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Abstract Tonsillectomy is one of the most common operations. Tonsillectomy is also one of the most painful surgical procedures. However, there is still no satisfactory standard for postoperative pain management. Four databases (Cochrane Library, Ovid Technologies, PubMed, Web of Science) were searched for the period from 1908 to 2019. The systematic literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were pooled using random-effects and fixed-effects models. Randomized controlled trials, reviews and meta-analyses were included. Primary outcomes were quantitative pain intensity in the first 24 h after tonsillectomy and on days 1, 3, and 7 postoperatively. The search yielded 1594 publications, of which 111 publications with 7566 patients, both children and adults, could be included. Intraoperative medication with intravenous dexamethasone significantly reduced pain (mean difference [MD] -0.42; 95% confidence interval [CI]: -0.61- -0.24). Among the local anesthetics, only the preoperative injection of levobupivacaine into the tonsillar compartment was able to provide sufficient pain reduction up to three days after tonsillectomy (MD: -1.92; 95% CI: -2.73 - -1.11). Preoperative or intraoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) significantly reduced pain (MD: -0.75; 95% CI: -0.87- -0.63). Steroids and NSAIDs are an important part of pain management after tonsillectomy.

Abstract Background Low back pain, a common problem worldwide, causes more global disability than any other condition and is associated with high costs to society. This observational registry-based study describes the current trends in the medical treatment of neuropathic low back pain in the Swedish region of Västra Götaland, which has a population of 1.7 million. The study aims to; (1) identify the prevalence of neuropathic low back pain within the study population; (2) to explore the patterns of medical treatment utilization, including the prevalence and distribution of opioids (OG) and analgesics specified for neuropathic low back pain (NG) and (3) to evaluate the long-term trends and changes in medical treatment practice for neuropathic low back pain over the study period. Methods This study includes a descriptive analysis of aggregated data extracted from the Swedish primary care registry VEGA and the pharmaceutical prescription registry Digitalis between the years 2017 and 2021. The data were stratified by year, age, gender, pharmaceutical code (ATC), and sub-diagnoses and presented as the prevalence of unique patients retrieving prescribed medication within six months before or after a registered diagnosis of neuropathic low back pain. The pharmaceutical codes were furthermore grouped into two groups depending on their mechanism of action; opioid group (OG) and neuropathic group (NG). Results In all four diagnosis groups, more patients used opioid analgesics than neuropathic analgesics. The greatest difference between the opioid group and neuropathic group was in the lumbar spinal stenosis diagnosis group (67.1% vs. 40.6%), followed by the lumbar root canal stenosis diagnosis (65.9% vs. 44.2%), the nerve root and plexus compressions in intervertebral disc disorders diagnosis (57.5% vs. 40.8%), and lumbago with sciatica diagnosis (38.4% vs. 22.7%). Conclusions The trends suggest a general increase in the prescription rate and therefore patients’ use of neuropathic analgesics for neuropathic pain associated with the studied diagnoses. However, opioid treatment remains the most common. The results indicate that the treatment for neuropathic low back pain needs to be improved.

Pain is a subjective concept which is ever-present in the medical field. Health professionals are confronted with a variety of pain types and sources, as well as the challenge of managing a patient with acute or chronic suffering. An even bigger challenge is presented in the pediatric population, which often cannot quantify pain in a numerical scale like adults. Infants and small children especially show their discomfort through behavioral and physiological indicators, leaving the health provider with the task of rating the pain. Depending on the pathophysiology of it, pain can be classified as neuropathic or nociceptive, with the first being defined by an irregular signal processing in the nervous system and the second appearing in cases of direct tissue damage or prolonged contact with a certain stimulant. The approach is generally either pharmacological or non-pharmacological and it can vary from using NSAIDs, local anesthetics, opiates to physical and psychological routes. Unfortunately, some pathologies involve either intense or chronic pain that cannot be managed with traditional methods. Recent studies have involved nanoparticles with special characteristics such as small dimension and large surface area that can facilitate carrying treatments to tissues and even offer intrinsic analgesic properties. Pediatrics has benefited significantly from the application of nanotechnology, which has enabled the development of novel strategies for drug delivery, disease diagnosis, and tissue engineering. This narrative review aims to evaluate the role of nanotechnology in current pain therapy, with emphasis on pain in children.

Objective: The objective of the present study was to know the effect of coffee on occurrence of postdural puncture headache (PDPH) in post-operative patients related to bio-physical parameters among the patients who underwent spinal anaesthesia procedures. Methods: The samples were recruited of about 60 nos. of patients from the accessible population and were further distributed randomly to group - I (30) and group – II (30). The patients were compared the biophysical parameters related to earlier PDPH pain score for both groups after administration of three doses of coffee at intervals 24hrs, 48hrs and 72hrs of spinal anaesthesia were considered as observation one, two and three (O1, O2 and O3), respectively for group - I patients and normal routine care for group - II patients. Results: The main findings in this study were that the incidence of PDPH is lower in group-I after coffee consumption but no statistically significant difference were observed on different biophysical parameters viz. pulse rate, respiration rate, SBP, DBP and BMI related to NRS pain score observations at O1, O2 and O3, respectively but respiration rate and SBP were found statistically significant (P

Background and Objectives: Enucleation of an eye is the most invasive procedure in ophthalmologic surgery. It can be the result of various diseases (malignant/chronic/trauma/infection) and is nevertheless relatively rare, but leads to the loss of a strongly innervated neuronal organ. This study systematically evaluates postoperative pain levels following enucleation of the eye globe. Materials and Methods: This prospective single-center study enrolled twenty-four patients undergoing enucleation of the eye globe. Perioperatively all patients completed (preoperative day, day of surgery, 1st, 2nd, and 3rd day following surgery) standardized questionnaires concerning their pain experience and treatment-related side-effects (internal protocol, QUIPS, painDETECT®). Patients received usual pain therapy in an unstandardized individual manner. Results: Preoperatively, mean average pain intensity of all included patients was 3.29 ± 2.46 (range, 0–8), 3.29 ± 3.24 (range, 0–8) on the day of surgery, 4.67 ± 1.90 (range, 2–10) on day 1, 3.25 ± 1.39 (range, 1–6) on day 2, and 2.71 ± 1.30 (range, 1–6) on day 3 after surgery. Mean maximum pain intensity was 4.71 ± 3.28 (range, 0–10) preoperatively, 4.04 ± 3.78 (range, 0–10) on the day of surgery, 5.75 ± 2.01 (range, 2–10) on day 1, 4.25 ± 1.89 (range, 2–10) on day 2, and 3.88 ± 1.54 (range, 2–8) on day 3 after surgery. Nineteen patients (79.2%) stated that they would have preferred more pain therapy. Conclusions: Patients undergoing eye enucleation report pain sensations in need of intervention in this university hospital. Thus, effective standardized pain treatment concepts are now a high priority to be established in an interdisciplinary manner containing standardized regimens and continuous regional procedures. Awareness of this problem in the medical team should be sharpened through targeted training and information.

• Introduction: The assessment and treatment of pain in the pediatric population is a huge challenge for doctors and medical staff dealing with this group of patients. It is also one of the most important elements of pediatric care practice. There are many factors that contribute to the difficulty of assessing and managing pain in children, but the most important seems to be the lack of unified standards of care. In pain therapy, both pharmacotherapy and behavioral methods and psychological care are used. • Purpose of the work: The aim of this work is to systematize the current state of knowledge in the field of pain therapy in the pediatric population, focusing particular attention on pharmacotherapy • Materials and Evidence: We reviewed the literature available in the PubMed database using the following keywords: pediatric; pain therapy; analgesia • Summary: Pain therapy in the pediatric population, despite the fact that it is often underestimated and insufficiently managed, is crucial both in terms of avoiding health complications and in the overall therapeutic process. Despite the presence of many drugs for pain therapy on the market, many of them are not approved for use in this group of patients. Knowledge of their mechanisms of action and predicting the impact on metabolism in a pediatric patient compared to an adult is crucial for the management of both acute and chronic pain syndromes. Despite the current knowledge, there is still a need for broader research on the possibility of the drugs used, their impact on the therapy process and side effects in the youngest patients.

Abstract Background The Combined Mandibulectomy and Neck Dissection (COMMANDO) surgery results in severe postoperative pain and requires multimodal analgesia (MMA) for its management. We speculated that the erector spinae plane block (ESPB) which is the ultrasound (US)-guided regional technique and has been used in various types of surgeries due to its analgesic benefits could be used as an effective analgesic adjunct in COMMANDO surgery. Case presentation We report a case of a 68-year-old female patient who underwent left side COMMANDO surgery for carcinoma cheek. She was given an ultrasound-guided left erector spinae plane block (ESPB) in the preoperative period with catheter insertion at T3 (3rd thoracic vertebral level). Two boluses of local anesthetic were given each with 10 ml 0.25% ropivacaine one before and one after surgery, and then, the infusion was started with a volumetric pump. The ESPB provided effective intraoperative as well as postoperative pain relief without any side effects. Conclusion US-guided ESPB could be used as a potential opioid-sparing multimodal analgesic in head and neck surgeries based on the pain relief provided and the spread of contrast on imaging. This hypothesis needs to be explored in the form of case series and adequately powered randomized controlled trials.

Jeffrey Gudin,1 Seferina Mavroudi,2,3 Aigli Korfiati,3 Konstantinos Theofilatos,3 Derek Dietze,4 Peter Hurwitz5 1Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Nursing, School of Health Rehabilitation Sciences, University of Patras, Pátrai, Greece; 3InSyBio Ltd, Winchester, UK; 4Metrics for Learning LLC, Queen Creek, Arizona, USA; 5Clarity Science LLC, Narragansett, Rhode Island, USACorrespondence: Peter HurwitzClarity Science LLC, 750 Boston Neck Road, Suite 11, Narragansett, RI 02882, USATel +1917 757 0521Fax +1855-891-8303Email peterh@claritysciences.orgPurpose: Chronic pain is a life changing condition, and non-opioid treatments have been lately introduced to overcome the addictive nature of opioid therapies and their side effects. In the present study, we explore the potential of machine learning methods to discriminate chronic pain patients into ones who will benefit from such a treatment and ones who will not, aiming to personalize their treatment.Patients and Methods: In the current study, data from the OPERA study were used, with 631 chronic pain patients answering the Brief Pain Inventory (BPI) validated questionnaire along with supplemental questions before and after a follow-up period. A novel machine learning approach combining multi-objective optimization and support vector regression was used to build prediction models which can predict, using responses in the baseline, the four different outcomes of the study: total drugs change, total interference change, total severity change, and total complaints change. Data were split to training (504 patients) and testing (127 patients) sets and all results are measured on the independent test set.Results: The machine learning models extracted in the present study significantly overcame other state of the art machine learning methods which were deployed for comparative purposes. The experimental results indicated that the machine learning models can predict the outcomes of this study with considerably high accuracy (AUC 73.8– 87.2%) and this allowed their incorporation in a decision support system for the selection of the treatment of chronic pain patients.Conclusion: Results of this study revealed the potential of machine learning for an individualized medicine application for chronic pain therapies. Topical analgesics treatment were proven to be, in general, beneficial but carefully selecting with the suggested individualized medicine decision support system was able to decrease by approximately 10% the patients which would have been subscribed with topical analgesics without having benefits from it.Keywords: individualized medicine, pain therapy, non-opioid treatment, machine learning, predictive analytics, regression, multi-objective optimization, support vector regression

Sports-related pain and injury is directly linked to tissue inflammation, thus involving the autonomic nervous system (ANS). In the present experimental study, we disable the sympathetic part of the ANS by applying a stellate ganglion block (SGB) in an experimental model of delayed onset muscle soreness (DOMS) of the biceps muscle. We included 45 healthy participants (female 11, male 34, age 24.16 ± 6.67 years [range 18–53], BMI 23.22 ± 2.09 kg/m2) who were equally randomized to receive either (i) an SGB prior to exercise-induced DOMS (preventive), (ii) sham intervention in addition to DOMS (control/sham), or (iii) SGB after the induction of DOMS (rehabilitative). The aim of the study was to determine whether and to what extent sympathetically maintained pain (SMP) is involved in DOMS processing. Focusing on the muscular area with the greatest eccentric load (biceps distal fifth), a significant time × group interaction on the pressure pain threshold was observed between preventive SGB and sham (p = 0.034). There was a significant effect on pain at motion (p = 0.048), with post hoc statistical difference at 48 h (preventive SGB Δ1.09 ± 0.82 cm VAS vs. sham Δ2.05 ± 1.51 cm VAS; p = 0.04). DOMS mediated an increase in venous cfDNA -as a potential molecular/inflammatory marker of DOMS- within the first 24 h after eccentric exercise (time effect p = 0.018), with a peak at 20 and 60 min. After 60 min, cfDNA levels were significantly decreased comparing preventive SGB to sham (unpaired t-test p = 0.008). At both times, 20 and 60 min, cfDNA significantly correlated with observed changes in PPT. The 20-min increase was more sensitive, as it tended toward significance at 48 h (r = 0.44; p = 0.1) and predicted the early decrease of PPT following preventive stellate blocks at 24 h (r = 0.53; p = 0.04). Our study reveals the broad impact of the ANS on DOMS and exercise-induced pain. For the first time, we have obtained insights into the sympathetic regulation of pain and inflammation following exercise overload. As this study is of a translational pilot character, further research is encouraged to confirm and specify our observations.

The incidence rates of adverse events secondary to any operation are a well-known problem in any surgical field. One outstanding example of such adverse events is postoperative pain. Thus, the incidence of acute postoperative pain following any surgical procedure and its treatment are central issues for every surgeon. In the times of Enhanced Recovery After Surgery (ERAS) programs, acute pain therapy became an increasingly well investigated and accepted aspect in almost all surgical subspecialties. However, if it comes to the reduction of postoperative complications, in the actual context of postoperative pain, surgeons tend to focus on the operative process rather than on the perioperative procedures. Undoubtedly, postoperative pain became an important factor with regard to the quality of surgical care: both, the extent and the quality of the surgical procedure and the extent and the quality of the analgesic technique are decisive issues for a successful pain management. There is growing evidence that supports the role of acute pain therapy in reducing postoperative morbidity, and it has been demonstrated that high pain scores postoperatively may contribute to a complicated postoperative course. This overview comprises the current knowledge on the role of acute pain therapy with regard to the occurrence of postoperative complications. Most of the knowledge is derived from studies that primarily focus on the type and quality of postoperative pain therapy in relation to specific surgical procedures and only secondary on complications. As far as existent, data that report on the recovery period after surgery, on the rehabilitation status, on perioperative morbidity, on the development of chronic pain after surgery, and on possible solutions of the latter problem with the institution of transitional pain services will be presented.

Ulderico Freo,1 Patrizia Romualdi,2 Hans G Kress31Anesthesiology and Intensive Medicine, Department of Medicine DIMED, University of Padua, 35100 Padua, Italy; 2Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126, Bologna, Italy; 3Department of Special Anaesthesia and Pain Medicine, Medical University/AKH of Vienna, Vienna, AustriaAbstract: Neuropathic pain (NP) is an enormous burden for patients, caregivers and society. NP is a pain state that may develop after injury of the peripheral or central nervous system because of a wide range of diseases and traumas. A NP symptom component can be found also in several types of chronic pain. Many NP patients are substantially disabled for years. Due to its chronicity, severity and unpredictability, NP is difficult to treat. Tapentadol is a central-acting oral analgesic with combined opioid and noradrenergic properties, which make it potentially suitable for a wide range of pain conditions, particularly whenever a NP component is present or cannot be excluded. In randomized controlled trials, tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain. In observational studies, tapentadol reduced NP in chemotherapy-induced peripheral neuropathies, blood and solid cancers, and the NP component in neck pain and Parkinson’s disease. This narrative review aims to provide clinicians with a broad overview of tapentadol effects on NP.Keywords: neuropathic pain, tapentadol, pain therapy

Opiates are routinely used for chronic pain patients, and up to 44% of them will have a prescription for an opiate medication for pain alleviation. However, of the 76 million adults prescribed opiates for pain management, about 12% report misuse, and a large number of these may find themselves addicted to opioid medications. Opioid addiction is an ongoing epidemic, costing many lives. Withdrawal is very difficult. This requires providers to consider alternative analgesic plans and minimize opiate use. Here we report the use of a dexamethasone-dexmedetomidine combination for a regional nerve block in an elderly woman chronically treated with opiate medications who had previously failed opiate weaning. Following her nerve block, she was able to completely wean off of opioids and continues having good pain control with an opioid-free regimen.

Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.

Cancer pain remains a significant clinical problem worldwide. Cancer pain causes are multifactorial and complex and varying with a variety of factors and processes related both to the tumor process and to the host itself. Even though the quality of pharmacologic pain management has improved in the last decades, 1 in 3 patients do not receive pain medication appropriate for the intensity of experienced pain. Chronic cancer pain in urologic patients has different traits, since this carcinoma might originate from various organ:, prostate, kidneys, adrenal glands, urinary bladder or the penis. Urogenital neoplasm very often metastasized into the bones (spine, pelvis and head bones) and they are associated with pathological fractures, hypercalcemia, and neurological deficits, which lead to a significant reduction in quality of life. Pain induced by bone metastases is nociceptive pain, but may also be associated with neuropathic pain if the tumor performs compression or invasion of the nerve, spinal cord or nerve plexus. In 70-90% of urological cancer patients pain can be adequately relieved by consistent adherence to the WHO cancer pain recommendations. However, additional pain relief therapies, such as radiation and psychosocial treatment of these patients have to be considered.

Chronic pain management requires increasing doses of opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable analgesia with low doses of opioids is thus imperative. N-palmitoylethanolamine (PEA) is an endogenous lipid compound endowed with pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate morphine’s effects, delaying tolerance and improving efficacy. To evaluate the possible application to other opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate analgesia and tolerance induced by oxycodone and tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg−1, daily, per os) delayed the onset of opioid tolerance and enhanced opioid analgesia when it was acutely administered in association with tramadol (20 mg kg−1, daily, subcutaneously) or oxycodone (0.5 mg kg−1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with opioids for stable, long-lasting analgesia. To that purpose, the oxycodone dose needed to be increased from 0.3 mg kg−1 (day 1) up to 1 mg kg−1 (day 31) in the oxycodone + vehicle group; the tramadol dose was progressively enhanced from 15 mg kg−1 to 50 mg kg−1 in 31 days in the tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg−1) achieved the same analgesia without increasing the dose of both opioids. The behavioural effects of PEA on opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of opioid tolerance) and with a modulation of mRNA expression of IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of tramadol tolerance, potentiating either oxycodone or tramadol analgesia and allowing a long-lasting analgesic effect with a low opioid dose regimen. The use of PEA is suggested for clinical purposes to support the opioid-based management of persistent pain.

Application of music has positive effects on physical, emotional and spiritual well-being, stress reduction, patients' and medical staff mood improvement, making the work environment more pleasant for both patients and staff. The aim of this narrative review is to present facts about perioperative music implementation and effects on patients and medical staff. In highly developed countries, music provided by professionals in the form of music therapy is incorporated in patients' care on the wards or in the recovery room to improve their mood, prevent depression and enable physical rehabilitation and relaxation. Perioperative music application decreases postoperative pain intensity and anxiety level, and increases patient's satisfaction. So far, music therapy application was studied in patients undergoing gynecological procedures, Caesarean section, breast surgery, urological procedures, cardiovascular surgery, abdominal surgery, orthopedic and maxilofacial surgery and different kinds of diagnostic and interventional procedures. Moreover, in real life, music is present on daily bases during performances in the operating rooms all over the world. There is an open question about music's influence on surgical team performance. In the operating room, choice of music and its perception differs depending on professional status and medical specialty. Music can improve surgeons' performance in the operating room. Type of music and its volume needs to be carefully chosen if music is used in the operating room, to prevent distraction of medical staff during performance. In surgical patients, music as nonpharmacological method can be safely used in the perioperative period as adjuvant therapy to pain medications, for anxiety and pain relief.

Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease.

Introduction: Chronic pain in the abdomen occurs as a consequence of malignancy in these parts of the body, surgical, of radiological and chemotherapy treatments. It may also be as a result of relapse of the basic process. Non-invasive therapy of oral and transdermal analgesic was successful for some time, where necessary applies and epidural catheter. Case Report: The patient had a diagnosis of chronic postoperative pain malignant etiology. He is already used transdermal fentanyl and Nonsteroidal Anti-Inflammatory Drugs, but without success (VAS score 8-10). We increased doses of analgesics, but without success. In order of pain therapy, peridural catheter placed in the level L3 - L4. 5 ml of a solution of 8 ml of 0.25% bupivacaine, 2 ml (100 micrograms) of fentanyl and 10 ml of saline was administered every 6 hours through epidural catheter. The former chronic non-invasive treatment of pain did not stop. The first three to five days of pain relief was quite satisfactory in this way. Then the pain intensified but the peridural catheter had to be removed due to local infection. New peridural catheter was placed in the level L2 -L3. Then, 5 ml of the solution: of 8 ml 0,25% bupivacaine, 2 ml (100 micrograms) of fentanyl and 10 ml of saline is administered through peridural catheter. Peridural catheter was total used for 45 days. We had a need for more and more frequently administering analgesics through a catheter during use. The patient was using transdermal fentanyl and Nonsteroidal Anti-Inflammatory Drugs, all the time. The patient soon died due to progression of the underlying disease. Conclusion: After long-term administration of opioids, it is necessary to change the type and route of administration of the drug to achieve the success of the therapy. In this case it was the use of analgesics and local anesthetics through the peridural catheter.

Marta Kiałka,1 Tomasz Milewicz,1 Krystyna Sztefko,2 Iwona Rogatko,2 Renata Majewska3 1Department of Gynecological Endocrinology, Jagiellonian University, Medical College, Kraków, Poland; 2Department of Clinical Biochemistry, Jagiellonian University, Medical College, Kraków, Poland; 3Department of Epidemiology, Chair of Epidemiology and Preventive Medicine, Jagiellonian University Medical College, Kraków, Poland Background: Despite the strong preclinical rationale, there are only very few data considering the utility of metformin as a potential pain therapeutic in humans. The aim of this study was to determine the association between metformin therapy and pressure pain threshold (PPT) in lean women with polycystic ovary syndrome (PCOS). We hypothesized that metformin therapy in lean PCOS women increases PPT. Materials and methods: Twenty-seven lean PCOS women with free androgen index phenotype >5 and 18 lean healthy controls were enrolled in the study. Fifteen of the PCOS women were randomly assigned to be treated with metformin 1,500 mg daily for 6 months. PPT and plasma β-endorphin levels were measured in all women at the beginning of the study and after 6 months of observation. Results: We observed an increase in PPT values measured on deltoid and trapezius muscle in the PCOS with metformin group after 6 months of metformin administration (4.81±0.88 kg/cm², P

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

The facilitation of opioid medication is eliciting a nemetic problem since increasing overdose deaths involve prescription of opioid pain relievers. Chronic painful diseases require higher doses of opioids, progressively with the development of tolerance to the antinociceptive effect. Novel strategies for the maintenance of low dosed opioid effectiveness are necessary to relieve pain and decrease abuse, overdose, and side effects. N-Palmitoylethanolamine (PEA) is an endogenous compound able to preserve the homeostasis of the nervous system and to delay the development of morphine tolerance. In the present study, a preemptive and continuative treatment with ultramicronized PEA (30 mg/kg, daily, per os) enhanced the acute antinociceptive efficacy of morphine (10 mg/kg subcutaneously) in rats and prolonged the responsiveness to the natural opioid. Moreover, PEA-treated animals had a more rapid recovery from tolerance. Four opioid free days were enough to regain sensitivity to morphine whereas control animals needed 31 days for full recovery of tolerance. Characteristically, PEA acquired per se antinociceptive properties in tolerant animals, suggesting the possibility of an integrated morphine/PEA treatment protocol. To maintain a significant analgesia, morphine dose had to be increased from 5 up to 100 mg/kg over 17 days of daily treatment. The same pain threshold increase was achieved in animals using preemptive PEA (30 mg/kg, daily) joined to a combinatorial acute treatment with morphine (5–20 mg/kg s.c.) and PEA (30–120 mg/kg, p.o.). Representatively, on day 17, the magnitude of analgesia induced by 100 mg/kg morphine was obtained by combining 13 mg/kg of morphine with 120 mg/kg of PEA. PEA strengthens the efficacy and potency of morphine analgesia, allowing prolonged and effective pain relief with low doses. PEA is suggested in association with morphine for chronic pain therapies distinguished by low risk of side effects.

ABSTRACT Etodolac is a non-steroidal anti-inflammatory drug (NSAID) and approved by USFDA as a COX2 inhibitor. Although etodolac therapy provides clinical benefits, it is associated with upper gastrointestinal (GI) tract complications also. Etodolac loaded gum Katira microsphere (ELGKM) was prepared by W1/O/W2 emulsion solvent evaporation technique. The gastric irritation properties of orally administered pure etodolac, ELGKM and blank microspheres (without etodolac) were evaluated in experimental rats treated for 6 days. The stomach examination and biochemical investigation of stomach tissue of treated rats indicated that ELGKM formulation remarkably reduced ulcerogenecity as compared to pure etodolac. The anti-inflammatory activities of pure etodolac and ELGKMs were ascertained by the implantation of cotton pellets in rats for 6 days. Based on the results, ELGKMs showed significant anti-inflammatory activities (P

Although the coexistence of rare pathologies in the same patient is considered an exceptional event, the possibility to contend with a condition such like this may occur in clinical practice. In these cases, a multidisciplinary approach is required in order to find the most appropriate therapeutic strategy. Here we describe the clinical case of a 61 years old female affected with a rare genetic pathology known as lateral meningocele syndrome (LMS) who developed a pathological condition that could be framed in the context of a multiple chemical sensitivity syndrome (MCSS) characterized by intolerance to several drugs, foods as well as environmental and chemical agents.

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography−mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.

Pain is a major problem in patients with rheumatoid arthritis (RA). It produces a serious psychological discomfort, causes sleep disorders, and drastically limits physical activity. Pain is one of the main signs of inflammation and its intensity correlates with inflammatory activity. The early use of disease-modifying antirheumatic drugs, regular monitoring, and timely correction of therapy in accordance with the treat-to-target principle make it possible to effectively monitor the activity of RA and to delay its progression. However, despite a marked decrease in RA activity, pain does not go away completely and may increase with time in a number of cases. Pain occurring in patients with RA is always far short of being caused by arthritis. It may be also related to comorbidity, osteoarthritis or fibromyalgia in particular. Pain induced by comorbidity may seriously distort the result of assessment of inflammatory activity and a physician's decision made to correct drug therapy in accordance with the treat-to-target principle.Nonsteroidal antiinflammatory drugs (NSAIDs) are in most common use for the symptomatic therapy of RA. In spite of a significant reduction in pain and stiffness during therapy with NSAIDs, they do not affect the progression of X-ray changes. Virtually all NSAIDs may relieve pain when used in doses substantially smaller than those required to suppress inflammation. NSAIDs are an essential component of combination therapy for RA. They are given just at the early stage of the disease, by taking into account the gastrointestinal tract, kidney, and cardiovascular system. The National Institute for Health and Clinical Excellence in the United Kingdom proposes to administer analgesics (paracetamol and codeine) to reduce needs for NSAIDs in RA. For the time being, the use of analgesics in RA has, however, a weak evidence base.Different trials have also studied the efficiency of monotherapy with weak opioids, but it has proven to be also low. It is well, where possible, to avoid the long-term use of opioids.Along with NSAIDs and paracetamol, the recent guidelines of the International Expert Group of Pain Pharmacotherapy to use tricyclic antidepressants as additional agents to treat joint inflammatory diseases, which may be effective in some cohort of patients, such as those with RA and comorbid depressive disorders.Besides drug therapy, nonpharmacological methods are also successfully used in the treatment of pain in RA. The effective suppression of pain makes it possible not only to considerably reduce existing discomfort in a patient, but also to more correctly choose treatment policy in each specific case.

Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, controlled clinical studies show promising results in neuropathic and other chronic pain disorders. In comparison with other conventional and non-conventional analgesic drugs, the greatest advantages of BoNT/A use are its sustained effect after a single application and its safety. Its efficacy in certain therapy-resistant pain conditions is of special importance. Novel results in recent years has led to a better understanding of its actions, although further experimental and clinical research is warranted. Here, we summarize the effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters.

The incidence of arthritis is increasing every year, as does the need for pain medication. The current work reviews an American Indian liniment that is traditionally used for pain therapy. The chemistry, therapeutic use and safety of the liniment are reviewed. The liniment contains monoterpenoids, sesquiterpenes, flavonoids, alkaloids and other compounds.

When physicians experience negative reactions to patients, they often perceive the patients as "difficult". Such patients make up 15% to 30% of primary care practice populations. They are those whom most physicians dread. The dependency of difficult patients heavily influences the doctor-patient relationship and the outcome of the treatment. These patients often present with physical symptoms that could not be medically explained. Pain is the most frequent complaint, though unrecognized psychopatological disorders are more prevalent among these patients. Conversely, difficult patients are rather common in chronic pain syndromes, particularly in back pain, failed back syndrome and atypical facial pain. Diagnosis can be achieved on phenomenological, psychopathological and psychodynamic grounds. The management of difficult patients can prove to be a tough task for both physicians and nurses, as they are time-consuming, draining the emotional resources of the therapist, and evoke feelings of aversion and frustration. Appropriate use of patient-doctor communication skills and an effort to improve relations with the patient through empathy, tolerance and non-judgemental listening are suggested as ways of transform a difficult encounter into a workable patient-doctor relationship.

Until recently, pain therapy in Italy was conducted with largely sub-optimal standards, as revealed by one of the lowest mean morphine consumption values, an important indicator of pain therapy quality according to the WHO, among industrialized countries. The recognition of such a negative situation has led to an important effort to improvement, carried out by the law-maker, institutions and health professionals. As suggested by the WHO, these efforts aimed at three main objectives: reducing the cultural barriers to appropriate opioid use through targeted education and information, easing of analgesic drug prescription and availability, and improvement of the integration among hospital-based and domiciliar pain management and care-giving. In this article, the new legal framework concerning the prescription and administration of analgesics - regulatory innovations started in February 2001 - is presented and its practical implications for health professionals are discussed. Alongside the new laws, some regulatory interventions recently adopted by the Italian Drug Agency (AIFA) are presented and discussed, as they share the proposition of simplifying pain therapy and permit the prescription of more analgesics paid for by the National Health Service. In the last years, the premises for a more rational and modern approach to pain therapy in Italy have been created, which will need to be followed by cultural, organizing and clinical practice adaptations in order to warrant effective and efficient management of algic patients.

Almost three decades ago, the M current was identified and characterized in frog sympathetic neurons (Brown and Adams, 1980). The years following this discovery have seen a huge progress in the understanding of the function and the pharmacology of this current as well as on the structure of the underlying ion channels. Therapies for a number of syndromes involving abnormal levels of excitability in neurons are benefiting from research on M currents. At present, the potential of M current openers as analgesics for neuropathic pain is under discussion. Here we offer a critical view of existing data on the involvement of M currents in pain processing. We believe that enhancement of M currents at the site of injury may become a powerful strategy to alleviate pain in some peripheral neuropathies.

Editorial about italian algology, Federdolore, SICD and Pathos.