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.

Quantitative somatosensory assessments in patients with persistent pain following groin hernia repair: A systematic review with a meta-analytical approach.

OBJECTIVES: Quantitative sensory testing (QST) provides an assessment of cutaneous and deep tissue sensitivity and pain perception under normal and pathological settings. Approximately 2-4% of individuals undergoing groin hernia repair (GHR) develop severe persistent postsurgical pain (PPSP). The aims of this systematic review of PPSP-patients were (1) to retrieve and methodologically characterize the available QST literature and (2) to explore the role of QST in understanding mechanisms underlying PPSP following GHR. METHODS: A systematic literature search was conducted from JAN-1992 to SEP-2022 in PubMed, EMBASE, and Google Scholar. For inclusion, studies had to report at least one QST-modality in patients with PPSP. Risk of bias assessment of the studies was conducted utilizing the Newcastle Ottawa Scale and Cochrane's Risk of Bias assessment tool 2.0. The review provided both a qualitative and quantitative analysis of the results. A random effects model was used for meta-analysis. RESULTS: Twenty-five studies were included (5 randomized controlled trials, 20 non-randomized controlled trials). Overall, risk of bias was low. Compared with the contralateral side or controls, there were significant alterations in somatosensory function of the surgical site in PPSP-patients. Following thresholds were significantly increased: mechanical detection thresholds for punctate stimuli (mean difference (95% CI) 3.3 (1.6, 6.9) mN (P = 0.002)), warmth detection thresholds (3.2 (1.6, 4.7) °C (P = 0.0001)), cool detection thresholds (-3.2 (-4.9, -1.6) °C (P = 0.0001)), and heat pain thresholds (1.9 (1.1, 2.7) °C (P = 0.00001)). However, the pressure pain thresholds were significantly decreased (-76 (-123, -30) kPa (P = 0.001)). CONCLUSION: Our review demonstrates a plethora of methods used regarding outcome assessments, data processing, and data interpretation. From a pathophysiological perspective, the most consistent findings were postsurgical cutaneous deafferentation and development of a pain generator in deeper connective tissues. TRIAL REGISTRATION: CRD42022331750.

Somatosensory Outcomes Following Re-Surgery in Persistent Severe Pain After Groin Hernia Repair: A Prospective Observational Study.

Purpose: After groin hernia repair (globally more than 20 million/year) 2-4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy. Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory "component" indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8-11.5) months before and 4.0 (3.5-4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed. Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of -2.0, -2.5, and -2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function ("deafferentation"). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001). Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep "pain generator". The QST-analyses are useful adjuncts in mechanism-based somatosensory research.

The Harald Breivik lecture 2022. Pathophysiology in persistent severe pain after groin hernia repair.

The transition from a healthy to a persistent severe pain state following otherwise successful elective surgery is a feared complication. Groin hernia repair, previously considered minor surgery, is a standard surgical procedure annually performed on 2,000 individuals per one million residents. A trajectory into persistent severe pain is, unfortunately, seen in 2-4%, severely impeding physical and psychosocial daily functions.

Trajectories in severe persistent pain after groin hernia repair: a retrospective analysis.

OBJECTIVES: Severe persistent post-surgical pain (PPSP) remains a significant healthcare problem. In the third most common surgical procedure in the U.K., groin hernia repair, including 85,000 surgeries, estimated 1,500-3,000 patients will annually develop severe PPSP. While the trajectory of PPSP is generally considered a continuation of the acute post-surgery pain, recent data suggest the condition may develop with a delayed onset. This study evaluated pain-trajectories in a consecutive cohort referred from groin hernia repair-surgeons to a tertiary PPSP-center. Potential explanatory variables based on individual psychometric, sensory, and surgical profiles were analyzed. METHODS: Patients completed graphs on pain trajectories and questionnaires on neuropathic pain, pain-related functional assessments, and psychometrics. Surgical records and quantitative sensory testing profiles were obtained. Pain trajectories were normalized, and pre- and post-surgical segments were analyzed by a normalized area-under-the-curve (AUC) technique. Principal component analysis (PCA) was applied to the explanatory variables. Significant PCA-components were further examined using multiple logistic regression models. RESULTS: In 95 patients, the AUC identified groups of post-surgical pain trajectories (p<0.0001): group I (n=48), acute high-intensity pain progressing to PPSP; group II (n=28), delayed onset of PPSP; group III (n=7), repeat-surgery gradually inducing PPSP. Data from groups IV (n=3) and V (n=9) were not included in the statistical analysis due to small sample size and data heterogeneity, respectively. The PCA/logistic analyses indicated that neuropathic pain scores, composite pain scores, and pain-related functional assessments were explanatory variables for groups I and II. CONCLUSIONS: Pain trajectories in PPSP after groin hernia repair are heterogeneous but can be classified into meaningful groups. Examination of pain trajectories, mirroring the transition from acute to severe persistent post-surgical pain, has the potential of uncovering clinically relevant pathophysiological mechanisms.

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.

A national center for persistent severe pain after groin hernia repair: Five-year prospective data.

Severe persistent pain after groin hernia repair impairs quality-of-life. Prospective, consecutive cohort study including patients with pain-related impairment of physical and social life. Relevant surgical records were obtained, and examinations were by standardized clinical and neurophysiological tests. Patients demonstrating pain sensitivity to pressure algometry in the operated groin underwent re-surgery, while patients with neuropathic pain received pharmacotherapy. Questionnaires at baseline (Q0) and at the 5-year time point (Q5Y) were used in outcome analyses of pain intensity (numeric rating scale [NRS] 0-10) and pain-related effect on the activity-of-daily-living (Activities Assessment Scale [AAS]). Data are mean (95% CI).Analyses were made in 172/204 (84%) eligible patients. In 54/172 (31%) patients re-surgery (meshectomy/selective neurectomy) was performed, while the remaining 118/172 (69%) patients received pharmacotherapy. In the re-surgery group, activity-related, and average NRS-scores at Q0 were 6.6 (5.6-7.9) and 5.9 (5.6-5.9), respectively. Correspondingly, NRS-scores at Q5Y was 4.1 (3.3-5.1) and 3.1 (2.3-4.0; Q0 vs. Q5Y: P < .0005), respectively. Although both groups experienced a significant improvement in AAS-scores comparing Q0 vs. Q5Y (re-surgery group: 28% (4-43%; P < .0001); pharmacotherapy group: 5% (0-11%; P = .005)) the improvement was significantly larger in the re-surgery group (P = .02).This 5-year cohort study in patients with severe persistent pain after groin hernia repair signals that selection to re-surgery or pharmacotherapy, based on examination of pain sensitivity, is associated with significant improvement in outcome. Analyzing composite endpoints, combining pain and physical function, are novel in exploring interventional effects.ClinicalTrials.gov Identifier NCT03713047.