Effects of conditioned pain modulation on Capsaicin-induced spreading muscle hyperalgesia in humans.

OBJECTIVES: Muscle pain can be associated with hyperalgesia that may spread outside the area of primary injury due to both peripheral and central sensitization. However, the influence of endogenous pain inhibition is yet unknown. This study investigated how endogenous pain inhibition might influence spreading hyperalgesia in experimental muscle pain. METHODS: Conditioned pain modulation (CPM) was assessed in 30 male volunteers by cold pressor test at the non-dominant hand as conditioning and pressure pain thresholds (PPT) at the dominant 2nd toe as test stimuli. Subjects were classified as having inhibitory or facilitating CPM based on published reference values. Subsequently, muscle pain and hyperalgesia were induced by capsaicin injection into the non-dominant supraspinatus muscle. Before and 5, 10, 15, 20, 30, 40, 50 and 60 min later, PPTs were recorded at the supraspinatus, infraspinatus and deltoid muscle, ring finger and toe. RESULTS: Compared to baseline, PPTs decreased at the supraspinatus, infraspinatus and deltoid muscle (p≤0.03), and increased at the finger and toe (p<0.001). In facilitating CPM (n=10), hyperalgesia occurred at 5, 10, 15, 20 and 40 min (p≤0.026). In inhibitory CPM (n=20), hyperalgesia only occurred after 10 and 15 min (p≤0.03). At the infraspinatus muscle, groups differed after 5 and 40 min (p≤0.008). CONCLUSIONS: The results suggest that facilitating CPM is associated with more spreading hyperalgesia than inhibitory CPM. This implies that poor endogenous pain modulation may predispose to muscle pain and spreading hyperalgesia after injury, and suggest that strategies to enhance endogenous pain modulation may provide clinical benefits.

Physician anaesthesia providers in Switzerland today and tomorrow: results of the National Anaesthesia Workforce Study (NAWOS).

AIMS OF THE STUDY: The Swiss healthcare system is highly ranked, given its unrestricted access to specialised care and short waiting lists for surgery. However, the need for anaesthetic and surgical care is escalating owing to the increasing size and ageing of the Swiss population. In addition, to address the persistent and recurrent SARS-CoV-2 pandemic crisis, the speciality of anaesthesia is under tremendous pressure to maintain an effective workforce in order to address population needs. The current number, characteristics and future evolution of the physician anaesthesia workforce in Switzerland are currently unknown. The purpose of this study was to assess the size and professional and sociodemographic characteristics of the current anaesthesia workforce in Switzerland and to forecast its development up to 2034. METHODS: We performed a cross-sectional study using a 150-item questionnaire prepared by the National Anaesthesia Workforce Study Group (NAWOS). We included all physicians (trainees and certified) practising anaesthesia in Switzerland. We collected demographic and professional information, such as the current position, hospital characteristics, workload, number of shifts and future life plans. We built a computer-based Markov model with Monte Carlo simulations to project both supply and demand for physician anaesthesia provider positions. RESULTS: Of the 2661 distributed questionnaires, 1985 (74.2%) were completed and returned. We found that the average age of anaesthesiologists practising in Switzerland was 45.2 years, with 44.3% of them being women and 76.9% holding a Swiss specialist title. Only 59.6% of respondents worked full time. The forecasting model showed a steady increase in the number of anaesthesiologists retiring by 2034, with 27% of full-time equivalent jobs being lost in the next 8 years. Even if existing full-time equivalent training positions are all filled, a gradual deficit of anaesthesiologists is to be expected after 2022, and the deficit should culminate in 2034 with a deficit ratio of 0.87. CONCLUSIONS: Due to the upcoming high retirement rate of anaesthesiologists, Switzerland is likely to face a shortage of anaesthesiologists in the near future. To compensate for the shortage, the country will likely increase its reliance on medical staff trained abroad. Southern and eastern cantons of Switzerland are particularly at risk, given that they already heavily rely on foreign anaesthesia workforce. This reliance should be considered a national priority because anaesthesiologists are heavily involved in both the treatment of patients with respiratory complications of SARS-CoV2 infection and the care of surgical patients, the number of which is expected to rise steadily in upcoming years.

Anti-nociceptive effects of oxytocin receptor modulation in healthy volunteers-A randomized, double-blinded, placebo-controlled study.

BACKGROUND: There is increasing evidence for oxytocin as a neurotransmitter in spinal nociceptive processes. Hypothalamic oxytocinergic neurons project to the spinal dorsal horn, where they activate GABA-ergic inhibitory interneurons. The present study tested whether the long-acting oxytocin-analogue carbetocin has anti-nociceptive effects in multi-modal experimental pain in humans. METHODS: Twenty-five male volunteers received carbetocin 100 mcg and placebo (0.9% NaCl) on two different sessions in a randomized, double-blinded, cross-over design. Multi-modal quantitative sensory testing (QST) including a model of capsaicin-induced hyperalgesia and allodynia were performed at baseline and at 10, 60 and 120 min after drug administration. QST data were analysed using mixed linear and logistic regression models. Carbetocin plasma concentrations and oxytocin receptor genotypes were quantified and assessed in an exploratory fashion. RESULTS: An anti-nociceptive effect of carbetocin was observed on intramuscular electrical temporal summation (estimated difference: 1.26 mA, 95% CI 1.01 to 1.56 mA, p = .04) and single-stimulus electrical pain thresholds (estimated difference: 1.21 mA, 95% CI 1.0 to 1.47 mA, p = .05). Furthermore, the area of capsaicin-induced allodynia was reduced after carbetocin compared to placebo (estimated difference: -6.5 cm2 , 95% CI -9.8 to -3.2 cm2 , p < .001). CONCLUSIONS: This study provides evidence of an anti-nociceptive effect of carbetocin on experimental pain in humans. SIGNIFICANCE: This study provides evidence of the anti-nociceptive effect of intravenous administration of the oxytocin agonist carbetocin in healthy male volunteers.

Reference values of conditioned pain modulation.

Background and aims Endogenous pain modulation can be studied in humans by conditioned pain modulation (CPM): pain induced by a test stimulus is attenuated by a distantly applied noxious conditioning stimulus. The detection of impaired CPM in individual patients is of potential importance to understand the pathophysiology and predict outcomes. However, it requires the availability of reference values. Methods We determined reference values of CPM in 146 pain-free subjects. Pressure and electrical stimulation were the test stimuli. For electrical stimuli, we recorded both pain threshold and threshold for the nociceptive withdrawal reflex. Cold pressor test was the conditioning stimulus. The 5th, 10th and 25th percentiles for the three tests were computed by quantile regression analyses. Results The average thresholds increased after the conditioning stimulus for all three tests. However, a subset of subjects displayed a decrease in thresholds during the conditioning stimulus. This produced negative values for most of the computed percentiles. Conclusions This study determined percentile reference values of CPM that can be used to better phenotype patients for clinical and research purposes. The negative value of percentiles suggests that a slightly negative CPM effect can be observed in pain-free volunteers. Implications Pain facilitation rather than inhibition during the conditioning stimulus occurs in some pain-free volunteers and may not necessarily represent an abnormal finding.

Effect of single-dose imipramine on chronic low-back and experimental pain. A randomized controlled trial.

Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed. A single oral dose of imipramine 75 mg was compared to active placebo (tolterodine 1 mg) in 50 patients (32 females) with chronic non-specific low-back pain. Intensity of low-back pain was assessed on a 0-10 numeric rating scale at baseline and every 30 minutes after drug intake. Multimodal QST were performed at baseline and in hourly intervals for 2 hours. Pharmacogenetic influences of cytochrome P450 were addressed by CYP2D6 genotyping. No significant analgesic effect was detected neither on low-back pain nor on any of the sensory tests in the overall analyses. However, evidence for an interaction of the imipramine effect and CYP2D6 genotype was found for electrical and for pressure pain detection thresholds. Intermediate but not extensive metabolizers had a 1.20 times greater electrical pain threshold (95%-CI 1.10 to 1.31) and a 1.10 times greater pressure pain threshold (95%-CI 1.01 to 1.21) 60 minutes after imipramine than after placebo (p<0.001 and p = 0.034, respectively). The present study failed to demonstrate an immediate analgesic effect of imipramine on low-back pain. Anti-nociceptive effects as assessed by quantitative sensory tests may depend on CYP2D6 genotype, indicating that metabolizer status should be accounted for when future studies with tricyclic antidepressants are undertaken.

Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity.

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain.

INTRODUCTION: Quantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. METHODS: In this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≥30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. RESULTS: Significant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65, 95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64, 95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63, 95%-CI 0.48 to 0.79). CONCLUSIONS: The results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST.

Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain.

BACKGROUND: Inability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated. METHODS/DESIGN: In this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients' global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables. DISCUSSION: Pharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a "trial and error" fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01179828.

Do central hypersensitivity and altered pain modulation predict the course of chronic low back and neck pain?

OBJECTIVES: Widespread central hypersensitivity and altered conditioned pain modulation (CPM) have been documented in chronic pain conditions. Information on their prognostic values is limited. This study tested the hypothesis that widespread central hypersensitivity (WCH) and altered CPM, assessed during the chronic phase of low back and neck pain, predict poor outcome. METHODS: A total of 169 consecutive patients with chronic low back or neck pain, referred to the pain clinic during 1 year, were analyzed. Pressure pain tolerance threshold at the second toe and tolerance time during cold pressor test at the hand assessed WCH. CPM was measured by the change in pressure pain tolerance threshold (test stimulus) after cold pressor test (conditioning stimulus). A structured telephone interview was performed 12 to 15 months after testing to record outcome parameters. Linear regression models were used, with average and maximum pain intensity of the last 24 hours at follow-up as endpoints. Multivariable analyses included sex, age, catastrophizing scale, Beck Depression Inventory, pain duration, intake of opioids, and type of pain syndrome. RESULTS: Statistically significant reductions from baseline to follow-up were observed in pain intensity (P<0.001). No evidence for an association between the measures of WCH or CPM and intensity of chronic pain at follow-up was found. DISCUSSION: A major predictive value of the measures that we used is unlikely. Future studies adopting other assessment modalities and possibly standardized treatments are needed to further elucidate the prognostic value of WCH and altered CPM in chronic pain.