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.

Orthotopic Liver Transplant in a Patient Anticoagulated With Rivaroxaban: A Case Report.

Direct oral anticoagulants are approved for use in the United States and Europe and are increasingly used in chronic liver disease patients who have or are at risk of thrombotic events. While these drugs are clinically attractive because no monitoring is required, the risks and benefits in patients with hepatic or renal insufficiency who undergo surgery remain unclear. In this report, we describe the perioperative consequences, safety issues, and lessons learned from a patient undergoing an orthotopic liver transplant who was anticoagulated with rivaroxaban due to partial superior mesenteric vein thrombosis.

Current evidence for central analgesic effects of NSAIDs: an overview of the literature.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for a variety of painful conditions. Their peripheral anti-inflammatory effect due to inhibition of prostaglandin synthesis is well documented. In the late 1980's, animal data suggested for the first time that NSAIDs might have central effects as well. Since that time, central inflammatory and nociceptive pathways that are potential targets of NSAIDs have been extensively studied in both animal and human models. This review provides an overview of the relevant literature implicated in the central effects of NSAIDs. The role of different enzymes and mediators, as well as the central effects of NSAIDs are discussed. Literature search was performed by PubMed NCBI. A large body of evidence supports the central effects of NSAIDs in animal models of inflammatory pain conditions. Relevant mechanisms that underlie this central action involve spinal upregulation of the enzyme cyclooxygenase, increased spinal prostaglandin E2 production, modulation of inhibitory fast synaptic currents in lamina I and II of the dorsal horn, and glycine-dependent modulation of pain. Results from animal models are not yet sufficiently supported by human studies. This does not necessarily imply that the central effects of NSAIDs are irrelevant to human pain, but rather that methodological and regulatory barriers are the limiting step to translating findings from animal studies to human research protocols.

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.

Psychophysical and Electrophysiological Evidence for Enhanced Pain Facilitation and Unaltered Pain Inhibition in Acute Low Back Pain Patients.

The aim of this case-control study was to examine differences in neural correlates of pain facilitatory and inhibitory mechanisms between acute low back pain (LBP) patients and healthy individuals. Pressure pain tolerance, electrical pain detection thresholds, pain ratings to repetitive suprathreshold electrical stimulation (SES) and conditioned pain modulation (CPM) were assessed in 18 patients with acute LBP and 18 healthy control participants. Furthermore, event-related potentials (ERPs) in response to repetitive SES were obtained from high-density electroencephalography. Results showed that the LBP group presented lower pressure pain tolerance and higher pain ratings to SES compared with the control group. Both groups displayed effective CPM, with no differences in CPM magnitude between groups. Both groups presented similar reductions in ERP amplitudes during CPM, but ERP responses to repetitive SES were significantly larger in the LBP group. In conclusion, acute LBP patients presented enhanced pain facilitatory mechanisms, whereas no significant changes in pain inhibitory mechanisms were observed. These results provide new insight into the central mechanisms underlying acute LBP. PERSPECTIVE: This article present evidence that acute LBP patients show enhanced pain facilitation and unaltered pain inhibition compared with pain-free volunteers. These results provide new insight into the central mechanisms underlying acute LBP.

Hormonal and Clinical Predictors for Post-egg Retrieval Pain in Women Undergoing Assisted Reproductive Technology Procedures.

OBJECTIVES: The intensity of post-egg retrieval pain is underestimated, with few studies examining postprocedural pain and predictors to identify women at risk for severe pain. We evaluated the influence of preprocedural hormonal levels, ovarian factors, and mechanical temporal summation (mTS) as predictors for post-egg retrieval pain in women undergoing in vitro fertilization. METHODS: Eighteen women scheduled for ultrasound-guided egg retrieval under standardized anesthesia and postprocedural analgesia were enrolled. Preprocedural mTS, questionnaires, clinical data related to anesthesia and the procedure itself, postprocedural pain scores, and pain medication for breakthrough pain were recorded. Statistical analysis included Pearson product-moment correlations, Mann-Whitney U tests, and multiple linear regressions. RESULTS: Average peak post-egg retrieval pain during the first 24 hours was 5.0±1.6 on a numerical response scale (0=no pain, 10=worst pain imaginable). Peak post-egg retrieval pain was correlated with basal antimullerian hormone (AMH) (r=0.549, P=0.018), preprocedural peak estradiol (r=0.582, P=0.011), total number of follicles (r=0.517, P=0.028), and number of retrieved eggs (r=0.510, P=0.031). Ovarian hyperstimulation syndrome (n=4) was associated with higher basal AMH (P=0.004), higher peak pain scores (P=0.049), but not with peak estradiol (P=0.13). The mTS did not correlate with peak postprocedural pain (r=0.266, P=0.286), or peak estradiol level (r=0.090, P=0.899). DISCUSSION: Peak post-egg retrieval pain intensity was higher than anticipated. Our results suggest that post-egg retrieval pain can be predicted by baseline AMH, high peak estradiol, and ovarian hyperstimulation syndrome. Further studies to evaluate intraprocedural and postprocedural pain in this population are needed, as well as clinical trials to assess postprocedural analgesia in women presenting with high hormonal levels.

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.

Reliability of Quantitative Sensory Tests in a Low Back Pain Population.

BACKGROUND AND OBJECTIVES: Reliability is an essential condition for using quantitative sensory tests (QSTs) in research and clinical practice, but information on reliability in patients with chronic pain is sparse. The aim of this study was to evaluate the reliability of different QST in patients with chronic low back pain. METHODS: Eighty-nine patients with chronic low back pain participated in 2 identical experimental sessions, separated by at least 7 days. The following parameters were recorded: pressure pain detection and tolerance thresholds at the toe, electrical pain thresholds to single and repeated stimulation, heat pain detection and tolerance thresholds at the arm and leg, cold pain detection threshold at the arm and leg, and conditioned pain modulation using the cold pressor test. Reliability was analyzed using the coefficient of variation, the coefficient of repeatability, and the intraclass correlation coefficient. It was judged as acceptable or not based primarily on the analysis of the coefficient of repeatability. RESULTS: The reliability of most tests was acceptable. Exceptions were cold pain detection thresholds at the leg and arm. CONCLUSIONS: Most QST measurements have acceptable reliability in patients with chronic low back pain.

Is the conditioned pain modulation paradigm reliable? A test-retest assessment using the nociceptive withdrawal reflex.

The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain. Trial registration: Clinical Trials.gov NCT01636440.

Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study.

BACKGROUND AND AIMS: Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. METHODS: In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. RESULTS: For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. CONCLUSIONS: Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011036.

Pharmacogenomic considerations in opioid analgesia.

Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.

Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction.

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class I, randomly allocated to three groups receiving remifentanil infusions targeting 0, 2, and 4 ng/ml. Propofol was given at stepwise increasing effect-site target concentrations. At each concentration, the observer assessment of alertness and sedation score, the response to eyelash and tetanic stimulation of the forearm, the bispectral index (BIS), and the acoustic evoked potential index (AAI) were recorded. The authors computed the NSRI for each stimulation and calculated the prediction probabilities (PKs) using a bootstrap technique. The PKs of the different predictors were compared with multiple pairwise comparisons with Bonferroni correction. RESULTS: The median (95% CI) PK of the NSRI, BIS, and AAI for loss of response to tetanic stimulation was 0.87 (0.75-0.96), 0.73 (0.58-0.85), and 0.70 (0.54-0.84), respectively. The PK of effect-site propofol concentration, BIS, and AAI for observer assessment of alertness and sedation score and loss of eyelash reflex were between 0.86 (0.80-0.92) and 0.92 (0.83-0.99), whereas the PKs of NSRI were 0.77 (0.68-0.85) and 0.82 (0.68-0.92). The PK of the NSRI for BIS and AAI was 0.66 (0.58-0.73) and 0.63 (0.55-0.70), respectively. CONCLUSION: The NSRI conveys information that better predicts the analgesic component of anesthesia than AAI, BIS, or predicted propofol or remifentanil concentrations. Prospective validation studies in the clinical setting are needed.

Anesthesia or sedation for gastroenterologic endoscopies.

PURPOSE OF REVIEW: Because propofol is the sedative preferred by gastroenterologists, we focus this review on gastroenterologist-directed propofol sedation, provide simulations of the respiratory depressant effect of different dosing protocols and give a perspective on future developments in computer-assisted sedation techniques. RECENT FINDINGS: Propofol use by nonanesthesiologists remains a contraindication in the package insert of propofol in most countries. Sedation guidelines produced by the American Society of Gastroenterology partially contradict those produced by the American Society of Anesthesiologists for sedation by nonanesthesiologists, whereas the German guidelines were developed with anesthesiologists involved. The use of fospropofol, recently approved by the US Food and Drug Administration for sedation, is considered an alternative to propofol by some gastroenterologists. Methodological errors in earlier pharmacological studies have to be solved before widespread use of fospropofol is justified, however. Our simulations show that dosing protocols with small boluses administered at reasonable intervals induce less respiratory depression than large boluses. Interindividual variability of propofol-induced respiratory depression is illustrated by different pharmacokinetic and dynamic parameter sets used in the simulation. Two computer-assisted propofol infusion systems are currently being investigated. They not only incorporate the target effect but also the side effects, which may limit respiratory depression. SUMMARY: Propofol use by gastroenterologists may be well tolerated if appropriate patient selection, staff training, monitoring and low-dose sedation protocols are applied.

Postischemic forearm skin reactive hyperemia is related to cardovascular risk factors in a healthy female population.

OBJECTIVE: To examine whether forearm postischemic skin reactive hyperemia (SRH) measured by laser Doppler flowmetry (LDF) can be used to explore microvascular function and whether LDF response is related to cardiovascular (CV) risk in a population study. METHODS: SRH of the forearm defined as the percentage increase in cutaneous blood flow from resting conditions to peak dilation following a 2 min upper arm occlusion and CV risk factors were measured prospectively in 862 healthy females screened for cardiovascular risk factors in the context of a campaign designed to promote the 'control' of CV risk factors in women. RESULTS: The Framingham risk score was constructed from age, sex, systolic and diastolic blood pressure, diabetes, total and high-density lipoprotein-cholesterol and left ventricular hypertrophy (Cornell product. The Cornell product for women was calculated as the QRS duration (ms) (R aVL + S V3 + 6 mV)). Although the score was low in this female population (CV event risk at 10 years 7.89) (95% confidence interval, 7.49-8.30) aged 40 to 75 years, we observed an inverse correlation between SRH of the forearm and the CV risk score ( P<0.001). Hormonal replacement therapy (39.4% of the study population was on hormone replacement therapy) had no significant influence on forearm postischemic SRH in this particular population. CONCLUSIONS: This study shows that in a very low CV risk female population, a significant correlation can be observed between the weight of CV risks and the impairment of postischemic forearm SRH. Thus, skin laser Doppler flowmetry may represent a valuable, simple and non-invasive tool to assess and monitor microvascular function in future prospective observational and interventional studies.