Mirogabalin Decreases Pain-like Behaviors by Inhibiting the Microglial/Macrophage Activation, p38MAPK Signaling, and Pronociceptive CCL2 and CCL5 Release in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a chronic condition that significantly reduces the quality of life of many patients as a result of ineffective pain relief therapy. For that reason, looking for new analgesics remains an important issue. Mirogabalin is a new gabapentinoid that is a specific ligand for the α2σ-1 and α2σ-2 subunits of voltage-gated calcium channels. In the present study, we compared the analgesic effect of pregabalin and mirogabalin in a neuropathic pain chronic constriction injury (CCI) of the sciatic nerve in a mouse model. The main purpose of our study was to determine the effectiveness of mirogabalin administered both once and repeatedly and to explain how the drug influences highly activated cells at the spinal cord level in neuropathy. We also sought to understand whether mirogabalin modulates the selected intracellular pathways (p38MAPK, ERK, JNK) and chemokines (CCL2, CCL5) important for nociceptive transmission, which is crucial information from a clinical perspective. First, our study provides evidence that a single mirogabalin administration diminishes tactile hypersensitivity more effectively than pregabalin. Second, research shows that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This study reports that repeated intraperitoneally (i.p.) mirogabalin administration strongly prevents spinal microglia/macrophage activation evoked by nerve injury, slightly suppresses astroglia and neutrophil infiltration, and reduces the p38MAPK levels associated with neuropathic pain, as measured on Day 7. Moreover, mirogabalin strongly diminished the levels of the pronociceptive chemokines CCL2 and CCL5. Our results indicate that mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain.

Neuropathic pain remains a clinical challenge due to its complex and not yet fully understood pathomechanism, which result in limited analgesic effectiveness of the management offered, particularly for patients with acute, refractory neuropathic pain states. In addition to the introduction of several modern therapeutic approaches, such as neuromodulation or novel anti-neuropathic drugs, significant efforts have been made in the repurposing of well-known substances such as phenytoin. Although its main mechanism of action occurs at sodium channels in excitable and non-excitable cells and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level and how it influences morphine-induced analgesia have not been clarified, both being crucial from a clinical perspective. We demonstrated that single and repeated systemic administrations of phenytoin decreased tactile and thermal hypersensitivity in an animal model of neuropathic pain. Importantly, we observed an increase in the antinociceptive effect on thermal stimuli with repeated administrations of phenytoin. This is the first study to report that phenytoin improves morphine-induced antinociceptive effects and influences microglia/macrophage activity at the spinal cord and dorsal root ganglion levels in a neuropathic pain model. Our findings support the hypothesis that phenytoin may represent an effective strategy for neuropathic pain management in clinical practice, particularly when combination with opioids is needed.

Topical clonidine for neuropathic pain in adults.

BACKGROUND: Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015. OBJECTIVES: The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain. SEARCH METHODS: For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model.  The review primary outcomes were: participant-reported pain relief of 50% or greater; participant-reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow-up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables. MAIN RESULTS: We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double-blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double-blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant-reported pain relief of 30% or greater during longest follow-up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow-up period (12 weeks) or very much improved on PGIC during the longest follow-up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow-up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow-up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence).  TC compared to active comparator There was no evidence of a difference in the number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported. AUTHORS' CONCLUSIONS: This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.

Use of Continuous Veno-Venous Hemodialysis (CVVHD) in Treatment of a Polytrauma Patient with Severe Hemophilia A.

BACKGROUND There are very few reports in the literature worldwide on how to deliver continuous renal replacement therapy (CRRT) to patients with multi-organ trauma and severe hemophilia A. The aim of this case report is to describe successful multidisciplinary, intensive treatment of a patient with multi-organ trauma suffering from severe hemophilia A with the use of continuous veno-venous hemodialysis with regional citrate anticoagulation (Ci-Ca CVVHD). CASE REPORT We report a case of a 47-year-old man with severe hemophilia A, who had multi-organ trauma as a result of a serious traffic accident and was admitted to the Trauma Centre of Emergency and Disaster Medicine in Krakow, Poland in critical condition. Due to elevated laboratory markers of kidney damage (creatinine 204 mmol/l, glomerular filtration rate (GFR) 32 ml/min/1.73 m²), very high myoglobin level (>1000 µ/l) associated with rhabdomyolysis, oliguria (diuresis <0.5 ml/kg/h), and overhydration as a consequence of massive transfusion of blood products and fluids, on day 2 after the injury Ci-Ca CVVHD was initiated as a part of intensive, multidisciplinary treatment. This approach proved to be successful in our patient as he was discharged from the Intensive Care Unit on day 45 after the injury in good general condition, with stable circulatory and respiratory system, without any apparent neurological deficits, and with good renal function (creatinine 50 mmol/l, GFR >60 ml/min/1.73 m²). CONCLUSIONS Our case report shows that intensive, multidisciplinary treatment with implementation of Ci-Ca CVVHD may be an effective and safe method of care for patients with multi-organ trauma and hemophilia A.

Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain.

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

The frequency and risk factors for surgery dissatisfaction in patients undergoing lumbar or cervical surgery for degenerative spinal conditions.

This study evaluated the frequency and risk factors for surgery dissatisfaction in patients undergoing lumbar or cervical surgery for degenerative spinal conditions. Based on the Patient Satisfaction Index (PSI) at 6 months after surgery, we divided patients into two groups: a satisfied and a dissatisfied group. We evaluated the association between patient dissatisfaction and five categories of variables:1) sociodemographic; 2) preoperative pain and disability [pain duration, level of surgery, previous spinal surgeries, pain scores as measured by the Short Form McGill Pain Questionnaire (SF-MPQ), numerical rating of average pain (NRS), disability as measured by the Oswestry Disability Index (ODI)]; 3) preoperative psychological status [depression, anxiety, and overall distress as measured by the Hospital Anxiety and Depression Scale (HADS), life satisfaction as measured by the Satisfaction With Life Scale (SWLS), and surgery expectations (SE) as measured by a Likert scale]; 4) postoperative improvements in pain and disability [improvements in SF-MPQ, improvement in ODI] and 5) postoperative psychological status [HADS, SWLS]. Results showed that 17.8% patients were dissatisfied with surgery. In the multivariate logistic analysis, more negative surgery expectations, smaller improvement in ODI scores, and a greater postoperative overall distress were significant risk factors associated with patient dissatisfaction with surgery.

The volume of infusion fluids correlates with treatment outcomes in critically ill trauma patients.

Background: Appropriate fluid management is essential in the treatment of critically ill trauma patients. Both insufficient and excessive fluid volume can be associated with worse outcomes. Intensive fluid resuscitation is a crucial element of early resuscitation in trauma; however, excessive fluid infusion may lead to fluid accumulation and consequent complications such as pulmonary edema, cardiac failure, impaired bowel function, and delayed wound healing. The aim of this study was to examine the volumes of fluids infused in critically ill trauma patients during the first hours and days of treatment and their relationship to survival and outcomes. Methods: We retrospectively screened records of all consecutive patients admitted to the intensive care unit (ICU) from the beginning of 2019 to the end of 2020. All adults who were admitted to ICU after trauma and were hospitalized for a minimum of 2 days were included in the study. We used multivariate regression analysis models to assess a relationship between volume of infused fluid or fluid balance, age, ISS or APACHE II score, and mortality. We also compared volumes of fluids in survivors and non-survivors including additional analyses in subgroups depending on disease severity (ISS score, APACHE II score), blood loss, and age. Results: A total of 52 patients met the inclusion criteria for the study. The volume of infused fluids and fluid balance were positively correlated with mortality, complication rate, time on mechanical ventilation, length of stay in the ICU, INR, and APTT. Fluid volumes were significantly higher in non-survivors than in survivors at the end of the second day of ICU stay (2.77 vs. 2.14 ml/kg/h) and non-survivors had a highly positive fluid balance (6.21 compared with 2.48 L in survivors). Conclusion: In critically ill trauma patients, worse outcomes were associated with higher volumes of infusion fluids and a more positive fluid balance. Although fluid resuscitation is lifesaving, especially in the first hours after trauma, fluid infusion should be limited to a necessary minimum to avoid fluid overload and its negative consequences.

The role of complementary and alternative methods in the treatment of pain in patients with cancer - current evidence and clinical practice: a narrative review.

INTRODUCTION: Pain related to cancer, despite the numerous treatment options available, is still a challenge in contemporary pain medicine. The unsatisfactory treatment of cancer pain is one of the main reasons why patients seek complementary and alternative methods (CAM) and a more integrative/holistic approach to pain management. The popularity of CAM forces healthcare professionals to provide patients with current and evidence-based information on the effectiveness and safety of CAM. The aim of the paper is to present current evidence and limitations regarding CAM commonly used in the pain management of cancer patients. MATERIAL AND METHODS: The paper comprehensively reviews the current and most relevant literature considering the integrative approach to management of pain due to cancer disease and/or cancer treatment. RESULTS: The available data from clinical trials, meta-analyses, and systematic reviews supports the effectiveness of acupuncture, massage, physical exercises, music therapy, and mind-body therapies as adjunct therapies for alleviating pain in cancer patients, although the supporting evidence is weak or moderate. CONCLUSIONS: Based on the available knowledge, physicians should be capable of advising the cancer patient as to which CAM methods can be used safely, which are contraindicated, and what therapeutic effects they may expect, especially when standard pain treatment fails or induces serious side effects. An integrative approach to cancer pain management may improve the quality of pain treatment, patients' quality of life, and satisfaction with pain relief.

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review.

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

Mirogabalin-A Novel Selective Ligand for the α2δ Calcium Channel Subunit.

The efficacy of neuropathic pain control remains unsatisfactory. Despite the availability of a variety of therapies, a significant proportion of patients suffer from poorly controlled pain of this kind. Consequently, new drugs and treatments are still being sought to remedy the situation. One such new drug is mirogabalin, a selective ligand for the α2δ subunits of voltage-gated calcium channels (VGCC) developed by Sankyo group for the management of neuropathic pain. In 2019 in Japan, mirogabalin was approved for peripheral neuropathic pain following the encouraging results of clinical trials conducted with diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) patients. The ligand selectivity of mirogabalin for α2δ-1 and α2δ-2 and its slower dissociation rate for α2δ-1 than for α2δ-2 subunits of VGCC may contribute to its strong analgesic effects, wide safety margin, and relatively lower incidence of adverse effects compared to pregabalin and gabapentin. This article discusses the mechanism of action of mirogabalin, presents data on its pharmacodynamics and pharmacokinetics, and reviews the available experimental and clinical studies that have assessed the efficacy and safety of the drug in the treatment of selected neuropathic pain syndromes.

Peripheral Mechanisms of Neuropathic Pain-the Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain.

Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been described, pointing out at the molecular/cellular underlying mechanisms of neuropathic pain, which might be potentially targeted by topical treatments in clinical practice. The modulation of the complex neuro-immuno-cutaneous interactions in the periphery represents a strategy for the development of new topical analgesics and their utilization in clinical settings.

Metamizole relieves pain by influencing cytokine levels in dorsal root ganglia in a rat model of neuropathic pain.

BACKGROUND: Treatment of neuropathic pain is still challenging. Recent studies have suggested that dorsal root ganglia (DRG), which carry sensory neural signals from the peripheral nervous system to the central nervous system, are important for pathological nociception. A proper understanding of the significance and function of DRG and their role in pharmacotherapy can help to improve the treatment of neuropathic pain. Metamizole, also known as sulpyrine or dipyrone, is a non-opioid analgesic commonly used in clinical practice, but it is not used for neuropathic pain treatment. METHODS: Chronic constriction injury (CCI) of the sciatic nerve was induced in Wistar rats. Metamizole was administered intraperitoneally (ip) preemptively at 16 and 1 h before CCI and then twice a day for 7 days. To evaluate tactile and thermal hypersensitivity, von Frey and cold plate tests were conducted, respectively. RESULTS: Our behavioral results provide evidence that repeated intraperitoneal administration of metamizole diminishes the development of neuropathic pain symptoms in rats. Simultaneously, our findings provide evidence that metamizole diminishes the expression of pronociceptive interleukins (IL-1beta, IL-6, and IL-18) and chemokines (CCL2, CCL4, and CCL7) in DRG measured 7 days after sciatic nerve injury. These assays indicate, for the first time, that metamizole exerts antinociceptive effects on nerve injury-induced neuropathic pain at the DRG level. CONCLUSIONS: Finally, we indicate that metamizole-induced analgesia in neuropathy is associated with silencing of a broad spectrum of cytokines in DRG. Our results also suggest that metamizole is likely to be an effective medication for neuropathic pain.

Bone Pain in Cancer Patients: Mechanisms and Current Treatment.

The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be multimodal (pharmacological and non-pharmacological), including causal anticancer and symptomatic analgesic treatment to improve quality of life (QoL). The aim of this paper is to discuss the mechanisms involved in the occurrence and persistence of cancer-associated bone pain and to review the treatment methods recommended by experts in clinical practice. The final part of the paper reviews experimental therapeutic methods that are currently being studied and that may improve the efficacy of bone pain treatment in cancer patients in the future.

Perioperative restrictive versus goal-directed fluid therapy for adults undergoing major non-cardiac surgery.

BACKGROUND: Perioperative fluid management is a crucial element of perioperative care and has been studied extensively recently; however, 'the right amount' remains uncertain. One concept in perioperative fluid handling is goal-directed fluid therapy (GDFT), wherein fluid administration targets various continuously measured haemodynamic variables with the aim of optimizing oxygen delivery. Another recently raised concept is that perioperative restrictive fluid therapy (RFT) may be beneficial and at least as effective as GDFT, with lower cost and less resource utilization. OBJECTIVES: To investigate whether RFT may be more beneficial than GDFT for adults undergoing major non-cardiac surgery. SEARCH METHODS: We searched the following electronic databases on 11 October 2019: Cochrane Central Register of Controlled Trials, in the Cochrane Libary; MEDLINE; and Embase. Additionally, we performed a targeted search in Google Scholar and searched trial registries (World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov) for ongoing and unpublished trials. We scanned the reference lists and citations of included trials and any relevant systematic reviews identified. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing perioperative RFT versus GDFT for adults (aged ≥ 18 years) undergoing major non-cardiac surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. We resolved discrepancies by discussion and consulted a third review author if necessary. When necessary, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and for continuous outcomes as mean differences (MDs) with standard deviations (SDs). We used Review Manager 5 software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model. We used Poisson regression models to compare the average number of complications per person. MAIN RESULTS: From 6396 citations, we included six studies with a total of 562 participants. Five studies were performed in participants undergoing abdominal surgery (including one study in participants undergoing cytoreductive abdominal surgery with hyperthermic intraperitoneal chemotherapy (HIPEC)), and one study was performed in participants undergoing orthopaedic surgery. In all studies, surgeries were elective. In five studies, crystalloids were used for basal infusion and colloids for boluses, and in one study, colloid was used for both basal infusion and boluses. Five studies reported the ASA (American Society of Anesthesiologists) status of participants. Most participants were ASA II (60.4%), 22.7% were ASA I, and only 16.9% were ASA III. No study participants were ASA IV. For the GDFT group, oesophageal doppler monitoring was used in three studies, uncalibrated invasive arterial pressure analysis systems in two studies, and a non-invasive arterial pressure monitoring system in one study. In all studies, GDFT optimization was conducted only intraoperatively. Only one study was at low risk of bias in all domains. The other five studies were at unclear or high risk of bias in one to three domains. RFT may have no effect on the rate of major complications compared to GDFT, but the evidence is very uncertain (RR 1.61, 95% CI 0.78 to 3.34; 484 participants; 5 studies; very low-certainty evidence). RFT may increase the risk of all-cause mortality compared to GDFT, but the evidence on this is also very uncertain (RD 0.03, 95% CI 0.00 to 0.06; 544 participants; 6 studies; very low-certainty evidence). In a post-hoc analysis using a Peto odds ratio (OR) or a Poisson regression model, the odds of all-cause mortality were 4.81 times greater with the use of RFT compared to GDFT, but the evidence again is very uncertain (Peto OR 4.81, 95% CI 1.38 to 16.84; 544 participants; 6 studies; very low-certainty evidence). Nevertheless, sensitivity analysis shows that exclusion of a study in which the final volume of fluid received intraoperatively was higher in the RFT group than in the GDFT group revealed no differences in mortality. Based on analysis of secondary outcomes, such as length of hospital stay (464 participants; 5 studies; very low-certainty evidence), surgery-related complications (364 participants; 4 studies; very low-certainty evidence), non-surgery-related complications (74 participants; 1 study; very low-certainty evidence), renal failure (410 participants; 4 studies; very low-certainty evidence), and quality of surgical recovery (74 participants; 1 study; very low-certainty evidence), GDFT may have no effect on the risk of these outcomes compared to RFT, but the evidence is very uncertain. Included studies provided no data on administration of vasopressors or inotropes to correct haemodynamic instability nor on cost of treatment. AUTHORS' CONCLUSIONS: Based on very low-certainty evidence, we are uncertain whether RFT is inferior to GDFT in selected populations of adults undergoing major non-cardiac surgery. The evidence is based mainly on data from studies on abdominal surgery in a low-risk population. The evidence does not address higher-risk populations or other surgery types. Larger, higher-quality RCTs including a wider spectrum of surgery types and a wider spectrum of patient groups, including high-risk populations, are needed to determine effects of the intervention.

Postoperative pain relief in general surgery - recommendations of the Association of Polish Surgeons, Polish Society of Anaesthesiology and Intensive Therapy, Polish Association for the Study of Pain and Polish Association of Regional Anaesthesia and Pain Treatment.

It is estimated that there are over 310 million surgeries performed in the world every year. Appropriate analgesic management in the perioperative period constitutes a fundamental right of every patient, significantly reducing the number of postoperative complications and the time and costs of hospitalization, particularly in the high-risk group of patients (ASA III-V) subject to extensive surgical procedures and hospitalized in intensive care units. Despite such significant arguments speaking for the conduct of effective analgesia in the perioperative period, nearly 79% of patients operated in hospitalization settings and 71% of patients operated in outpatient settings (so-called first day surgery) experienced postoperative pain of moderate, strong or extreme intensity. Hence, effective relief of postoperative pain should constitute one of the priorities of integrated, modern perioperative management, the components of which apart from adequate analgesia involve early nutrition through the alimentary canal, early patient activation and active physiotherapy. In the currently published "Guidelines", a team of authors has updated the previous "Recommendations" primarily in terms of methods for optimizing postoperative pain relief and new techniques and drugs introduced for postoperative pain therapy in recent years. The algorithms of postoperative pain management in different treatment categories were also updated.

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonlyused drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

The role of oxycodone/naloxone in the management of patients with pain and opioid-induced constipation.

INTRODUCTION: Common opioid adverse effects (AE) of the gastrointestinal tract include opioid-induced constipation (OIC) and opioid-induced bowel dysfunction (OIBD) with traditional laxatives being of limited efficacy, having AEs and not addressing the pathophysiology of OIC or OIBD. Targeted treatment comprises of PAMORA (peripherally acting mu-opioid receptor antagonists) and a combination of an opioid receptor agonist with its antagonist, namely prolonged-release oxycodone with prolonged-release naloxone (OXN) tablets at a fixed ratio of 2:1. Oxycodone provides analgesia, whereas naloxone prevents binding or displaces it from opioid receptors located in the gut wall. Areas covered: The authors review the role of OXN in the management of patients with pain and OIC. A literature search was performed using the search terms 'oxycodone/naloxone' and 'opioid-induced constipation' using the PubMed database up to October 2018. Expert opinion: OXN delivers analgesia comparable (or superior versus placebo and in observational studies) to oxycodone alone and other opioids with a limited or decreased disturbing effect on bowel function. OXN in daily doses of up to 160 mg/80 mg provides effective analgesia with little negative impact on bowel function. OXN may be successfully used in patients with chronic pain, to prevent or treat symptoms of OIC and OIBD.

Pharmacotherapy of pain in cancer patients - recommendations of the Polish Association for the Study of Pain, Polish Society of Palliative Medicine, Polish Society of Oncology, Polish Society of Family Medicine, Polish Society of Anaesthesiology and Intensive Therapy and Association of Polish Surgeons.

Guidelines for the pharmacotherapy of pain in cancer patients were developed by a group of 21 experts of the Polish Association for the Study of Pain, Polish Society of Palliative Medicine, Polish Society of Oncology, Polish Society of Family Medicine, Polish Society of Anaesthesiology and Intensive Therapy and Association of Polish Surgeons. During a series of meetings, the experts carried out an overview of the available literature on the treatment of pain in cancer patients, paying particular attention to systematic reviews and more recent randomized studies not included in the reviews. The search was performed in the EMBASE, MEDLINE, and Cochrane Central Register of Controlled Trials databases using such keywords as "pain", "cancer", "pharmacotherapy", "analgesics", and similar. The overviewed articles included studies of pathomechanisms of pain in cancer patients, methods for the assessment of pain in cancer patients, and drugs used in the pharmacotherapy of pain in cancer patients, including non-opioid analgesics (paracetamol, metamizole, non-steroidal anti-inflammatory drugs), opioids (strong and weak), coanalgesics (glucocorticosteroids, α2-adrenergic receptor agonists, NMDA receptor antagonists, antidepressants, anticonvulsants, topical medications) as well as drugs used to reduce the adverse effects of the analgesic treatment and symptoms other than pain in patients subjected to opioid treatment. The principles of opioid rotation and the management of patients with opioidophobia were discussed and recommendations for the management of opioid-induced hyperalgesia were presented. Drugs used in different types of pain experienced by cancer patients, including neuropathic pain, visceral pain, bone pain, and breakthrough pain, were included in the overview. Most common interactions of drugs used in the pharmacotherapy of pain in cancer patients as well as the principles for the management of crisis situations. In the final part of the recommendations, the issues of pain and care in dying patients are discussed. Recommendations are addressed to physicians of different specialties involved in the diagnostics and treatment of cancer in their daily practice. It is the hope of the experts who took part in the development of these recommendations that the recommendations would become helpful in everyday medical practice and thus contribute to the improvement in the quality of care and the efficacy of pain treatment in this group of patients.

Perioperative Immunosuppression and Risk of Cancer Progression: The Impact of Opioids on Pain Management.

Opioids comprise an important group of drugs used in cancer pain pharmacotherapy. In recent years, more and more studies have emerged indicating the potentially immunosuppressive effects of opioid analgesics and their serious consequences, including the risk of cancer progression. The identification of these risks has prompted a search for other effective, and most importantly, safer methods of perioperative analgesic management. Regional analgesia techniques, which allow for a significant reduction in opioid dosing and thus diminish the risk of immunosuppression associated with these drugs, seem to offer substantial hope in this respect. A number of studies available in the literature assess the effects of regional analgesia techniques on cancer progression; however, it is often difficult to interpret their results owing to several perioperative factors (such as surgical trauma, inadequate pain and stress relief, and hypothermia) which are also attributed immunosuppressive effects and tend to be implicated in increased risk of cancer progression. Further research is needed to verify the available data on both the potential adverse effects of opioids and the possible protective effects of regional analgesia techniques on cancer patients.

Postoperative pain management - 2018 consensus statement of the Section of Regional Anaesthesia and Pain Therapy of the Polish Society of Anaesthesiology and Intensive Therapy, the Polish Society of Regional Anaesthesia and Pain Therapy, the Polish Association for the Study of Pain and the National Consultant in Anaesthesiology and Intensive Therapy.

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