Effective Analgesic Treatment Research Articles

Comparison of the preclinical quality of analgesia of emergency physicians and paramedics based on trauma patients

Adequate prehospital pain management is acritical component of emergency medical services. With the introduction of the paramedic profession and the Paramedics Act in Germany, the basis for more extensive competencies of paramedics was established. In many emergency medical service areas it is thus possible for paramedics to perform analgesia and sedation with esketamine/midazolam according to pre-established instructions and/or standard operating procedures. This study assessed the quality of analgesia administered to trauma patients by paramedics compared to emergency medical service physicians. The study included trauma patients who received prehospital administration of analgesia by either emergency medical service physicians or paramedics and were subsequently admitted to the central emergency department of the Saarland University Hospital. Astandardized data collection form was used to collect information from the emergency service protocol and initial emergency department assessment. The evaluation employed descriptive statistical methods and a total of 207 completed records were analyzed. Both professional groups achieved significant pain reduction and fulfilled the criteria for effective pain management (pain reduction: emergency medical service physicians 5.5 ± 2.0/paramedic 4.4 ± 2.1, p < 0.001). Emergency medical service physicians, however, more frequently attained ahigher reduction in numerical rating scale scores and administered oxygen. Notable differences were observed in the range of medications used and the dosages. This study could show that prehospital analgesia is comparable between emergency medical service physicians and paramedics in terms of effectiveness for trauma patients if the indications are correctly set, while observing pre-existing instructions. With their competencies paramedics are able to perform an effective and safe analgesic treatment within the framework of preformulated procedural instructions, which can be equal to that of an emergency medical service physician.

Evaluation of pain related behaviors and disease related outcomes in an immunocompetent mouse model of prostate cancer induced bone pain

Cancer-induced bone pain (CIBP) is the most common and devastating symptom of bone metastatic cancer that substantially disrupts patients’ quality of life. Currently, there are few effective analgesic treatments for CIBP other than opioids which come with severe side effects. In order to better understand the factors and mechanisms responsible for CIBP it is essential to have clinically relevant animal models that mirror pain-related symptoms and disease progression observed in patients with bone metastatic cancer.In the current study, we characterize a syngeneic mouse model of prostate cancer induced bone pain. We transfected a prostate cancer cell line (RM1) with green fluorescent protein (GFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM1 prostate cancer cell line into male C57BL/6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. Daily running wheel performance was evaluated as a measure of functional impairment and potentially movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at optimal velocity between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. We utilized histological, radiographic and μCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions as well as extra-periosteal aberrant bone formation in the tumor bearing femur, similar to clinical findings in patients with bone metastatic prostate cancer. Within the tumor bearing femur, we observed reorganization of blood vessels, macrophage and nerve fibers within the intramedullary space and periosteum adjacent to tumor cells. Tumor bearing mice displayed significant increases in the injury marker ATF3 and upregulation of the neuropeptides SP and CGRP in the ipsilateral DRG as well as increased measures of central sensitization and glial activation in the ipsilateral spinal cord. This immunocompetent mouse model will be useful when combined with cell type selective transgenic mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone metastatic prostate cancer.

Management of a patient with frostbite

Introduction and purpose Frostbite is a serious injury caused by cold, which is an inseparable element of human contact with nature. It can cause tissue damage and loss of function if not properly treated. It treatment consists of several stages that require the involvement of many people. The purpose of the article is to summarize information on epidemiology, pathophysiology, prehospital and hospital procedures and to draw attention to the complexity of patient care. Materials and methods A literature review based on PubMed and Google Scholar using the following keywords: frostbite, cold injury. Description of the state of knowledge: The literature review shows the breadth of the issue. The effectiveness of therapy depends on: knowledge of pathophysiology and risk factors, early diagnosis, discontinuation of exposure to cold, effective analgesic treatment, fluid therapy, transport of the victim to the appropriate center, rapid warming of frozen tissues, imaging diagnostics, initiation of thrombolytic treatment and, if necessary, surgery. It is also important to remember about long-term complications that worsen the quality of life of patients, such as chronic pain, hyperaesthesia or impairment or loss of limb functionality. Conclusions Frostbite is a relatively rare problem, but especially in winter, every medic will have to deal with it sooner or later. Considering the above information, the management of a patient with frostbite is a demanding and long-term process in which the cooperation and involvement of many medics is important, so it is worth having knowledge about them.

Sedative and adverse effect comparison between oral midazolam and nitrous oxide inhalation in tooth extraction: a meta-analysis

ObjectiveOral midazolam and nitrous oxide inhalation were commonly used sedative and analgesic techniques during tooth extraction. It is still controversial whether oral midazolam can replace the nitrous oxide inhalation for sedative and analgesic treatment of tooth extraction. Therefore, we conducted this study in order to provide a reference for doctors to choose effective sedative and analgesic treatment in tooth extraction.MethodsWe searched the Chinese and English databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang and VIP information databases.ResultsThrough this meta-analysis, we found that the success rate of sedation and analgesia treatment with oral midazolam during tooth extraction was 75.67% and the incidence of adverse reactions was 21.74%. The success rate of sedation and analgesia treatment using nitrous oxide inhalation during tooth extraction was 93.6% and the incidence of adverse reactions was 3.95%.ConclusionThe use of nitrous oxide inhalation for sedation and analgesia during tooth extraction is very effective, and oral midazolam can be used as an alternative to nitrous oxide inhalation.

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport.

Opioids are substances derived from opium (natural opioids). In its raw state, opium is a gummy latex extracted from Papaver somniferum. The use of opioids and their negative health consequences among people who use drugs have been studied. Today, opioids are still the most commonly used and effective analgesic treatments for severe pain, but their use and abuse causes detrimental side effects for health, including addiction, thus impacting the user's quality of life and causing overdose. The mesocorticolimbic dopaminergic circuitry represents the brain circuit mediating both natural rewards and the rewarding aspects of nearly all drugs of abuse, including opioids. Hence, understanding how opioids affect the function of dopaminergic circuitry may be useful for better knowledge of the process and to develop effective therapeutic strategies in addiction. The aim of this review was to summarize the main features of opioids and opioid receptors and focus on the molecular and upcoming epigenetic mechanisms leading to opioid addiction. Since synthetic opioids can be effective for pain management, their ability to induce addiction in athletes, with the risk of incurring doping, is also discussed.

Pharmacokinetics and effects of codeine in combination with acetaminophen on thermal nociception in horses.

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate-to-severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6-6.4 mg/kg acetaminophen) in a three-way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter-individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively.

Effects of Multimodal Therapy, Blinding, and Multi-laboratory Protocol Conduct on the Robustness of the Rat Model of Adjuvant Induced Arthritis.

The aim of this study was to investigate the effects of multimodal therapy comprising buprenorphine (BUP) and indomethacin (IND) on key translational parameters in the rat adjuvant induced arthritis (AIA) model. Furthermore, we investigated the difference between visual assessment scores and histology scores generated by blinded and non-blinded assessors and the robustness and generalizability of results by conducting a multi-laboratory study. The experiment was terminated on day 26 after 11 days (days 15-25) of voluntarily ingested buprenorphine and 7 days of gavage delivered indomethacin treatment (days 19-25). The treatment effects were assessed on the last day of the study, relying on body weight assessment, serum concentrations of α1- acid glycoprotein, and assessment of affected hind paws swelling, in-life and post mortem. Across two laboratories, the combined analgesic treatments had minimal effects on the measured model parameters indicating that multimodal treatment did not affect the translatability of the model. We found an improvement in clinical scores (a negative change in scores) in nearly all medicated animals when scored informed, whereas it was essentially 50:50 for the blinded scorings and no difference between the blinded and informed histological scoring. The present results support the use of more effective analgesic treatment regimens and the good practice recommendations advocating blinding as a mandatory practice in conduct of preclinical in vivo efficacy studies. In spite of minor differences between results obtained at the two sites, there was good agreement between them indicating robustness of the AIA model.

The analgesic effect of low-dose radiotherapy in treating benign musculoskeletal painful disorders using different energies: A retrospective cohort study

Abstract Introduction: This retrospective cohort study tries to determine if there is a correlation between the effectiveness of low-dose radiotherapy (LDRT) in treating painful inflammatory or degenerative musculoskeletal disorders (MSDs) and the applied radiotherapy energy. Patients and Methods: Between September 2019 and January 2020, a total of 91 patients with either painful inflammatory or degenerative MSDs were treated with LDRT. The inclusion criteria were patients older than 40 years with either painful inflammatory disorders such as epicondylitis humeri, plantar fasciitis or degenerative osteoarticular disorders of the wrist or ankle joints. All patients were treated with a single dose of 0·5 Gy and a total dose of 6·0 Gy (2 to 3 fractions weekly). Patients were divided into two groups. Orthovolt group was treated with 200 Kv, 15 mA and 1 mm copper filtration with different tubes according to the site to treatment using direct fields. The second group included patients treated with Linac machines with opposing fields using energies between 6 and 18 MV. The pain was evaluated before and on the last day of treatment and 4–6 months later using the Numerical Rating Scale. Results: 91 patients compatible with the inclusion criteria were identified with a median of 60 years. The median duration of symptoms was 6 months. 46% of patients were males, and 54% were females. The Orthovolt group included 49% of the patients and the Megavoltage group 51%. Most of the patients (98%) were previously treated with other methods such as local corticosteroid injection, painkillers or physiotherapy. At the end of the treatment, 60% of the patient’s showed subjective pain relief and only 6% had a complete response. The follow-up conducted 4 to 6 months after the treatment showed that 65% of patients had a complete response and 8% had an improvement. The comparison between both studied groups shows that the used energy does not affect the response either at the end of the treatment or at the second control. The relationship between the aetiology and the early and late responses shows no difference in the early response but a better late response in patients suffering from inflammatory diseases with a p-value of 0·015. The response according to the treated location shows that patients with osteoarthritis of the ankle joint have a worse response in comparison to other examined joints and plantar fasciitis. Conclusion: LDRT is an effective analgesic treatment option for both inflammatory and degenerative MSDs. There is no difference in response according to the used energy, and most of the patients show late responses 4 to 6 months after the treatment.

Palliative radiotherapy of bone metastases in octogenarians: How do the oldest olds respond? Results from a tertiary cancer center with 288 treated patients

BackgroundAccompanied by the demographic change, the number of octogenarian cancer patients with bone metastases will increase in the future. Palliative radiotherapy constitutes an effective analgesic treatment; however, as pain perception and bone metabolism change with increasing age, the analgesic efficacy of radiotherapy may be altered in elderly patients. We therefore investigated the treatment outcomes of palliative radiotherapy for bone metastases in octogenarians.MethodsPatients between 80 and 89 years undergoing radiotherapy for bone metastases between 2009 and 2019 at a tertiary cancer center were analyzed for patterns-of-care, pain response and overall survival (OS). Logistic regression analyses were carried out to examine parameters associated with pain response, and Cox analyses were conducted to reveal prognostic parameters for OS.ResultsA total of 288 patients with 516 irradiated lesions were included in the analysis. The majority (n = 249, 86%) completed all courses of radiotherapy. Radiotherapy led to pain reduction in 176 patients (61%) at the end of treatment. Complete pain relief at the first follow-up was achieved in 84 patients (29%). Bisphosphonate administration was significantly associated with higher rates of pain response at the first follow-up (p < 0.05). Median OS amounted to 9 months, and 1-year, 2-year and 3-year OS were 43%, 28% and 17%. In the multivariate analysis, ECOG (p < 0.001), Mizumoto score (p < 0.01) and Spinal Instability Neoplastic Score (SINS) (p < 0.001) were independent prognosticators for OS.ConclusionPalliative radiotherapy for bone metastases constitutes a feasible and effective analgesic treatment in octogenarian patients. ECOG, Mizumoto score and SINS are prognosic variables for survival and may aid treatment decisions regarding radiotherapy fractionation in this patient group. Single-fraction radiotherapy with 8 Gy should be applied for patients with uncomplicated bone metastases and poor prognosis. Prospective trials focusing on quality of life of these very old cancer patients with bone metastases are warranted to reveal the optimal radiotherapeutic management for this vulnerable population.

Mitragynine Reverses Paclitaxel Chemotherapy‐Induced Peripheral Neuropathy and is Mediated via Opioid Receptor Involvement

Chemotherapy‐induced peripheral neuropathy (CIPN) is a problematic side effect in patients receiving chemotherapeutic cancer treatments. Clinical use of approved analgesic drugs often does not adequately control the pathological pain arising from CIPN and does not account for potential abuse with opioid therapeutics. Mitragyna speciosa (kratom) contains the alkaloid mitragynine, which exhibits analgesic properties. However, the underlying pharmacological mechanisms that underlie these analgesic properties are complex and not completely understood. Male and female C57bl/6 mice received 8 mg/kg intraperitoneal injections of paclitaxel, a taxane class chemotherapeutic, every other day over the course of 7 days. To confirm the development of CIPN, the von Frey assay was utilized to determine the onset mechanical allodynia, which arises when a previously non‐painful stimulus is perceived as painful. Intraperitoneal mitragynine and the prototypical opioid agonist morphine both dose‐relatedly reversed CIPN‐induced mechanical allodynia. Effective doses (ED)50 were as follows – morphine: 7.02 (6.56 – 7.51) mg/kg, mitragynine: 109.80 (104.27 – 115.62) mg/kg. Pretreatment with the opioid antagonist naltrexone 0.032 mg/kg, intraperitoneally produced a rightward shift in both morphine and mitragynine dose‐response curves. Effective doses (ED)50 were as follows – naltrexone + morphine: 27.93 (24.84 – 31.40), naltrexone + mitragynine: 245.41 (211.76 – 284.39), resulting in a 3.98 and 2.24 fold shift of dose response curves, respectively. Here we show that mitragynine reverses mechanical allodynia associated with paclitaxel CIPN. We also show that opioid receptors mediate such activity, though additional data suggest a role for adrenergic and serotonin receptors as well. Mitragynine may be an effective analgesic treatment option for patients experiencing painful CIPN.

Beyond the epidural: Alternatives to neuraxial labor analgesia.

Labor creates an intense pain experienced by women across the world. Although neuraxial analgesia is the most effective treatment of labor pain, in many cases, it may not be undesired, not available, or have contraindications. In addition, satisfaction with labor analgesia is not only determined by the efficacy of analgesia but a woman's sense of agency and involvement in the childbirth experience are also key contributors. Providing safe choices for labor analgesia and support is central to creating a tailored, safe, and effective analgesic treatment plan with high maternal satisfaction. Healthcare provider knowledge of various nonneuraxial analgesic options, including efficacy, contraindications, safe clinical implementation, and side effects of various techniques is needed for optimal patient care and satisfaction. Future rigorous scientific studies addressing all of these labor analgesia options are needed to improve our understanding. This review summarizes the current published literature for commonly available non-neuraxial labor analgesic options.

Recent Advances of Microneedles and Their Application in Disease Treatment.

For decades, scientists have been doing a lot of research and exploration to find effective long-term analgesic and/or disease-modifying treatments. Microneedles (MNs) are a simple, effective, and painless transdermal drug delivery technology that has emerged in recent years, and exhibits great promise for realizing intelligent drug delivery. With the development of materials science and fabrication technology, the MN transdermal drug delivery technology has been applied and popularized in more and more fields, including chronic illnesses such as arthritis or diabetes, cancer, dermatocosmetology, family planning, and epidemic disease prevention, and has made fruitful achievements. This paper mainly reviews the latest research status of MNs and their fabrication methodology, and summarizes the application of MNs in the treatment of various diseases, as well as the potential to use nanotechnology to develop more intelligent MNs-based drug delivery systems.

Post-Mastectomy Pain: An Updated Overview on Risk Factors, Predictors, and Markers.

After breast surgery, women frequently develop chronic post-mastectomy pain (PMP). PMP refers to the occurrence of pain in and around the area of the mastectomy lasting beyond three months after surgery. The nature of factors leading to PMP is not well known. When PMP is refractory to analgesic treatment, it negatively impacts the lives of patients, increasing emotional stress and disability. For this reason, optimizing the quality of life of patients treated for this pathology has gained more importance. On the basis of the findings and opinions above, we present an overview of risk factors and predictors to be used as potential biomarkers in the personalized management of individual PMP. For this overview, we discuss scientific articles published in peer-reviewed journals written in the English language describing risk factors, predictors, and potential biomarkers associated with chronic pain after breast surgery. Our overview confirms that the identification of women at risk for PMP is fundamental to setting up the best treatment to prevent this outcome. Clinical practice can be planned through the interpretation of genotyping data, choosing drugs, and tailoring doses for each patient with the aim to provide safer and more effective individual analgesic treatment.

Low-dose radiotherapy for painful osteoarthritis of the elderly: A\xa0multicenter analysis of 970\xa0patients with 1185 treated sites

PurposePainful osteoarthritis is common in elderly patients, and low-dose radiotherapy has been demonstrated to provide effective symptomatic treatment. We examined the analgesic effects of low-dose radiotherapy for osteoarthritis in the elderly aiming to reveal potential differences in the response rates relating to increasing age.MethodsA retrospective analysis was performed at two university hospitals including elderly patients (≥ 65 years) undergoing radiotherapy for osteoarthritis between 2008 and 2020. Pain intensity and response were quantified using the numerical rating scale (NRS) and the Pannewitz score. Age groups were defined for young old (65–74 years), older old (75–84 years), and oldest old patients (≥ 85 years).ResultsIn all, 970 patients with 1185 treated sites and a median age of 76 years were analyzed. Mean NRS was 66 at baseline (t0), 53 after radiotherapy (t1), and 44 at first follow-up (t2) (p < 0.001 for t0–t1, t1–t2, and t0–t2). At t1, 1.5% exhibited a Pannewitz score of 0 (no pain), 58.5% of 1–2 (less pain), 36.1% of 3 (equal pain), and 3.9% of 4 (worse pain), while at t2, pain response shifted towards 6.9% (0), 58.6% (1–2), 28.1% (3), and 6.3% (4). Pain response did not differ between age groups at t1 (p = 0.172) or t2 (p = 0.684). In addition, pain response after re-irradiation (n = 384 sites) was 61.0% and was comparable between age groups (p = 0.535).ConclusionLow-dose radiotherapy results in pain reduction in about two-thirds of treated sites with no difference relating to increasing age, showing that radiotherapy is an effective analgesic treatment for osteoarthritis even at advanced ages.

Towards an improved pain assessment in castrated horses using facial expressions (HGS) and circulating miRNAs.

Pain in horses is an emergent welfare concern, and its assessment represents a challenge for equine clinicians. This study aimed at improving pain assessment in horses through a convergent validation of existing tools: we investigated whether an effective analgesic treatment influences the horse grimace scale (HGS) and the concentration of specific circulating microRNAs (miRNAs). Eleven stallions underwent routine surgical castration under general anaesthesia. They were divided into two analgesic treatment groups: castration with the administration of preoperative flunixin and castration with preoperative flunixin plus a local injection of mepivacaine into the spermatic cords. HGS and levels of seven circulating miRNAs were evaluated pre-, 8 and 20 hours post-procedure. Compared to pre-castration, HGS, miR-126-5p, miR-145 and miR-let7e increased significantly in horses receiving flunixin at 8 hours post-castration (Friedman test, p<0.05). Both behavioural and molecular changes occurred in horses receiving flunixin only, confirming that the addition of local mepivacaine is an effective analgesic treatment. Combining the use of HGS and circulating miRNAs, particularly miR-145, could be meaningful to monitor acute pain conditions in horses. Our results further validate the HGS as a method to assess acute pain in horses and point out miR-145 as a promising biomarker to identify pain.

Research advances on assisted analgesic and sedative treatment of burn children

Burn children would experience pain and anxiety during treatment and rehabilitation, thus analgesic and sedative treatment should be applied throughout the whole process of burn treatment. Due to the unique physiological and psychological status of burn children, analgesic and sedative treatment for burn children is a relatively complex process compared with that for adult burn patients. Therefore, how to provide the effective and safe analgesic and sedative treatment for burn children is a clinical challenge. This paper reviewed the related progress of assisted analgesic and sedative treatment of burn children, in order to provide a reference for clinical treatment.

'Reinventing the wheel' to advance the development of pain therapeutics.

Chronic pain affects approximately one-third of the population worldwide. The primary goal of animal research is to understand the neural mechanisms underlying pain so better treatments can be developed. Despite an enormous investment in time and money, almost no novel treatments for pain have been developed. There are many factors that contribute to this lack of translation in drug development. The mismatch between the goals of drug development in animals (inhibition of pain-evoked responses) and treatment in humans (restoration of function) is a major problem. To solve this problem, a number of pain-depressed behavioral tests have been developed to assess changes in normal behavior in laboratory animals. The use of home cage wheel running as a pain assessment tool is especially useful in that it is easy to use, provides an objective measurement of the magnitude and duration of pain, and is a clinically relevant method to screen novel drugs. Pain depresses activity in humans and animals, and effective analgesic treatments restore activity. Unlike traditional pain-evoked tests (e.g., hot plate, tail flick, von Frey test), restoration of home cage wheel running evaluates treatments for both antinociceptive efficacy and the absence of disruptive side effects (e.g., sedation, paralysis, nausea). This article reviews the literature using wheel running to assess pain and makes the case for home cage wheel running as an effective and clinically relevant method to screen novel analgesics for therapeutic potential.

Integrated rehabilitation in chronic pain

A rehabilitation protocol has been developed at the Rehabilitation and Rehabilitation Physiotherapy Center, University of Chieti-Pescara, which provides for the combined use of Frems, Manual Therapy and Cyclotronic Bioresonanceon patients with chronic pain.Chronic pain management represents one of the most important health challenges of the 21st century. According tosurveys, it is estimated that one in five Europeans suffers from it and that 26% of the Italian population is affected bythis pathological status, to the point of believing its treatment has become a priority for our national health system.Pain - which is nothing but one of the symptomatic manifestations of the disease, therefore a consequence of a preexisting / previous pathological state - represents one of the main discomforts as regards the life of patients, being, inthis perspective, the due to a significant deterioration in the quality of the same. Improper or absent pain managementcreates significant physical, psychological and social effects; moreover, considering the lost working days, it can alsohave an important economic impact.The identification of a therapeutic model capable of guaranteeing effective analgesic treatment for the population iscertainly a crucial objective, which can only be achieved through a better preparation of the medical profession, aswell as promoting the creation of appropriate service networks, aimed at involve all health professionals.

Integrated rehabilitation in chronic pain

A rehabilitation protocol has been developed at the Rehabilitation and Rehabilitation Physio-therapy Center, University of Chieti-Pescara, which provides for the combined use of Frems, Manual Therapy and Cyclotronic Bioresonance on patients with chronic pain. Chronic pain management represents one of the most important health challenges of the 21st century. According to surveys, it is estimated that one in five Europeans suffers from it and that 26% of the Italian population is affected by this pathological status, to the point of believing its treatment has become a priority for our national health system. Pain - which is nothing but one of the symptomatic manifestations of the disease, therefore a consequence of a pre-existing / previous pathological state - represents one of the main discom-forts as regards the life of patients, being, in this perspective, the due to a significant deteriora-tion in the quality of the same. Improper or absent pain management creates significant physi-cal, psychological and social effects; moreover, considering the lost working days, it can also have an important economic impact. The identification of a therapeutic model capable of guaranteeing effective analgesic treatment for the population is certainly a crucial objective, which can only be achieved through a better preparation of the medical profession, as well as promoting the creation of appropriate service networks, aimed at involve all health professionals.

ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain

Effective analgesic treatment for neuropathic pain remains an unmet need, so previous evidence that epidermal growth factor receptor inhibitors (EGFRIs) provide unexpected rapid pain relief in a clinical setting points to a novel therapeutic opportunity. The present study utilises rodent models to address the cellular and molecular basis for the findings, focusing on primary sensory neurons because clinical pain relief is provided not only by small molecule EGFRIs, but also by the anti-EGFR antibodies cetuximab and panitumumab, which are unlikely to access the central nervous system in therapeutic concentrations. We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of greater-than-additive, synergistic analgesia; highlighting the prospect of a unique new combination therapy in which enhanced efficacy could be accompanied by minimisation of side-effects. Peripheral (intraplantar) administration of EGF elicited hypersensitivity only following nerve injury and this was reversed by local co-administration of selective inhibitors of either ErbB1 or ErbB2. Investigating how ErbB1 is activated in neuropathic pain, we found evidence for a role of Src tyrosine kinase, which can be activated by signals from inflammatory mediators, chemokines and cytokines during neuroinflammation. Considering downstream consequences of ErbB1 activation in neuropathic pain, we found direct recruitment to ErbB1 of an adapter for PI 3-kinase and Akt signalling together with clear Akt activation and robust analgesia from selective Akt inhibitors. The known Akt target and regulator of vesicular trafficking, AS160 was strongly phosphorylated at a perinuclear location during neuropathic pain in an ErbB1-, ErbB2- and Akt-dependent manner, corresponding to clustering and translocation of an AS160-partner, the vesicular chaperone, LRP1. Exploring whether neuronal ion channels that could contribute to hyperexcitability might be transported by this vesicular trafficking pathway we were able to identify Nav1.9, (Nav1.8) and Cav1.2 moving towards the plasma membrane or into proximal axonal locations – a process prevented by ErbB1 or Akt inhibitors. Overall these findings newly reveal both upstream and downstream signals to explain how ErbB1 can act as a signalling hub in neuropathic pain models and identify the trafficking of key ion channels to neuronal subcellular locations likely to contribute to hyperexcitability. The new concept of combined treatment with ErbB1 plus ErbB2 blockers is mechanistically validated as a promising strategy for the relief of neuropathic pain.