Assessment of somatosensory profiles by quantitative sensory testing in children and adolescents with and without cerebral palsy and chronic pain.

OBJECTIVE: We investigated differences in somatosensory profiles (SSPs) assessed by quantitative sensory testing in children and adolescents with cerebral palsy (CCP) with and without chronic pain and compared these differences to those in a group of typically developed children and adolescents (TDC) with and without chronic pain. METHOD: All included subjects were consecutively recruited from and tested at the same outpatient orthopedic clinic by the same investigator. The subjects had their reaction times tested. The SSP consisted of the following tests: warmth (WDT), cool (CDT), mechanical (MDT), and vibration (VDT) detection thresholds; heat (HPT), pressure (PPT), and mechanical (MPT) pain thresholds; wind-up ratio (WUR); dynamic mechanical allodynia (DMA) and cold pressor test (CPT) using a conditioned pain modulation (CPM) paradigm. RESULTS: We included 25 CCP and 26 TDC. TDC without chronic pain served as controls. In TDC with chronic pain, WDT, HPT, HPT intensity, and PPT were higher than in controls. No differences in SSPs between CCP with and without chronic pain were observed. In CCP, the MDT, WDT, CDT, and HPT intensity were higher than in controls. CCP had longer reaction times than TDC. There were no differences regarding the remaining variables. DISCUSSION: In CCP, the SSPs were independent of pain status and findings on MR images. In all CCP the SSPs resembled TDC with chronic pain, compared to TDC without chronic pain. This suggests that CCP do not have the normal neuroplastic adaptive processes that activate and elicit functional changes in the central and peripheral nervous systems.

Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

Methodology and applicability of the human contact burn injury model: A systematic review.

The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose µ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

BACKGROUND: Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. METHODS: Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg-1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. RESULTS: Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were -32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. CONCLUSIONS: A parent-metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. CLINICAL TRIALS REGISTRATION: NCT01992146.

Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical.

BACKGROUND: Pain intensity ratings and opioid consumption (OC) are ubiquitous indicators of pain in postoperative trials of the efficacy of interventional procedures. Unfortunately, consensus on the appropriate statistical handling of these outcomes has not been reached. The aim of this article was, therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. METHODS: Data from a randomized, double-blind, placebo-controlled study investigating the analgesic efficacy of a regional anesthetic block following a major elective surgical procedure were analyzed. The original data included measurements of pain intensity (visual analog scale [VAS]) at rest and during coughing (VAS0/2/4/6/12/18/24 h) and OC0-6/0-24 h administered by patient-controlled analgesia. The statistical analyses included comparisons of discrete pain intensity scores (VAS0/2/4/6/12/18/24 h), summary measures of pain intensity ratings (area under the curve [AUC]-VAS0-6/0-24 h; mean VAS0-6/0-24 h), and OC0-6/0-24 h. Finally, the analyses also included an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC0-6/0-24 h). Also, estimation of effect size, generalized odds ratio of the individual analgesic outcome variables was performed. RESULTS: Sixty-one patients were included in the final data analysis. Discrete pain intensity ratings differed significantly between the treatment groups at specific postoperative time points, but appropriate correction for multiple comparisons eliminated some of these differences. AUC-VAS0-6 h differed significantly at rest and during coughing, while no difference was found for AUC-VAS0-24 h. In contrast, mean VAS0-6 h and VAS0-24 h differed significantly between treatment groups at rest and during coughing. OC0-6/0-24 h differed significantly between the treatment groups. Finally, also PIOC0-6/0-24 h differed significantly at rest and during coughing. CONCLUSIONS: Our analyses demonstrate that the applied statistical method may alter the statistical significance and estimates of effect size of analgesic outcome variables in postoperative pain trials. Our findings underline the importance of defining valid statistical methods for future analgesic drug trials. We propose an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC). The method combines two interdependent analgesic outcomes, lowers the risk of mass significance, and provides more accurate representation of the dynamic nature of postoperative pain and analgesic drug efficacy.

Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation.

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury, and to secondary hyperalgesia in normal skin surrounding the injury. Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic. To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min, 9 cm(2)) on the non-dominant lower-leg. Areas of secondary hyperalgesia were assessed 100 min after the injury. We measured neuronal activation by recording blood-oxygen-level-dependent-signals (BOLD-signals) during mechanical noxious stimulation before burn injury and in both primary and secondary hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application of the burn-injury) (p < 0.05). After the burn-injury, we found significant differences between responders during noxious stimulation of both primary (p < 0.01) and secondary hyperalgesia (p ≤ 0.04) skin areas. A decreased volume of the right (p = 0.001) and left caudate nucleus (p = 0.01) was detected in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype, which may have predictive value on the susceptibility to development of high-intensity acute and persistent pain.

Spatial summation of thermal stimuli assessed by a standardized, randomized, single-blinded technique.

Background and aims Quantitative sensory testing of thermal perception (QTT) is a valuable method in clinical and experimental assessment of the function of small nerve fibres. Previous studies have indicated existence of spatial summation for warmth, cool and heat pain stimulation, but study designs and assessment methods have not always been mutually consistent. The aims of this study were, first, to examine spatial summation of QTT by differently sized contact thermodes, and, second, to evaluate if these differences are significant from a clinical and scientific perspective. Methods Sixteen healthy subjects were included. Warmth detection (WDT), cool detection (CDT) and heat pain (HPT) thresholds were assessed in random order, with the stimulation areas of the contact thermodes of 3.0, 6.3 and 12.5 cm2, blinded to the subjects. Assessments were made bilaterally at volar part of the distal arm and medial part of the lower leg. Data analyses were by a mixed model with random effect for subject and fixed-effects for the variables, site (arm/leg), thermode area (ln thermode area) and side (dominant/non-dominant), in addition to conventional pairwise non-parametric comparisons. Results Data from 2 subjects were excluded. In the remaining 14 subjects only 4 subjects were able to identify the correct sequence of thermode sizes. The model demonstrated highly statistical significant relationships regarding main effects: thermode area (P < 0.0001) and stimulation site (P < 0.0001; except for CDT P = 0.011). The only significant interaction was between thermode area*site (P = 0.005) for CDT. The study demonstrated in 17 of 18 possible comparisons between thermode size and stimulation site, a significant spatial summation for WDT, CDT and HPT. Conclusion This randomized, single-blind study of thermal thresholds demonstrated spatial summation and that considerable deviations may occur if values obtained with differing thermode sizes are used uncritically. Implications Data from the present study enable interpolation of thermal thresholds with differing thermode sizes, facilitating comparisons across studies.

Persistent postsurgical pain: evidence from breast cancer surgery, groin hernia repair, and lung cancer surgery.

The prevalences of severe persistent postsurgical pain (PPP) following breast cancer surgery (BCS), groin hernia repair (GHR), and lung cancer surgery (LCS) are 13, 2, and 4-12 %, respectively. Estimates indicate that 80,000 patients each year in the U.S.A. are affected by severe pain and debilitating impairment in the aftermath of BCS, GHR, and LCS. Data across the three surgical procedures indicate a 35-65 % decrease in prevalence of PPP at 4-6 years follow-up. However, this is outweighed by late-onset PPP, which appears following a pain-free interval. The consequences of PPP include severe impairments of physical, psychological, and socioeconomic aspects of life. The pathophysiology underlying PPP consists of a continuing inflammatory response, a neuropathic component, and/or a late reinstatement of postsurgical inflammatory pain. While the sensory profiles of PPP-patients and pain-free controls are comparable with hypofunction on the surgical side, this seems to be accentuated in PPP-patients. In BCS-patients and GHR-patients, the sensory profiles indicate inflammatory and neuropathic components with contribution of central sensitization. A number of surgical factors including increased duration of surgery, repeat surgery, more invasive surgical techniques, and intraoperative nerve lesion have been associated with PPP. One of the most consistent predictive factors for PPP is high intensity acute postsurgical pain, but also psychological factors including anxiety, catastrophizing trait, depression, and psychological vulnerability have been identified as significant predictors of PPP. The quest to identify improved surgical and anesthesiological techniques to prevent severe pain and functional impairment in patients after surgery continues.

General anaesthesia with multimodal principles versus intrathecal analgesia with conventional principles in total knee arthroplasty: a consecutive, randomized study.

BACKGROUND: Postoperative outcomes following major surgery are influenced by surgical and anaesthesiological factors. While techniques of minimal invasive surgery have been associated with improved outcome, the techniques of minimal invasive, multimodal anaesthesia have not been adequately investigated. The aim of this study was to compare intrathecally based anaesthesia (ITA) including standardized, traditional intraoperative and postoperative care, with, general anaesthesia (GA) combined with intraoperative glucocorticoids, exclusion of intraoperative tourniquet and indwelling urethral catheter, and, an accelerated postoperative care regime. Outcome variables in the study were pain, requirement of analgesics, global satisfaction score and length-of-hospital stay. METHODS: Sixty patients were included and randomized to the ITA or the GA group. The ITA group received intrathecal bupivacaine (12.5 - 15.0 mg)/morphine (0.1 mg)/clonidine (0.03 mg), a standard surgical procedure, local infiltration analgesia (LIA) with ropivacaine (110 mg) /epinephrine (0.5 mg)/morphine (10 mg), an indwelling urethral catheter and mobilization with start Day 1 after the surgery. The GA group received a target-controlled infusion of propofol/remifentanil, betamethasone 4 mg i.v. intraoperatively, surgery was performed without a tourniquet, an indwelling urethral catheter was not used, LIA was with ropivacaine (250 mg)/epinephrine (0.3 mg) and mobilization was planned with start ≤ 2 hrs. after end of surgery. Outcomes were followed daily for the first 96 hrs. and at visits 3 months and 12 months postoperatively. RESULTS: Requirement of analgesics was decreased in the ITA group in the immediate postoperative period (P < 0.05). Pain scores were significantly lower in the ITA group (P < 0.01) between 0 - 12 hrs and in the GA group (P < 0.05) between 12 - 24 hrs after surgery. Fifteen of the patients in the GA group had to be intermittent catheterized due to bladder volumes > 400 mL. The LOS in the ITA group was significantly longer compared to the GA group (P < 0.01). There was no difference in global satisfaction score. CONCLUSION: General anaesthesia combined with intraoperative glucocorticoids and accelerated postoperative care, compared with, intrathecal blockade and traditional postoperative care, seems to generate the same overall pain ratings and a decrease in length-of-hospital stay, in patients undergoing elective total knee arthroplasty.

Neurophysiological characterization of persistent postthoracotomy pain.

OBJECTIVES: The postthoracotomy pain syndrome (PTPS) has a prevalence of 30% to 40%. Although intraoperative nerve damage during thoracotomy has been demonstrated, it has not been clearly linked to PTPS and detailed quantitative sensory characterization data have so far not been presented, comparing PTPS and pain-free patients. METHODS: Neurophysiological characterization was performed in 17 patients with PTPS and 24 pain-free postthoracotomy patients using a detailed quantitative sensory testing protocol and psychometric questionnaires. RESULTS: Pain and pain-free patients had increased thresholds to tactile detection (P=0.001 and P=0.01) and cool detection (P<0.001 and P<0.01) on the operated side versus the contralateral side. Pain patients also had increased thresholds for warmth detection (P<0.001) and heat pain (P<0.01) on the operated side. The PTPS patients demonstrated increased side-to-side differences for warmth detection (P<0.01), heat pain (P<0.05), and cool detection (P<0.05) thresholds compared with pain-free patients. Pain patients also more frequently experienced cool hyperesthesia (8 of 17 vs. 1 of 24, P<0.01), but no differences were found for pressure pain, temporal summation, or sensory mapping to cool (200 cm vs. 76 cm, P=0.18). Hospital Anxiety and Depression Scale scores were higher for PTPS than for pain-free patients (P<0.01). DISCUSSION: Neurophysiological assessments indicate nerve injury to be common in pain and pain-free patients after thoracotomy. The combination of increased thresholds together with hyperesthesia, suggests consequences of nerve injury to be more pronounced in PTPS patients.

[Role of paracetamol in the acute pain management]. / Rôle du paracétamol dans la prise en charge des douleurs aiguës.

Paracetamol (acetaminophen) has been shown to be an effective analgesic for the treatment of moderate pain where it is chiefly indicated, as shown in placebo-controlled studies in the perioperative setting and other acute pain states. In addition, an opioid-sparing effect has been demonstrated. No clinically relevant adverse effects are usually apparent with recommended doses. Paracetamol is an effective component in 'multimodal analgesia' in combination with morphine, weak opioids and non-steroidal anti-inflammatory drugs. Although most studies involve the perioperative setting, similar results have been obtained in other acute pain states, such as acute musculoskeletal pain, migraine, etc. In conclusion, paracetamol has a favourable efficacy-tolerability profile and is therefore recommended as a basic, first-line analgesic in acute pain states and as a valuable component in multimodal analgesia.