Cold Pain Test Research Articles

Pharmacokinetics, pharmacodynamics, and safety of LPM3480392 in two phase I clinical trials in healthy Chinese male subjects.

Drugs for acute postoperative pain and breakthrough cancer pain are still urgent on clinical. LPM3480392 is a G-protein-biased ligand at the μ-opioid receptor and showed potent analgesia in nonclinical studies. Two phase I studies of LPM3480392 were conducted in healthy Chinese male volunteers to explore its tolerability, pharmacokinetics, and pharmacodynamics under single ascending doses (Study I 0.1-3.0 mg, 30 min) and different infusion time (Study II, 0.6-1.0 mg, 2-15 min). There was one serious adverse event (AE) observed in Study II, and the rest AEs were mild or moderate in severity and resolved by the end of the study. Plasma LPM3480392 maximum concentration (Cmax ) (under lower infusion rate) and area under the plasma concentration-time curve (AUCs) were generally increased with dose. Moreover, LPM3480392 at dose of 0.6 mg under 2 min infusion rate elicited effective analgesia as the peak effect within 10-30 min, which measured by cold pain test and pupillometry. These findings suggest that LPM3480392 could be a potential treatment for acute pain management.

Predictive models for fentanyl dose requirement and postoperative pain using clinical and genetic factors in patients undergoing major breast surgery.

Fentanyl exhibits interindividual variability in its dose requirement due to various nongenetic and genetic factors such as single nucleotide polymorphisms (SNPs). This study aims to develop and cross-validate robust predictive models for postoperative fentanyl analgesic requirement and other related outcomes in patients undergoing major breast surgery. Data regarding genotypes of 10 candidate SNPs, cold pain test (CPT) scores, pupillary response to fentanyl (PRF), and other common clinical characteristics were recorded from 257 patients undergoing major breast surgery. Predictive models for 24-hour fentanyl requirement, 24-hour pain scores, and time for first analgesic (TFA) in the postoperative period were developed using 4 different algorithms: generalised linear regression model, linear support vector machine learning (SVM-Linear), random forest (RF), and Bayesian regularised neural network. The variant genotype of OPRM1 (rs1799971) and higher CPT scores were associated with higher 24-hour postoperative fentanyl consumption, whereas higher PRF and history of hypertension were associated with lower fentanyl requirement. The variant allele of COMT (rs4680) and higher CPT scores were associated with 24-hour postoperative pain scores. The variant genotype of CTSG (rs2070697), higher intraoperative fentanyl use, and higher CPT scores were associated with significantly lower TFA. The predictive models for 24-hour postoperative fentanyl requirement, pain scores, and TFA had R-squared values of 0.313 (SVM-Linear), 0.434 (SVM-Linear), and 0.532 (RF), respectively. We have developed and cross-validated predictive models for 24-hour postoperative fentanyl requirement, 24-hour postoperative pain scores, and TFA with satisfactory performance characteristics and incorporated them in a novel web application.

Association between the rs7583431 single nucleotide polymorphism close to the activating transcription factor 2 gene and the analgesic effect of fentanyl in the cold pain test

BackgroundActivating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects.ResultsIn this study, 33 single nucleotide polymorphisms (SNPs) were selected, and a total of 2 linkage disequilibrium blocks with 6 Tag SNPs (rs1153702, rs7583431, rs2302663, rs3845744, rs268214, and rs1982235) were observed in the region within and around the ATF2 gene. We further analyzed associations between these Tag SNPs and clinical data. Even after multiple testing with Bonferroni adjustments, an increase in the analgesic effect of fentanyl in the cold pressor‐induced pain test was significantly associated with a greater number of the A allele of the rs7583431 SNP (linear regression, P = .001).ConclusionsThe present findings may contribute to adequate pain relief in individual patients. Although more research on the genetic factors that influence opioid sensitivity is needed, analgesic requirements may be predicted by analyzing ATF2 SNPs, together with other polymorphisms of genes that are reportedly associated with opioid sensitivity, such as CREB1,OPRM1, and GIRK2.

Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis

BackgroundTo prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients’ performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain. MethodsWe analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2–4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain. ResultsWhether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the “persistent pain” group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate. ConclusionsResults provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116seconds latency vs 75seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (−15.9 for morphine versus −7.3, −7.6, and −9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.

Comparison of pain models to detect opioid-induced hyperalgesia

ObjectiveChronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.MethodsThis open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.ResultsThe opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3) in the buprenorphine group and 4.5 (95% CI 1.7–15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3]) and ischemic tests (hazard ratio for tolerance, 2.7 [95% CI 1.2–6.1]). There were significant correlations between cold and ischemic tolerances (r = 0.50; P = 0.003) and between electrical and mechanical pain tolerances (r = 0.52; P = 0.002).ConclusionThese findings indicate that cold pain is the most suitable of the methods tested to detect opioid-induced hyperalgesia. This is consistent with its sensitivity to detect opioid analgesia.

Asians differ from non-Hispanic Whites in experimental pain sensitivity

This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.

Comparison of the Cold Pressor Test and Contact Thermode-Delivered Cold Stimuli for the Assessment of Cold Pain Sensitivity

Sensitivity to suprathreshold cold pain stimuli constitutes an important part of comprehensive pain sensitivity testing and can be assessed by the cold pressor test or by using a contact thermode-based testing device. One major difference between the 2 methods is the size of the surface area stimulated, which is thought to affect both recruitment of endogenous pain control mechanisms and vasomotor reactions. It is therefore not clear if the 2 methods can be used interchangeably for the assessment of cold pain. Here we applied 60-second-long stimuli at approximately 3 degrees C to the hands of 47 subjects by both methods. Pain intensity ratings (on a scale from 0 to 10) were significantly higher in the cold pressor test than in the thermode cold test (6.3 +/- 1.8 vs 3.9 +/- 2), associated with a higher rate of dropouts within the 60 seconds (64 vs 11%). Nonetheless, pain intensity ratings obtained with both methods were highly correlated (r = .70). However, the thermode cold test shared a larger amount of variance with 1 or more of the other pain intensity rating tests (phasic and tonic heat, pinprick) than the cold pressor test (53% vs 30%) while the cold pressor test contained a larger proportion of unique variance (39 vs 26%). This article compares 2 methods of cold pain assessment in humans and analyzes their relationship to heat and pinprick pain. It could help researchers select the appropriate cold pain test for their study. It may also promote our understanding of commonalities and differences between different pain modalities.

Metabotyping of Biofluids Reveals Stress-Based Differences in Gut Permeability in Healthy Individuals

Life stress promotes gut dysfunction, but underlying biochemical events are not well-understood. In the present study, we describe the metabolic events associated with background stress and its potential influence on the response to novel incoming stress stimulus in healthy subjects. A 15 min cold pain test was carried out in healthy men and women stratified according to low (LS; n = 21) and moderate background stress (MS; n = 9) during jejunal segmental perfusion. Cold pain induced a stronger psychological response in MS compared to LS subjects, but similar increases in heart rate and blood pressure. Urine and plasma were analyzed using 1H NMR-based metabonomics. Basal stress levels were imprinted in the metabolic profiles indicating different energy and lipid homeostasis. Cold pain increased gut permeability, as determined by mannitol and xylose levels, the response being greater in LS subjects. Moreover, the rate of plasma clearance of mannitol and xylose was dependent on background stress level and gender. In addition, cold pain modulated the levels of circulating ketone bodies, Krebs's cycle intermediates, glucose, and the glucogenic alanine and lactate, which brings further evidence of an alteration of energy homeostasis. Therefore, unravelling life stress with metabonomics may provide a system biology basis for the clinical management and therapeutic surveillance of gut health and disorders.

Sensory recovery in a split skin graft: pinprick or a thermal sensory analyzer?

Sensory return in a split skin graft is an important factor in the protection of this graft from injury. Hence, three tests were compared: (1) the standard pain test using a simple pin, (2) the cold pain test, and (3) the hot pain test. Both the hot and cold pain tests were performed using the thermal sensory analyzer device. Thirteen patients were investigated; all had split skin grafts applied directly onto deep fascia after malignant melanoma excision on the lower limb. The period after grafting ranged from 4 to 15 years, and the mean age was 46.5 years. The normal contralateral side of each patient was used as the control for that patient. The results were collected in simple data tables and were analyzed using paired t tables for small samples with the level of significance set at p < 0.05. The standard pain test demonstrated that the split skin grafts applied on deep fascia did not recover sensation, even 15 years after surgery (p < 0.001). The hot and cold pain tests were both in agreement with the standard pain test at p < 0.001 and p < 0.03, respectively. The standard pain test is usually performed, as described in this study, using a pin, which is cheap and readily available in any plastic surgery and burn clinic. However, the cold and hot pain tests as performed here using the thermal sensory analyzer device are accurate but are costly, cumbersome, and not available in all clinics except for highly specialized units. Hence, the author would like to dispel the myth that the standard pain test is inaccurate. This might be so in testing sensation in "normal" skin but not in testing the recovery of sensation in a skin graft.