in the alpha-wave range can influence the perception of acute pain in humans.

Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans.

Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. Functional blockade of TRPV1-positive nociceptors by high-concentration capsaicin (verified by loss of heat pain) significantly reduced pain ratings to high frequency stimulation by 47% (P < 0.001), homotopic pain-long-term potentiation by 71% (P < 0.01), heterotopic pain-long-term potentiation by 92% (P < 0.001) and the area of secondary hyperalgesia by 76% (P < 0.001). The selective blockade of A-fibre conduction by nerve compression (verified by loss of first pain to pinprick) significantly reduced pain ratings to high frequency stimulation by 37% (P < 0.01), but not homotopic pain-long-term potentiation (-5%). It had a marginal effect on heterotopic pain-long-term potentiation (-35%, P = 0.059), while the area of secondary hyperalgesia remained unchanged (-2%, P = 0.88). In conclusion, all nociceptor subclasses contribute to high frequency stimulation-induced pain (with a relative contribution of C > Aδ fibres, and an equal contribution of TRPV1-positive and TRPV1-negative fibres). TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain-long-term potentiation. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic pain-long-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not heterotopic pain-long-term potentiation. TRPV1-negative A-fibres are the main afferents mediating pinprick pain and hyperalgesia, however, they do not appear to contribute to the induction of pain-long-term potentiation. These findings show that distinct peripheral fibre classes mediate induction of long-term potentiation-like pain amplification, its spatial spread to adjacent skin (i.e. secondary hyperalgesia), and the resulting enhanced sensitivity to pinprick in humans. Nociceptive afferents that induce pain amplification can be readily dissociated from those mediating pain. These findings add substantially to our understanding of the mechanisms of pain amplification, that form the basis for understanding the mechanisms of hyperalgesia encountered in patients.See Sandkühler (doi:10.1093/brain/awv193) for a scientific commentary on this article.

Massage Impact on Pain in Opioid-dependent Patients in Substance Use Treatment.

Chronic pain is a common cause of health care utilization and high levels of pain are pronounced in individuals engaged in methadone maintenance treatment. Although massage has been demonstrated to alleviate chronic pain symptoms, its use as an adjunctive therapy to modify pain during opioid-replacement treatment is absent from the literature. To consider the efficacy of Swedish massage in reducing pain in opioid-dependent patients with chronic pain receiving methadone treatment. Trial was conducted at a nonprofit methadone treatment center serving low-income patients. A randomized clinical trial with randomized to either 1) massage plus treatment-as-usual (TAU) (n = 27) or 2) TAU (n = 24). Durability of treatment effect was evaluated at Week 12. Eight weekly 50-minute Swedish massage sessions plus TAU or TAU alone. Pain, anxiety, depression, physical functioning, decreased substance use, and improvement in treatment engagement. Randomized participants were comparable at Baseline for demographic, pain, physical, and emotional variables. Massage group reported improved pain scores; worst pain had a clinically significant 2-point improvement while the other pain scores did not. Overall improvements were not observed in treatment engagement or levels of anxiety, depression, or physical functioning. A subgroup of the participants, who felt they could be pain-free, consistently reported improvements in pain from Baseline to Week 8, and this was most pronounced and clinically significant in the massage group. These preliminary findings do not support an overall clinically significant positive effect of Swedish massage on reduction in pain ratings or improvement in anxiety, depression, or treatment engagement in a substance-using, opioid-dependent population with chronic pain. Future nonpharmacologic pain research in marginalized substance-using populations may wish to consider some of the challenges and limitations faced in this project.

Social Support Attenuates Physiological Stress Responses and Experimental Pain Sensitivity to Cold Pressor Pain.

Social support improves health and has been shown to attenuate stress and pain. The precise characteristics of social support responsible for these effects, however, remain elusive. The purpose of this study is to examine the relative efficacy of social support versus a neutral non-verbal social presence to attenuate stress and pain. Seventy-six participants provided pain ratings and task assessments during a cold pressor task (CPT) in one of three conditions: verbal social support, neutral non-support, or alone. Reactivity to the CPT was assessed via cardiovascular measures, cortisol, and subjective ratings. Participants receiving social support showed attenuated blood pressure, heart rate, and cortisol reactivity, as well as reduced pain ratings, task difficulty, tension, and effort compared to neutral non-support and alone conditions. Social support, not the mere presence of another individual, attenuated stress and pain during a CPT. Given the negative health consequences of stress and pain, clinical studies incorporating social support into medical procedures and treatments are warranted.

Are there sex differences in placebo analgesia during visceral pain processing? A fMRI study in healthy subjects.

We explored sex differences in the neural mechanisms mediating placebo analgesia in an established visceral pain model involving painful rectal distensions in healthy volunteers. N = 15 men and N = 15 women underwent three consecutive functional magnetic resonance imaging sessions during which cued painful rectal distensions were delivered. After an adaptation session, positive expectations were induced with deceptive instructions regarding administration of an analgesic drug (placebo session). In the other session (control), truthful information about an inert substance was given. Sex differences in placebo-induced modulation of neural activation during anticipation and pain were analyzed along with ratings of expected and perceived pain intensity. Placebo-induced reductions in pain ratings were comparable between men and women. At the level of the brain, group comparisons with respect to differences between the placebo and control conditions revealed greater modulation of the posterior insula (regions-of-interest analysis: pFWE < 0.05) and dorsolateral prefrontal cortex (whole-brain analysis: p < 0.001, uncorrected) during pain anticipation in women. During pain, placebo-induced down-regulation of the insula was altered in women compared to men (ROI analysis: pFWE < 0.05). Our data provide first evidence supporting sex differences in pain-induced neural modulation during visceral placebo analgesia despite similar placebo-induced reductions in perceived pain intensity. These preliminary findings might contribute to elucidating mechanisms mediating placebo effects in clinical conditions associated with chronic abdominal pain such as in irritable bowel syndrome.

Dilution of a mepivacaine-adrenaline solution in isotonic sodium bicarbonate for reducing subcutaneous infiltration pain in ambulatory phlebectomy procedures: A randomized, double-blind, controlled trial

Varicose veins are treated under local infiltration anesthesia. Literature shows that adding sodium bicarbonate reduces the pain associated with local infiltration anesthesia. Nonetheless, sodium bicarbonate is underused. We sought to assess if the use of a solution of mepivacaine 2% plus adrenaline with sodium bicarbonate 1.4% results in less pain associated with local infiltration anesthesia preceding ambulatory phlebectomies, compared with standard preparation diluted with normal saline. In all, 100 adult patients undergoing scheduled ambulatory phlebectomy were randomized to receive either a solution of mepivacaine chlorhydrate 2% plus adrenaline in sodium bicarbonate 1.4% or a similar solution diluted in normal saline 0.9%. Median pain scores associated with local infiltration anesthesia reported in the intervention and control groups were 2 (SD=1.6) and 5 (SD=2.0) (P<.0001), respectively. A general linear model with bootstrapped confidence intervals showed that using the alkalinized solution would lead to a reduction in pain rating of about 3 points. Patients were not asked to distinguish the pain of the needle stick from the pain of the infiltration. Moreover, a complete clinical study of sensitivity on the infiltrated area was not conducted. Data obtained from this study may contribute to improve local infiltration anesthesia in ambulatory phlebectomy and other phlebologic procedures.

Intensity Thresholds for Aerobic Exercise-Induced Hypoalgesia

Despite many studies investigating exercise-induced hypoalgesia, there is limited understanding of the optimal intensity of aerobic exercise in producing hypoalgesic effects across different types of pain stimuli. Given that not all individuals are willing or capable of engaging in high-intensity aerobic exercise, whether moderate-intensity aerobic exercise (MAE) is associated with a hypoalgesic response and whether this response generalizes to multiple pain induction techniques needs to be substantiated. This study's purpose is to test for differences in the magnitude of pressure and heat pain modulation induced by MAE and vigorous-intensity aerobic exercise (VAE). Twelve healthy young males and 15 females completed one training session and three testing sessions consisting of 25 min of 1) stationary cycling at 70% HR reserve, 2) stationary cycling at 50% HR reserve, or 3) quiet rest (control). Pain testing was conducted on both forearms before and immediately after each condition and included the following tests: pressure pain thresholds, suprathreshold pressure pain test, static continuous heat test, and repetitive pulse heat pain test. Repeated-measures ANOVA was conducted on each pain measure. VAE and MAE reduced pain ratings during static continuous heat stimuli and repetitive heat pulse stimuli, with VAE producing larger effects. VAE also increased pressure pain thresholds, whereas neither exercise influenced suprathreshold pressure pain ratings. These results suggest that MAE is capable of producing a hypoalgesic effect using continuous and repetitive pulse heat stimuli. However, a dose-response effect was evident as VAE produced larger effects than MAE.

Non-pharmacological Intervention for Chronic Pain in Veterans: A Pilot Study of Heart Rate Variability Biofeedback.

Objective:Chronic pain is an emotionally and physically debilitating form of pain that activates the body's stress response and over time can result in lowered heart rate variability (HRV) power, which is associated with reduced resiliency and lower self-regulatory capacity. This pilot project was intended to determine the effectiveness of HRV coherence biofeedback (HRVCB) as a pain and stress management intervention for veterans with chronic pain and to estimate the effect sizes. It was hypothesized that HRVCB will increase parasympathetic activity resulting in higher HRV coherence measured as power and decrease self-reported pain symptoms in chronic pain patients.Study design:Fourteen veterans receiving treatment for chronic pain were enrolled in the pre-post intervention study. They were randomly assigned, with 8 subjects enrolled in the treatment group and 6 in the control group. The treatment group received biofeedback intervention plus standard care, and the other group received standard care only. The treatment group received four HRVCB training sessions as the intervention.Measures:Pre-post measurements of HRV amplitude, HRV power spectrum variables, cardiac coherence, and self-ratings of perceived pain, stress, negative emotions, and physical activity limitation were made for both treatment and control groups.Results:The mean pain severity for all subjects at baseline, using the self-scored Brief Pain Inventory (BPI), was 26.71 (SD=4.46; range=21–35) indicating a moderate to severe perceived pain level across the study subjects. There was no significant difference between the treatment and control groups at baseline on any of the measures. Post-HRVCB, the treatment group was significantly higher on coherence (P=.01) and lower (P=.02) on pain ratings than the control group. The treatment group showed marked and statistically significant (1-tailed) increases over the baseline in coherence ratio (191%, P=.04) and marked, significant (1-tailed) reduction in pain ratings (36%, P<.001), stress perception (16%, P=.02), negative emotions (49%, P<.001), and physical activity limitation (42%, P<.001). Significant between-group effects on all measures were found when pre-training values were used as covariates.Conclusions:HRVCB intervention was effective in increasing HRV coherence measured as power in the upper range of the LF band and reduced perceived pain, stress, negative emotions, and physical activity limitation in veterans suffering from chronic pain. HRVCB shows promise as an effective non-pharmacological intervention to support standard treatments for chronic pain.

Pain Relief after Isometric Exercise Is Not Task-Dependent in Older Men and Women

This study assessed the effect of isometric contractions that varied in intensity and duration on pain perception in adults older than 60 yr. Pain perception was measured in 24 men and women (mean ± SD age = 72.2 ± 6.2 yr) using a pressure pain device applied to the right index finger before and after isometric contractions of the left elbow flexor muscles of the following doses: 1) three brief maximal voluntary contractions (MVC), 2) 25% MVC held for 2 min, and 3) 25% MVC held to task failure. Older adults reported increased pain thresholds (58 s vs 49 s, P < 0.001) and decreased pain ratings (2.8 vs 3.4, P < 0.001) after exercise, and these changes were similar across all three tasks (P = 0.94 and P = 0.55, respectively). Sex differences were identified with older women reporting greater pain sensitivity (lower pain thresholds [P = 0.01] and higher pain ratings [P = 0.004]) and larger reductions in pain ratings than men (23% vs 9%, P = 0.003) after isometric contractions. Older adults experienced similar reductions in pain after several different intensities and durations of isometric contractions. Both older men and women experienced increases in pain threshold, but only older women experienced reductions in pain ratings.

Chronic pain in children and adolescents: 24-42 month outcomes of an inpatient/day hospital interdisciplinary pain rehabilitation program.

The purpose of this research was to describe 24-42 month outcomes of a combined inpatient/day hospital interdisciplinary pain rehabilitation program for children and adolescents with chronic pain and functional disability. One-hundred-seventy-three children and adolescents (mean age=15.1 years, SD=2.5) were treated in the three-week program. Mixed effects regression models (MERM) examined changes over time in pain ratings (0-10), school days missed by children and work days missed by parents in the preceding week, and the number of days hospitalized in the preceding month. Participants reported a significant decline in pain from admission to 24-42 month follow-up. The largest declines in pain occurred from discharge to 1-month follow-up (6.20 vs. 4.81 on a 0-10 numerical rating scale) and from 12 months to 24-42 month follow-up (4.90 vs. 3.56). Two distinct trajectories of treatment response were identified using growth mixture modeling: children with initially high pain ratings exhibited large reductions in pain ratings, while those with lower pain ratings at admission showed minimal reductions. Treatment resulted in significant reductions in school and work days missed and the number of days hospitalized (all p's < 0.001), with reductions evident at 1-month follow-up and maintained through 24-42 month follow-up. These results suggest that interdisciplinary pain rehabilitation is a promising approach to chronic pain and associated disability in children, with enduring improvements found 24-42 months following program completion. Distinct trajectories of treatment response were identified.

Changes in pain perception and hormones pre- and post-kumdo competition

The psychological stress of competition is a powerful stimulus affecting numerous hormones, which in turn change how pain is perceived. This study investigated whether a kumdo (kendo) team competition may be related to changes in hormones and pain. Seventeen healthy male kumdo practitioners participated in this experiment. Pain experiments were conducted by applying noxious stimuli with a thermal stimulator 10min before a kumdo competition and 30min post-competition. Serum testosterone, cortisol, beta-endorphin levels, pain thresholds, pain ratings at 48°C and during blood sampling (sampling pain), anxiety, blood pressure, and heart rate were measured pre- and post-competition. Anxiety, pain threshold, testosterone/cortisol ratio, and blood pressure were significantly higher pre-competition compared to post-competition, while cortisol and pain ratings were significantly lower pre-competition than post-competition. There were significant correlations between the number of previous competitions and testosterone levels both pre-competition and post-competition. In pre-competition measurements, sampling pain increased with an increase in systolic blood pressure, heart rate, and beta-endorphins, and a decrease in age. In post-competition measurements, sampling pain increased with an increase in diastolic blood pressure and a decrease in testosterone levels. These results indicate that severe psychological pre-competition stress was associated with reduced pain ratings, perhaps in order to improve athletic performance. This also suggests that competitors may be at risk of potential injury due to changes in pain perception, and careful consideration should be taken to avoid potential injury before and during competition.

Functional Connectivity of the Default Mode Network and Its Association With Pain Networks in Irritable Bowel Patients Assessed via Lidocaine Treatment

The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the DMN's internal connectivity and its temporal relationship (ie, functional network connectivity) with pain-related neural networks in chronic pain conditions is poorly understood, as is the DMN's sensitivity to analgesic effects. The current study assessed how DMN functional connectivity and its temporal association with 3 pain-related networks changed after rectal lidocaine treatment in irritable bowel syndrome patients. Eleven females with irritable bowel syndrome underwent a rectal balloon distension paradigm during functional magnetic resonance imaging in 2 conditions: natural history (ie, baseline) and lidocaine. Results showed increased DMN connectivity with pain-related regions during natural history and increased within-network connectivity of DMN structures under lidocaine. Further, there was a significantly greater lag time between 2 of the pain networks, those involved in cognitive and in affective pain processes, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects, and 2) reduced pain ratings via analgesia reflect DMN connectivity more similar to pain-free individuals. Findings show potential implications of this network as an approach for understanding clinical pain management techniques. PerspectiveThis study shows that lidocaine, a peripheral analgesic, significantly altered DMN connectivity and affected its relationship with pain-related networks. These findings suggest that the DMN, which is hypothesized to represent non-goal-oriented activity, is sensitive to analgesic effects and could be useful to understand pain treatment mechanisms.

Music-induced analgesia in chronic pain: Efficacy and assessment through a primary-task paradigm

Research into music-induced analgesia, the ability of music to affect the perception of pain, has under-represented the non-acute, chronic pain population. This longitudinal study aimed to investigate the impact of music listening on chronic pain. In order to extend questionnaire-based approaches of pain assessment, a computerized visual search task was used before and after music listening as an objective measure of pain-related cognitive processing difficulties. Twenty-three participants (chronic pain sufferers or age/gender matched controls) listened to music for 28 days. Questionnaire-based results indicated that music listening consistently reduced pain intensity, unpleasantness and anxiety levels in the short term. However, there were no long-term or cumulative changes in pain relief or anxiety, with participant ratings at baseline comparable to those at 28 days. Visual search task performance demonstrated that chronic pain sufferers showed pain-related cognitive processing inhibitions on the target deviations demanding the greatest processing capacity. This suggests that, though music-induced analgesia was demonstrated through reduced pain ratings, chronic pain continued to interfere with cognitive processing. Durability of music-induced analgesia is therefore likely to be time-limited and hindered by pain-related attentional disruption, reduced engagement and low absorption levels. Explanations of results and suggestions for alternative objective measures of music listening interventions are offered.

No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

BackgroundNasal insufflation of CO2 has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO2 inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO2 on a human model of craniofacial pain elicited by nasal application of capsaicin.MethodsIn a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO2 or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO2 or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec.ResultsContrary to previous animal studies, the effects of CO2 on experimental trigeminal pain were only marginal. In the first experiment, CO2 reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F1,47 = 4.438; p = 0.041) and the interaction term TIME*GROUP (F2.6,121.2 = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO2 or placebo with no significant changes for the main factors or the interaction term.ConclusionsAlthough mild modulatory effects of low-flow intranasal CO2 could be seen in this human model of TRPV-1 mediated activation of nociceptive trigeminal neurons, utility is limited as observed changes in pain ratings are clinically non-significant.

The PICHFORK (Pain InCHildren Fentanyl OR Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial

BackgroundThe effectiveness of intranasal (IN) fentanyl as an analgesic for painful pediatric limb injuries in the Emergency Department (ED) has been reported previously. However, efficacy of IN ketamine in sub-dissociative doses is not well studied in the ED setting. A non-blinded pilot study undertaken by this study group suggested that IN ketamine showed similar analgesic effectiveness to that reported with IN fentanyl in similar non-blinded studies. The aim of this randomized, controlled, equivalence trial is to compare the analgesic effect of sub-dissociative dose IN ketamine with IN fentanyl for children with isolated musculoskeletal limb injuries.Methods/DesignThis is a prospective, randomized, controlled, double-blind equivalence trial of children agedthree to thirteen years and less than 50 kg body weight, with isolated musculoskeletal limb injury, presenting to the ED with moderate to severe pain, defined as a verbal response of at least six to a standard 11-point scale (0 = none, 10 = worst pain imaginable). Pain score, sedation, satisfaction with analgesic intervention, and adverse effects will be assessed over a 60 minute interval for each participant. Intranasal ketamine (1 mg/kg) or fentanyl (1.5 microgram/kg) will be administered via blinded syringe and mucosal atomization device in a standardized volume at 0.03 ml/kg, with a maximum volume of 1.5 ml divided equally to both nares. Participants will also receive 10 mg/kg ibuprofen orally. The primary outcome measure will be median change in pain score from pre-administration to 30 minutes post-administration. Non-parametric Mann–Whitney U tests will be computed to compare median change in the primary outcome measure for IN ketamine and fentanyl. A sample size of 36 participants per group is needed to detect the expected 40 mm reduction in pain rating with a 95% confidence interval (CI) no greater than ± 10 mm at 30 minutes. Rescue analgesia will be given as IN fentanyl or intravenous morphine.DiscussionThis is the first randomized-controlled trial comparing the efficacy of these two analgesic agents via the intranasal route. If IN ketamine is found to be equally effective to IN fentanyl for this indication, it will provide another analgesic agent that may be considered for the relief of acute pain in children in the ED.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12612000795897.

Personality Trait Predictors of Placebo Analgesia and Neurobiological Correlates

Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here, we assessed psychological traits in 50 healthy controls as to their capacity to predict placebo analgesic effects, placebo-induced activation of μ-opioid neurotransmission and changes in cortisol plasma levels during a sustained experimental pain challenge (hypertonic saline infused in the masseter muscle) with and without placebo administration. Statistical analyses showed that an aggregate of scores from Ego-Resiliency, NEO Altruism, NEO Straightforwardness (positive predictors) and NEO Angry Hostility (negative predictor) scales accounted for 25% of the variance in placebo analgesic responses. Molecular imaging showed that subjects scoring above the median in a composite of those trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the subgenual and dorsal anterior cingulate cortex (ACC), orbitofrontal cortex, insula, nucleus accumbens, amygdala and periaqueductal gray (PAG). Endogenous opioid release in the dorsal ACC and PAG was positively correlated with placebo-induced reductions in pain ratings. Significant reductions in cortisol levels were observed during placebo administration and were positively correlated with decreases in pain ratings, μ-opioid system activation in the dorsal ACC and PAG, and as a trend, negatively with NEO Angry Hostility scores. Our results show that personality traits explain a substantial proportion of the variance in placebo analgesic responses and are further associated with activations in endogenous opioid neurotransmission, and as a trend cortisol plasma levels. This initial data, if replicated in larger sample, suggest that simple trait measures easily deployable in the field could be utilized to reduce variability in clinical trials, but may also point to measures of individual resiliency in the face of aversive stimuli such as persistent pain and potentially other stressors.

The effect of transcutaneous vagus nerve stimulation on pain perception – An experimental study

BackgroundRecent preclinical work strongly suggests that vagus nerve stimulation efficiently modulates nociception and pain processing in humans. Most recently, a medical device has offered a transcutaneous electrical stimulation of the auricular branch of the vagus nerve (t-VNS) without any surgery. ObjectiveOur study investigates whether t-VNS may have the potential to alter pain processing using a controlled design. MethodsDifferent submodalities of the somatosensory system were assessed with quantitative sensory testing (QST) including a tonic heat pain paradigm in 48 healthy volunteers. Each subject participated in two experimental sessions with active t-VNS (stimulation) or sham t-VNS (no stimulation) on different days in a randomized order (crossed-over). One session consisted of two QST measurements on the ipsi- and contralateral hand, each before and during 1 h of a continuous t-VNS on the left ear using rectangular pulses (250 μS, 25 Hz). ResultsWe found an increase of mechanical and pressure pain threshold and a reduction of mechanical pain sensitivity. Moreover, active t-VNS significantly reduced pain ratings during sustained application of painful heat for 5 min compared to sham condition. No relevant alterations of cardiac or breathing activity or clinical relevant side effects were observed during t-VNS. ConclusionsOur findings of a reduced sensitivity of mechanically evoked pain and an inhibition of temporal summation of noxious tonic heat in healthy volunteers may pave the way for future studies on patients with chronic pain addressing the potential analgesic effects of t-VNS under clinical conditions.

Temporal changes in cortical activation during distraction from pain: A comparative LORETA study with conditioned pain modulation

Methods to cognitively distract subjects from pain and experimental paradigms to induce conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls or DNIC) have each highlighted activity changes in closely overlapping cortical areas. This is the first study, to our knowledge, to compare cortical activation changes during these 2 manipulations in the same experimental set-up. Our study sample included thirty healthy young right handed males capable of expressing CPM. We investigated brief consecutive time windows using 32-channel EEG-based sLORETA, to determine dynamic changes in localized cortical potentials evoked by phasic noxious heat stimuli to the left volar forearm. This was performed under visual cognitive distraction tasks and conditioning hot-water pain to the right hand (CPM), both individually and simultaneously. Previously we have shown that for CPM, there is increased activity in frontal cortical regions followed by reduced activation of the somatosensory areas, suggesting a pain inhibitory role for these frontal regions. We now observed that distraction caused a different extent of cortical activation; greater early activation of frontal areas (DLPFC, OFC and caudal ACC at 250–350ms post-stimulus), yet lesser reduction in the somatosensory cortices, ACC, PCC and SMA after 350ms post-stimulus, compared to CPM. Both CPM and distraction reduced subjective pain scores to a similar extent. Combining CPM and distraction further reduced pain ratings compared to CPM and distraction alone, supporting the dissimilarity of the mechanisms of pain modulation under these 2 manipulations. The results are discussed in terms of the differential functional roles of the prefrontal cortex.