A Perioperative Mental Health Intervention for Depressed and Anxious Older Surgical Patients: Results From a Feasibility Study.

OBJECTIVES: The perioperative period is challenging and stressful for older adults. Those with depression and/or anxiety have an increased risk of adverse surgical outcomes. We assessed the feasibility of a perioperative mental health intervention composed of medication optimization and a wellness program following principles of behavioral activation and care coordination for older surgical patients. METHODS: We included orthopedic, oncologic, and cardiac surgical patients aged 60 and older. Feasibility outcomes included study reach, the number of patients who agreed to participate out of the total eligible; and intervention reach, the number of patients who completed the intervention out of patients who agreed to participate. Intervention efficacy was assessed using the Patient Health Questionnaire for Anxiety and Depression (PHQ-ADS). Implementation potential and experiences were collected using patient surveys and qualitative interviews. Complementary caregiver feedback was also collected. RESULTS: Twenty-three out of 28 eligible older adults participated in this study (mean age 68.0 years, 65% women), achieving study reach of 82% and intervention reach of 83%. In qualitative interviews, patients (n = 15) and caregivers (complementary data, n = 5) described overwhelmingly positive experiences with both the intervention components and the interventionist, and reported improvement in managing depression and/or anxiety. Preliminary efficacy analysis indicated improvement in PHQ-ADS scores (F = 12.13, p <0.001). CONCLUSIONS: The study procedures were reported by participants as feasible and the perioperative mental health intervention to reduce anxiety and depression in older surgical patients showed strong implementation potential. Preliminary data suggest its efficacy for improving depression and/or anxiety symptoms. A randomized controlled trial assessing the intervention and implementation effectiveness is currently ongoing.

Brain-Hazardous Medications and Potential Subadequate Antidepressant Dosing in Older Surgical Patients Receiving Home Antidepressants: An Observational Study of a Large US Health System.

BACKGROUND: Older surgical patients with depression often experience poor postoperative outcomes. Poor outcomes may stem from brain-hazardous medications and subadequate antidepressant dosing. METHODS: This was a retrospective, observational cohort study covering the period between January 1, 2021 and December 31, 2021. Patients ≥60 years of age who underwent inpatient surgery and had an overnight stay at an integrated academic health care system comprising 14 hospitals were eligible. We analyzed the prevalence of home central nervous system (CNS)-active potentially inappropriate medication (PIM) and potential subadequate antidepressant dosing in older surgical patients receiving home antidepressants. Univariable and multivariable regression models were used to identify factors associated with home CNS-active PIM prescribing and potential subadequate antidepressant dosing. Additionally, outcomes were compared among patients receiving and not receiving CNS-active PIMs and patients receiving and not receiving subadequate antidepressant dosing. RESULTS: A total of 8031 patients were included in this study (47% female, mean age = 70 years) of whom 2087 (26%) were prescribed antidepressants. Roughly one-half (49%, 95% confidence interval [CI], 46.5-50.1) of patients receiving home antidepressants were also receiving ≥1 CNS-active PIM and 29% (95% CI, 27.0-29.3) were receiving a potential subadequate dose. Factors associated with an increased likelihood of receiving a home CNS-active PIM included female sex (adjusted odds ratio [aOR], 1.46), anxiety (aOR, 2.43), asthma or chronic obstructive pulmonary disease (aOR, 1.39), and serotonin-norepinephrine reuptake inhibitor use (aOR, 1.54). Patients aged ≥75 years (aOR, 1.57), black race (aOR, 1.48) and those with congestive heart failure (aOR, 1.33) were more likely to be prescribed a potential subadequate antidepressant dose. Patients receiving potential subadequate antidepressant doses were discharged home less often (64% vs 73%), had a longer hospital length of stay (9 days vs 7 days), and a higher mortality rate (18% vs 10%) compared to patients receiving adequate home antidepressant doses (P-value for all <0.01). No differences in these outcomes were found among patients receiving home antidepressants with or without CNS-active PIMs. CONCLUSIONS: Older surgical patients receiving antidepressants are frequently prescribed brain-hazardous medications and potentially subadequate antidepressant doses. Those receiving subadequate antidepressant doses may be at risk for worse postoperative outcomes compared to patients receiving adequate doses. The role of preoperative medication optimization to improve outcomes for older surgical patients should be evaluated.

Advances in diagnosis and management of distal sensory polyneuropathies.

Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Harnessing the conditioned pain modulation response in migraine diagnosis, outcome prediction, and treatment-A narrative review.

OBJECTIVE: To present the potential use and relevance of the conditioned pain modulation (CPM) response to migraine diagnosis, outcome prediction, and treatment. BACKGROUND: The CPM response is a widely used laboratory test to examine inhibitory pain modulation capabilities. METHODS: This narrative review summarizes and synthesizes the findings on the CPM response in patients with migraine. RESULTS: For diagnosis, we summarized the studies comparing CPM responses between patients with migraine and individuals without migraine or with other headache syndromes, as well as between patients with subtypes of migraine. For prediction, we summarized the studies utilizing the CPM response to predict migraine outcome, such as response to interventions. For treatment, we described a device that utilizes the CPM response for acute and preventative migraine treatment. In addition, we suggest the requirements needed for the CPM response to be used for migraine diagnosis, outcome prediction, and treatment. CONCLUSIONS: Although more research is needed, the CPM response could be a useful tool for improving migraine management.

An individualised tapering protocol reduces opioid use 1 year after spine surgery: A randomised controlled trial of patients with preoperative opioid use.

BACKGROUND: Persistent opioid use following surgery is common especially in patients with preoperative opioid use. This study aims to determine the long-term effect of an individualised opioid tapering plan versus standard of care in patients with a preoperative opioid use undergoing spine surgery at Aarhus University Hospital, Denmark. METHODS: This is the 1-year follow-up of a prospective, single-centre, randomised trial of 110 patients who underwent elective spine surgery for degenerative disease. The intervention was an individualised tapering plan at discharge and telephone counselling 1 week after discharge, compared to standard of care. Postoperative outcomes after 1 year include opioid use, reasons for opioid use and pain intensity. RESULTS: The overall response rate to the 1-year follow-up questionnaire was 94% (intervention group 52/55 patients and control group 51/55 patients). Forty-two patients (proportion = 0.81, 95% CI 0.67-0.89) in the intervention group compared to 31 (0.61, 95% CI 0.47-0.73; p = .026) patients in the control group succeeded in tapering to zero 1 year after discharge (p = .026). One patient (0.02, 95% CI 0.01-0.13) in the intervention group compared to seven patients (0.14, 95% CI 0.07-0.26) in the control group were unable to taper to their preoperative dose 1 year after discharge (p = .025). Back/neck and radicular pain intensity was similar between study groups. CONCLUSION: These results suggest that an individualised tapering plan at discharge combined with telephone counselling 1 week after discharge can reduce opioid use 1 year after spine surgery.

Ascertaining Design and Implementation Requirements for a Perioperative Neurocognitive Training Intervention for the Prevention of Persistent Pain After Surgery.

BACKGROUND: Persistent postsurgical pain (PPSP) is a common complication that impacts quality of life, often necessitating long-term opioid treatment. Certain neurocognitive factors, including reduced performance on cognitive flexibility tasks, are associated with increased risk of PPSP. We examine the perceptions of surgical patients and clinicians with regard to perioperative pain management activities and needs; patient acceptance and use of a perioperative neurocognitive training intervention; and implementation feasibility. METHODS: We conducted both individual and focus group interviews with patients undergoing thoracic surgery and clinicians in an academic medical center. The Consolidated Framework for Intervention Research guided the development of interview questions related to the adoption and implementation of a neurocognitive intervention to mitigate PPSP. A thematic analysis was used to analyze the responses. RESULTS: Forty patients and 15 clinicians participated. Interviews revealed that there is minimal discussion between clinicians and patients about PPSP. Most participants were receptive to a neurocognitive intervention to prevent PPSP, if evidence demonstrating its effectiveness were available. Potential barriers to neurocognitive training program adoption included fatigue, cognitive overload, lack of familiarity with the technology used for delivering the intervention, and immediate postoperative pain and stress. Implementation facilitators would include patient education about the intervention, incentives for its use, and daily reminders. CONCLUSION: The study identified several guiding principles for addressing patients' and clinicians' barriers to effectively implementing a neurocognitive training intervention to mitigate PPSP after surgery. To ensure the sustainability of neurocognitive interventions for preventing PPSP, such interventions would need to be adapted to meet patients' and clinicians' needs within the perioperative context.

Diagnostic criteria for idiopathic small fiber neuropathy: A systematic review.

Idiopathic small fiber neuropathy (iSFN) lacks broadly accepted diagnostic criteria, which hinders its timely diagnosis and treatment. A systematic literature review was performed to assess the published screening and diagnostic criteria for iSFN, excluding studies where SFN was of well-established etiology. Eighty-four clinical studies and seven guideline/review publications were included in this systematic review. Substantial heterogeneity existed in iSFN diagnostic criteria. The most common set of criteria to diagnose iSFN [presence of any symptoms of iSFN, absence of large fiber involvement, and reduced intraepidermal nerve fiber density (IENFD)] was used in only 14% of studies. Mandatory individual criteria to confirm iSFN included any sensory symptoms (60% of studies), pain (19% of studies), small fiber signs (20% of studies), absence of large fiber signs (62% of studies), reduced IENFD (38% of studies), and autonomic symptoms (1% of studies). This review highlights a clear need for standardized, evidence-based guidelines for diagnosing iSFN.

Factors Contributing to Lingering Pain after Surgery: The Role of Patient Expectations.

BACKGROUND: Pain that lingers beyond the early weeks after the acute postoperative period is an important risk factor for chronic postsurgical pain. This study examined the hypothesis that patients' expectations about their postsurgical pain would be independently associated with lingering postsurgical pain. METHODS: The study included 3,628 patients who underwent diverse surgeries between February 2015 and October 2016 in a single U.S. tertiary hospital and participated in the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) observational study. Preoperatively, patients were asked about their expectations about pain 1 month after surgery. Patients were considered to have lingering postsurgical pain if they endorsed having pain in the area related to their surgeries during a follow-up survey obtained 1 to 3 months postoperatively. The independent associations between preselected perioperative variables and lingering postsurgical pain were evaluated. RESULTS: Of the cohort, 36% (1,308 of 3,628) experienced lingering postsurgical pain. Overall, two thirds (2,414 of 3,628) expected their postsurgical pain to be absent or improved from baseline, and 73% of these had their positive expectations fulfilled. A total of 19% (686 of 3,628) expected new, unabated, or worsened pain, and only 39% (257 of 661) of these had their negative expectations fulfilled. Negative expectations were most common in patients with presurgical pain unrelated to the reason for surgery, undergoing surgeries not typically performed to help alleviate pain. Endorsing negative expectations was independently associated with lingering postsurgical pain (odds ratio, 1.56; 95% CI, 1.23 to 1.98; P < 0.001). Additional major factors associated with lingering postsurgical pain included recollection of severe acute postoperative pain (odds ratio, 3.13; 95% CI, 2.58 to 3.78; P < 0.001), undergoing a procedure typically performed to help alleviate pain (odds ratio, 2.18; 95% CI, 1.73 to 2.75; P < 0.001), and preoperative pain related to surgery (odds ratio, 1.91; 95% CI, 1.52 to 2.40; P < 0.001). CONCLUSIONS: Lingering postsurgical pain is relatively common after diverse surgeries and is associated with both fixed surgical characteristics and potentially modifiable factors like pain expectations and severe acute postoperative pain.

Surgical Complications in Older Adults Predict Decline in Self-Perceived Cognitive Function in the Ensuing Year: A Cohort Study.

BACKGROUND: Surgical complications are common among older adults and are potential indicators of poorer long-term outcomes. The authors examined the effects of in-hospital complications on changes in older adults' self-perceived cognitive function in the year after surgery. METHOD: The authors conducted a prospective longitudinal study with 2,155 older adults (age ≥ 65) undergoing surgery, investigating the association between self-reported, in-hospital complications after surgery and Patient-Reported Outcomes Measurement Information System Applied Cognition-Abilities survey (4 items, cognitive function) at 30 days and 1 year after surgery. Surveys were scored on a continuous scale of 0-100, with higher scores representing better self-perceived cognitive functioning. Patient characteristics including demographics, type of complications, surgery type, pain, and activities of daily living were also collected. RESULTS: Having one in-hospital complication was associated with a decrease of 1.79 points (95% confidence interval (CI): -2.78, -0.80), indicating lower self-perceived cognitive functioning at 1 year after surgery; having two or more in-hospital complications was associated with 2.82 point (95% CI: -4.50, -1.15) decrease at 1 year after surgery. Models specific to complication type indicated that respiratory [-3.04, (95% CI: -5.50, -0.57)], neural [-2.11, (95% CI: -3.97, -0.25)], and general complications [-2.39, (95% CI: -3.51, -1.28)] were associated with statistically significant decreases in cognitive function. DISCUSSION: Older surgical patients who suffer in-hospital complications show greater decline in self-perceived cognitive function during the ensuing year. Geriatric specialists may be able to intervene in the immediate perioperative period to reduce complications and possibly mitigate cognitive decline among older adults.

Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.

AIMS: Changes in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration. METHODS: Fifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS. RESULTS: The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26. CONCLUSIONS: After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration-time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.

Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process.

In many countries, liberalisation of the legislation regulating the use of cannabis has outpaced rigorous scientific studies, and a growing number of patients presenting for surgery consume cannabis regularly. Research to date suggests that cannabis can impact perioperative outcomes. We present recommendations obtained using a modified Delphi method for the perioperative care of cannabis-using patients. A steering committee was formed and a review of medical literature with respect to perioperative cannabis use was conducted. This was followed by the recruitment of a panel of 17 experts on the care of cannabis-consuming patients. Panellists were blinded to each other's participation and were provided with rater forms exploring the appropriateness of specific perioperative care elements. The completed rater forms were analysed for consensus. The expert panel was then unblinded and met to discuss the rater form analyses. Draft recommendations were then created and returned to the expert panel for further comment. The draft recommendations were also sent to four independent reviewers (a surgeon, a nurse practitioner, and two patients). The collected feedback was used to finalise the recommendations. The major recommendations obtained included emphasising the importance of eliciting a history of cannabis use, quantifying it, and ensuring contact with a cannabis authoriser (if one exists). Recommendations also included the consideration of perioperative cannabis weaning, additional postoperative nausea and vomiting prophylaxis, and additional attention to monitoring and maintaining anaesthetic depth. Postoperative recommendations included anticipating increased postoperative analgesic requirements and maintaining vigilance for cannabis withdrawal syndrome.

Pharmacokinetic Modeling of the Impact of P-glycoprotein on Ondansetron Disposition in the Central Nervous System.

PURPOSE: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. METHODS: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. RESULTS: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39-5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. CONCLUSIONS: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.

Cognitive flexibility and persistent post-surgical pain: the FLEXCAPP prospective observational study.

BACKGROUND: Impaired performance on tasks assessing executive function has been linked to chronic pain. We hypothesised that poor performance on tests assessing the ability to adjust thinking in response to changing environmental stimuli (cognitive flexibility) would be associated with persistent post-surgical pain. METHODS: We conducted a single-centre prospective observational study in two perioperative cohorts: patients undergoing total knee arthroplasty or noncardiac chest surgical procedures. The co-primary outcome measures compared preoperative performance on the Trail Making Test and the colour-word matching Stroop test between patients who developed persistent post-surgical pain and those who did not. Secondary outcome measures included the associations between these test scores and pain severity at 6 months. RESULTS: Of 300 participants enrolled, 198 provided 6 month follow-up data. There were no significant differences in preoperative Trail Making Test B minus A times (33 vs 34 s; P=0.59) or Stroop interference T-scores (47th vs 48th percentile; P=0.50) between patients with and without persistent post-surgical pain (primary outcome). Of those who reported persistent post-surgical pain, poorer baseline performance on the colour-word matching Stroop test was associated with higher pain scores at 6 months in both knee arthroplasty (r=-0.32; P=0.04) and chest (r=-0.44; P=0.02) surgeries (secondary outcome). CONCLUSIONS: Preoperative cognitive flexibility test performance was not predictive of overall persistent post-surgical pain incidence 6 months after surgery. However, poor performance on the colour-word matching Stroop test was independently associated with more severe persistent post-surgical pain in both cohorts. CLINICAL TRIAL REGISTRATION: NCT02579538.

Association between postoperative complications and lingering post-surgical pain: an observational cohort study.

BACKGROUND: Post-surgical pain that lingers beyond the initial few-week period of tissue healing is a major predictor of pain chronification, which leads to substantial disability and new persistent opioid analgesic use. We investigated whether postoperative medical complications increase the risk of lingering post-surgical pain. METHODS: The study population consisted of patients undergoing diverse elective surgical procedures in an academic referral centre in the USA, between September 2013 and May 2017. Multivariable logistic regression, adjusting for confounding variables and patient-specific risk factors, was used to test for an independent association between any major postoperative complication and functionally limiting lingering pain 1-3 months after surgery, as obtained from patient self-reports. RESULTS: The cohort included 11 986 adult surgical patients; 10 562 with complete data. At least one complication (cardiovascular, respiratory, renal/gastrointestinal, wound, thrombotic, or neural) was reported by 13.3% (95% confidence interval: 12.7-14.0) of patients, and 19.7% (19.0-20.5%) reported functionally limiting lingering post-surgical pain. After adjusting for known risk factors, the patients were twice as likely (odds ratio: 2.04; 1.78-2.35) to report lingering post-surgical pain if they also self-reported a postoperative complication. Experiencing a complication was also independently predictive of lingering post-surgical pain (odds ratio: 1.95; 1.26-3.04) when complication data were extracted from the National Surgical Quality Improvement Program registry, instead of being obtained from patient self-report. CONCLUSIONS: Medical complications were associated with a two-fold increase in functionally limiting pain 1-3 months after surgery. Understanding the mechanisms that link complications to pathological persistence of pain could help develop future approaches to prevent persistent post-surgical pain.

Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain.

Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (MΦs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs. Furthermore, AT2R activation in MΦs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MΦs) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MΦ-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.

Simultaneous quantification of ondansetron and tariquidar in rat and human plasma using a high performance liquid chromatography-ultraviolet method.

Ondansetron, a widely used antiemetic agent, is a P-glycoprotein (P-gp) substrate and therefore expression of P-gp at the blood-brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P-gp inhibitors. Tariquidar is a potent and selective third-generation P-gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third-generation P-gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.

Neuropathic Pain: Central vs. Peripheral Mechanisms.

PURPOSE OF REVIEW: Our goal is to examine the processes-both central and peripheral-that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals. RECENT FINDINGS: Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.

A Novel Proliposomal Ropivacaine Oil: Pharmacokinetic-Pharmacodynamic Studies After Subcutaneous Administration in Pigs.

BACKGROUND: Liposomal local anesthetics are limited by a short liposomal shelf-life, even when under refrigeration. We describe a novel proliposomal ropivacaine that produces liposomes in situ, only after exposure to aqueous media. METHODS: In vitro: Nanoparticles were assessed (particle size distribution analyzer, cryo-transmission electron microscopy) at baseline and after exposure to saline/plasma. TOXICITY: In porcine wound healing study (n = 12), healing was assessed by photography, clinical assessment, and histology. Pharmacodynamics: Seventeen young piglets were randomly assigned to plain 0.5% ropivacaine (n = 5), proliposomal 4% ropivacaine (n = 6), or sham (n = 6). Tactile threshold was assessed using von Frey filaments applied to the surgical wound; the nonoperated skin was used as a control. Tactile threshold over time was determined using area under the curve (AUC) and assessed by 1-way analysis of variance. PHARMACOKINETICS: 8 young piglets were randomly assigned to plain 0.5% (25 mg, n = 4) or proliposomal 4% (200 mg, n = 4) ropivacaine. Plasma ropivacaine was assessed by high-performance liquid chromatography at baseline and at intervals over 36 hours. Paired ropivacaine concentration (from wound exudate and plasma) was obtained at 96 hours. Data were analyzed using noncompartmental and compartmental models. RESULTS: In vitro: On exposure to saline and plasma, the study drug was transformed from a homogenous oil to an emulsion containing liposomes of approximately 1.4-µm diameter; this effect was dilution dependent and stable over time. TOXICITY: All wounds healed well; no effect of drug group was observed. Pharmacodynamics: Plain and proliposomal ropivacaine provided sensory anesthesia for approximately 6 and 30 hours, respectively. There was an approximately 7-fold increase in the AUC of anesthesia for proliposomal ropivacaine compared with plain ropivacaine (mean difference, 1010; 95% confidence interval [CI], 625-1396 g·h/mm; P < 0.0001). PHARMACOKINETICS: There was no difference in Cmax (2.31 ± 0.74 vs 2.32 ± 0.46 mg/L), despite an approximately 8-fold difference in dose. However, proliposomal ropivacaine was associated with a marked prolongation of Tmax (6.50 ± 6.35 vs 0.5 ± 0.0 hours), terminal half-life (16.07 ± 5.38 vs 3.46 ± 0.88 hours; P = 0.0036), and ropivacaine-time AUC (47.72 ± 7.16 vs 6.36 ± 2.07 h·mg/L; P < 0.0001), when compared with plain ropivacaine. The proliposomal formulation provided an approximately 250-fold higher ropivacaine concentration in the surgical wound (mean difference, 3783 ng/mL; 95% CI, 1708-5858; P = 0.001) and an approximately 25-fold higher wound:plasma ropivacaine concentration ratio (mean difference, 126; 95% CI 38-213; P = 0.011). CONCLUSIONS: Proliposomal ropivacaine exerted prolonged anesthesia with delayed elimination, typical for liposomal drugs. The advantage of this novel proliposomal ropivacaine is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.

Proliposomal Ropivacaine Oil: Pharmacokinetic and Pharmacodynamic Data After Subcutaneous Administration in Volunteers.

BACKGROUND: Slow-release liposomal formulations of local anesthetics prolong plasma redistribution and reduce peak plasma drug concentration, allowing safer administration of larger doses and further prolonging sensory effects. However, their clinical applicability is limited by expensive manufacture and liposomal leakage. Previously, we described the simple preparation of a novel proliposomal ropivacaine oil that produces multilamellar liposomal vesicles on exposure to aqueous media and that has a shelf-life of >2 years at room temperature. In this study, we present both pharmacodynamic and pharmacokinetic data in healthy volunteers after subcutaneous injection of this novel proliposomal preparation of ropivacaine. METHODS: In the pharmacodynamic phase of this study, 15 volunteers received 3 separate subcutaneous injections of 2.5 mL containing 1 of the following drugs: proliposomal 4% ropivacaine, plain 0.5% ropivacaine, and the ropivacaine-free proliposomal vehicle. Drugs were administered into the lower back, and their location was randomized and blinded; a separate area was used as an uninjected, open control. Experimental sensory assessment was made at repeated intervals over 72 hours using both pinprick sensation and experimental heat pain tolerance (assessed using quantitative sensory testing). In a separate pharmacokinetic phase of this study, 9 volunteers received subcutaneous injections of 2.5 mL of either proliposomal 4% ropivacaine (n = 6) or plain 0.5% ropivacaine (n = 3); these participants had plasma ropivacaine concentrations assessed at repeated intervals over 72 hours. RESULTS: The mean ± SE duration of pinprick anesthesia after proliposomal and plain ropivacaine administration lasted 28.8 ± 6.0 and 15.9 ± 3.5 hours, respectively (mean difference, 16.8 hours; 95% confidence interval, 10.0-23.7; P = 0.001). For experimental heat pain, the anesthesia duration was approximately 36 and 12 hours, respectively, with mean ± SE area under the curve of the normalized heat pain tolerance over time 55.0 ± 28.8 Δ°C·min for proliposomal ropivacaine and 9.6 ± 26.0 Δ°C·min for plain ropivacaine (mean difference, 64.6 Δ°C·min; 95% confidence interval, 10.2-119.0; P = 0.036). In the pharmacokinetic study, there was no significant difference in peak plasma concentration in the proliposomal ropivacaine group (164 ± 43 ng/mL compared with 100 ± 41 ng/mL in the plain ropivacaine group; P = 0.07) despite an 8-fold increase in ropivacaine dose in the proliposomal group. The 99% upper prediction limit for peak plasma concentrations (351 ng/mL proliposomal; 279 ng/mL plain) was well below the putative toxic plasma concentration for both groups. The mean ± SE terminal half-life and area under the curve for proliposomal ropivacaine versus plain ropivacaine were 13.8 ± 3.6 hours vs 5.9 ± 2.3 hours (P = 0.011) and 5090 ± 1476 h·ng/mL vs 593 ± 168 h·ng/mL (P = 0.0014), respectively. CONCLUSIONS: The prolonged pharmacodynamic effect of proliposomal ropivacaine, together with its delayed elimination and prolonged redistribution to plasma, is compatible to depot-related slow-release and similar to the performance of other liposomal local anesthetics. The advantage of the proliposomal oil is its ease of preparation and its extended shelf-stability at room temperature.