Non-opioid Analgesics Research Articles

Implementation of a Multimodal Enhanced Recovery Protocol in Ambulatory Anorectal Surgery: A Randomized Trial.

Few studies report outcomes for enhanced recovery pathways in ambulatory anorectal surgery. We hypothesize that an ambulatory anorectal enhanced recovery pathway with multimodal analgesia can reduce postoperative opioid use. To compare postoperative opioid use in patients undergoing ambulatory anorectal surgery who receive multimodal analgesia vs. standard of care without multimodal analgesia. A prospective randomized trial of patients undergoing elective anal fistula or hemorrhoid surgery from September 2018 to May 2022. Urban teaching hospital. Adults aged 18 to 70 undergoing elective anal fistula or hemorrhoid surgery from September 2018 to May 2022. Multimodal enhanced recovery pathway including pre- and postoperative non-opioid analgesia with oral acetaminophen, gabapentin and ketolorac. Primary endpoint was oral opioid use during the first postoperative week. Secondary endpoints included maximum pain and nausea scores, adverse events and emergency room or hospital admissions during the first 30 days postoperatively. Of the 109 enrolled patients, 20 were lost to follow-up. The remaining 89 patients had a median age of 38 (range, 20-67) years and included 41 (46%) females. There were no significant differences between the enhanced recovery protocol (Arm E) and non-enhanced recovery protocol (Arm NE) groups in terms of preoperative and surgical characteristics. The study primary endpoint, oral MME use during the first week, was significantly higher among patients in the NE arm (79 mg; range, 0-600) than patients in the E arm (8 mg; range, 0-390) (p = 0.002). On subgroup analysis, both fistula and hemorrhoid surgery patients assigned to the NE arm took significantly higher oral MME in the first week than patients in the E arm. There was no significant difference in secondary endpoints. Patients and providers were not blinded. Our findings are limited to hemorrhoid and fistula surgery and may not be applicable to other anorectal procedures. Enhanced recovery protocols including multimodal analgesia should be used in elective anal fistula and hemorrhoid surgery to decrease postoperative opioid use. See Video Abstract . ClinicalTrials.gov ID NCT03738904.

The impact of codeine rescheduling on non-opioid analgesic use by people who regularly use codeine: a prospective cohort study

BackgroundCodeine was rescheduled in Australia to prescription only in February 2018. Initial studies reported an increase in population level paracetamol and ibuprofen sales following codeine upscheduling. However, to date no study has been able to investigate changes in non-opioid analgesic use at the individual patient level to determine if sales data reflect actual consumption patterns.AimTo address this gap, we aimed to determine the impact of codeine rescheduling on non-opioid analgesic use in people who regularly used over-the-counter codeine, primarily for pain, prior to the rescheduling change.MethodWe conducted a prospective cohort study with 260 participants who reported regular over-the-counter codeine consumption at cohort entry. Surveys were completed at baseline (November 2017, 3 months before rescheduling) and at 1 month (February 2018), 4 months (June 2018), and 12 months (February 2019), following rescheduling. The primary outcomes were mean daily doses of non-opioid analgesics, captured through a 7 day medication diary.ResultsThe mean daily paracetamol dose decreased from 1754.4 mg (95% CI 1300.5–2208.3) at baseline to 1023.8 mg (95% CI 808.5–1239.1) at the final time-point (+ 12 months) (p = .009). The mean daily ibuprofen dose decreased from 305.1mg (95% CI 217.9–392.4) at baseline to 161.2 mg (95% CI 98.5–224.0) 12 months after rescheduling (p = .03). No significant change in doses of other medications remained was found.ConclusionIn people who regularly consumed over-the-counter codeine, doses of non-opioid analgesics either reduced or remained stable following codeine rescheduling, suggesting concerns of medication substitution or overuse following the change were not realised.

Central nervous system active medication use in Medicare enrollees receiving home health care: association with chronic pain and anxiety level.

No comparative effectiveness data exist on nonopioid analgesics and nonbenzodiazepine anxiolytics to treat pain with anxiety. We examined the relationship between drug class and central nervous system (CNS) active drug polypharmacy on pain and anxiety levels in Medicare enrollees receiving home health (HH) care. This retrospective cohort study included enrollees with diagnoses and 2+ assessments of pain and anxiety between HH admission and discharge. Three sets of linear regression difference-in-reduction analyses assessed the association of pain or anxiety reduction with number of drugs; drug type; and drug combinations in those with daily pain and daily anxiety. Logistic regression analysis assessed the effect of medication number and class on less-than-daily pain or anxiety at HH discharge. A sensitivity analysis using multinomial regression was conducted with a three-level improvement to further determine clinical significance. Of 85,403 HH patients, 43% received opioids, 27% benzodiazepines, 26% gabapentinoids, 32% selective serotonin reuptake inhibitors, and 8% serotonin and norepinephrine reuptake inhibitors (SNRI). Furthermore, 75% had depression, 40% had substance use disorder diagnoses, and 6.9% had PTSD diagnoses. At HH admission, 83%, 35%, and 30% of patients reported daily pain, daily anxiety, and both, respectively. Central nervous system polypharmacy was associated with worse pain control and had no significant effect on anxiety. For patients with daily pain plus anxiety, pain was best reduced with one medication or any drug combination without opioid/benzodiazepine; anxiety was best reduced with combinations other than opiate/benzodiazepine. Gabapentinoids or SNRI achieved clinically meaningful pain control. Selective serotonin reuptake inhibitors provided clinically meaningful anxiety relief.

Use of Baclofen Premedication as an Analgesic Adjuvant in Patients Undergoing Percutaneous Nephrolithotripsy: A Placebo-Controlled, Double-Blind Randomized Trial.

Baclofen, a clinically available GABAB receptor agonist, produces nonopioid analgesia in multiple models of pain but has had limited studies related to perioperative pain control.The present study seeks to study effects of baclofen on postoperative pain measures and opioid use in adult patients subjected to percutaneous nephrolithotomy (PCNL). Using a placebo-controlled, double-blind methodology, a single 10 mg oral dose of baclofen or placebo was given prior to a surgery in 34 patients undergoing PCNL.Standardized intraoperative and postoperative protocols related to opioid use were followed.Use of postoperative opioids in the post-anesthesia care unitand for the first 24 hours following surgery were recorded as were pain scores and other medication use. There was a significant positive correlation in the use of postoperative opioids in patients who had a preceding history of opioid use.However, there were no significant differences in opioid use which could be attributed to baclofen.There were also no differences in postoperative vital signs, side effects or other medication use. Analgesic benefits of preoperative baclofen were not observed at the dose employed.Safety of the drug was observed.

Perioperative N-acetylcysteine: evidence and indications.

Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulationand neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver functionand superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.

Opioid and non-opioid analgesic regimens after fracture and risk of serious opioid-related events

BackgroundNon-opioid analgesics are prescribed in combination with opioids among patients with long bone fracture to reduce opioid prescribing needs, yet evidence is limited on whether they reduce the risk of...

Risk of acute kidney injury after lower urinary tract reconstruction with early NSAID therapy: A propensity matched retrospective analysis

The opioid epidemic response led to increased use of postoperative, non-opioid analgesia. Some pediatric urologists do not routinely use non-steroidal anti-inflammatory drugs (NSAIDs) for fear of causing acute kidney injury (AKI). While previous studies have demonstrated the safety and efficacy of NSAIDs in children, safety after lower urinary tract reconstruction has not been well characterized. ptUsing the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI (increase in creatinine ≥0.3mg/dL or increase in creatinine ≥1.5x baseline or urine output <0.5mL/kg/hr for 6h), we hypothesized there would be a difference in the incidence of postoperative AKI between patients who did and did not receive NSAIDs following surgery. Patients 2-18 years old who underwent lower urinary tract reconstruction (i.e., bladder augmentation and/or creation of a catheterizable channel) from 2009 to 2021 and had documented urine output were retrospectively reviewed. Chronic kidney disease (CKD) stage was calculated from creatinine and cystatin C within 6 months of surgery using the CKiD U25 equations. Patients who received NSAIDs were propensity matched on 11 characteristics with patients undergoing similar surgeries who did not receive NSAIDs. The primary outcome was incidence of AKI within 48h of surgery. The unmatched cohorts included 243 patients. Propensity matching identified 166 patients in the NSAID arm and 41 in the no NSAID arm. 26 patients with CKD stage 2-3 were included. There was no significant difference in the incidence of postoperative AKI based on any KDIGO criteria (17.1% no NSAID versus 16.3% NSAID, p=0.87). Median postoperative opioids fell from 0.88mg/kg in the no NSAID arm to 0.37mg/kg morphine equivalents in the NSAID arm, although this was not statistically significant. Log-rank testing by Kaplan-Meier analysis demonstrated no difference in time to incidence of low urine output between the groups (p=0.32). In the whole population not stratified by NSAID use, no differences were seen in AKI between those with and without CKD (16.7% with versus 17.9% without CKD). There was no difference in the incidence of postoperative AKI among patients who did and did not receive NSAIDs after lower urinary tract reconstruction, excluding those with advanced CKD. These results support that postoperative NSAIDs were an unlikely source of AKI. However, AKI remained a risk following these surgeries, regardless of NSAID use, likely owing to underlying disease, longer operations, and fluid shifts.

Patient Satisfaction with Nonopioid Postoperative Analgesia in Head and Neck Surgery: A Prospective Randomized Trial.

To evaluate patients' satisfaction with opioid versus opioid-sparing postoperative analgesia in patients undergoing outpatient head and neck surgery. Prospective randomized trial. Tertiary care academic hospital. Adult patients undergoing outpatient head and neck surgery were randomly assigned to 1 of 3analgesic regimens. First- and second-line medications were the following by group (1) Hydrocodone-acetaminophen with ibuprofen, (2) ibuprofen with hydrocodone-acetaminophen, and (3) ibuprofen with acetaminophen. Preoperative counseling was provided to patients regarding expected pain and proper medication use. Postoperative questionnaires were administered to assess satisfaction. One hundred three patients were enrolled in the study (mean age, 56.5 years; women, 75 [73%]). The mean satisfaction score with the pain regimen assigned was similar between the 3 groups (scale 0-10, [7.7, 8.3, 8.5, P = .46]). A similar percentage of patients in each group reported that surgery was more painful than anticipated (25%, 32%, 26%, P = .978), and a similar percentage of patients reported willingness to utilize the same analgesic regimen following future surgeries (75%, 83%, 76%, P = .682). Additional questions evaluating the side effect profile, maximum and minimum pain scores, and difficulty of recovery were not statistically different between the 3groups. In the postoperative population for outpatient head and neck surgeries, there was no significant difference in patient satisfaction and pain control between the opioid and nonopioid arms. Providers should discuss opioid-sparing regimens preoperatively with patients and describe them as effective in providing adequate pain control without a significant impact on patient's perception of care.

Comparative efficacy of opioid and non-opioid analgesics in labor pain management: A network meta-analysis.

Effective labor pain management is crucial for parturient well-being, as it can improve the delivery experience of pregnant women and reduce anxiety and tension. This systematic review and network meta-analysis compared the efficacy and safety of various analgesics, classified by drug category and individual treatment methods, for labor pain control. A comprehensive literature search was conducted in Pubmed, EMBASE, Cochrane Library, and Web of Science databases. All searches commenced from the database's inception to the date of the literature search (May 31, 2023). The Cochrane Risk of Bias 2 tool assessed study bias risk. Network meta-analyses using a random-effects model and odds ratios (ORs) with 95% confidence intervals (CIs) were performed. Fifteen randomized controlled trials evaluating analgesic interventions in ASA I or II parturients were included. Combination therapies (OR: 5.81; 95% CI, 3.76-7.84; probability: 60%) and non-opioid analgesics (OR: 5.61; 95% CI, 2.91-8.30; probability: 39.2%) were superior to placebo for labor pain relief. Specifically, dexmedetomidine/ropivacaine/sufentanil (OR: 7.32; 95% CI, 2.73-11.89; probability: 40.6%) and dexmedetomidine/ropivacaine (OR: 6.50; 95% CI, 2.51-10.33; probability: 11.9%) combinations, bupivacaine/fentanyl and ropivacaine/sufentanil combinations, and remifentanil monotherapy showed improved analgesic efficacy versus placebo. Dexmedetomidine/ropivacaine reduced parturient nausea and vomiting versus alternatives. Non-opioids, opioids and combinations thereof effectively relieved labor pain. In addition, dexmedetomidine/ropivacaine combination demonstrated analgesic efficacy and lower nausea and vomiting incidence.

Safety of metamizole (dipyrone) for the treatment of mild to moderate pain-an overview of systematic reviews.

Metamizole, as known as dipyrone or novaminsulfone is widely used, especially in Latin America, for its analgesic and antipyretic function. However, several countries have banned it due to the risk of agranulocytosis, skin necrosis, and other serious adverse effects. To assess the safety of metamizole compared to other commonly used non-opioid analgesics (paracetamol, ibuprofen, and acetylsalicylic acid). An overview of systematic reviews. The searches were performed in the PubMed, Cochrane Library, Embase, Scopus and LILACS databases. Systematic reviews of randomized and nonrandomized clinical trials with adult patients with mild to moderate pain that assessed the adverse effects of metamizole were included. A methodological quality assessment was performed through ROBIS. The protocol of this systematic review was submitted to the International Prospective Register of Systematic Reviews (Prospero, CRD42021295272). Of 387 identified studies, four were included, with a total of 20,643 participants, all submitted to a single dose by oral, intramuscular, or intravenous route. No study reported a serious adverse effect. However, 60 of 778 patients (7.7%) who used metamizole; 120/828 (14.5%) who used acetylsalicylic acid; 56/443 (12.6%) who used paracetamol; and 27/213 (12.7%) who used ibuprofen had mild adverse effects. A complementary statistical analysis showed that metamizole, at any dose, has a 38.8% lower chance of adverse effects compared to paracetamol and 46.8% compared to acetylsalicylic acid. The results shows that metamizole is a safe drug with evidence of a lower incidence of adverse effects compared to paracetamol and acetylsalicylic acid.

Evaluation of Virtual Reality in the Reduction of Pain During Dressing Changes in Patients With Burn Wounds: A Pilot Study.

Burn injuries are among the most common life-threatening injuries for which medical attention is sought, and are accompanied by intense, severe pain, particularly during treatment. Burn therapy pain management with opioid and nonopioid analgesics is often insufficient when administered alone. Virtual reality (VR) interfaces provide an immersive experience that has demonstrable therapeutic benefits, including distraction from, and reduction of, pain. In this interventional pilot study, we assessed the correlation between VR and passive distraction and pain tolerance during burn wound treatment. This pilot study assessed patients undergoing burn wound dressing changes while receiving both pharmacological and VR intervention. Questionnaires and evaluation forms were subjectively completed by both patients and medical staff before and after treatment, and clinical metrics were recorded throughout the treatment. Forty-one patients ≥18 years old and 76.9% male that had primarily undergone ≥4 dressing changes before the study were included. Correlations were found between VR engagement during treatment and a decrease in subjective levels of nausea, anxiety, and pain sensation. Furthermore, high levels of VR engagement were correlated with high levels of VR enjoyment. These results suggest that highly engaging and enjoyable VR interfaces may reduce sensations of anxiety and pain in burn patients during dressing changes. Furthermore, these data suggest that VR technology may be applied as an adjunct therapy to pharmacological treatment in the standardization of burn wound care management. Further studies with control groups and larger sample populations are needed for better quantification of these benefits.

A Comprehensive Study Involving Comparison of Analgesics for Effective Pain Management in Pancreatitis

Pancreatitis is an inflammatory condition of the pancreas, which serves as both an exocrine organ for food digestion and an endocrine organ for regulating blood sugar levels. The disease is typically accompanied by moderate to severe pain, necessitating the use of analgesics for effective pain management. This research aims to evaluate and compare the efficacy of various analgesics in alleviating pain associated with pancreatitis. Ultimately, the study aims to gain a comprehensive understanding of the outcomes resulting from different pain management strategies in individuals with pancreatitis. A comparative research study was conducted at Basaveshwara General Hospital in Kalaburagi, Karnataka, over a period of six months, involving 100 patients selected from both general and university hospital settings. The findings revealed that out of 100 patients, 76% were males, and 24% were females affected by pancreatitis. Throughout the study, a total of 164 analgesics were administered, with the highest frequency of potent analgesics prescribed within the age group of 5-46 years. Notably, Nalbuphine emerged as the most commonly prescribed analgesic via the parenteral route, constituting 39% of the total prescriptions. For cases with mild to moderate pain, Paracetamol was the preferred analgesic, accounting for 35.3% of the prescriptions. This research investigates the variations in analgesic prescriptions for pancreatitis pain management, tailoring prescriptions to the severity of pain, with non-opioid analgesics recommended for mild to moderate pain levels

Regional Anaesthesia in the Prehospital Setting

Pain is often the main symptom in trauma patients. Although peripheral nerve blocks (PNB) provide fast, safe, and adequate analgesia, they are currently only rarely used outside the perioperative setting. In Germany, intravenous analgesia with non-opioid analgesics (NOPA) and strong opioids is the main treatment concept for prehospital pain. However, the use of highly potent opioids can be associated with significant side effects, especially in emergency patients. Therefore, PNBs are used in many hospitals for the treatment of perioperative pain. As with perioperative use, the advantages of early PNB in the prehospital analgesic treatment of trauma patients are obvious, especially for elderly and multimorbid patients. Early prehospital PNB can also facilitate the reduction of dislocated fractures or dislocated joints as well as the technical rescue of trauma patients. Common geriatric fractures, such as proximal femur or humerus fractures, can be treated appropriately and adequately with PNB.In this article, we show which PNB procedures can be useful in prehospital patient care and which requirements should be met for their safe use. We also present a concept for assessing whether and to what extent the prehospital use of PNB is indicated and appropriate. The aim of this article is to draw attention to PNB as a possible part of prehospital care concepts for trauma patients and to discuss its prehospital use.

The use of analgesics in pediatric patients with body injuries in pre-hospital conditions.

Despite the positive dynamic changes in medicine and science, injuries continue to be the dominant cause of death among people under 45 years of age. Children's injuries are particularly dangerous as they can lead to hypovolemic shock, disability or even death. EMS uses opioid and non-opioid analgesics in order to provide relief to patients suffering from pain. The aim of this work is to analyze the types of pharmacological substances used in children in pre-hospital conditions. The research tools included medical documentation of the emergency medical services in Poland. The analysis included 68,441 medical emergency treatment forms from 2016-2017, from which 464 interventions for children after trauma were selected. The general patient profile, characteristics of the event site, type of injuries suffered, type of intervening EMS, pharmacotherapy being used, as well as vital signs (GCS, RTS, HR, NiBP) were subject to assessment. The χ2 independence tests were performed, considering the results as statistically significant for P<0.05. There were 354 instances of BEMS (Basic Emergency Medical Services - without a doctor) and 110 instances of SEMS (Specialist Emergency Medical Services - with a doctor) sent to the emergency site. The mean age was 10.8±4.84 years. Boys were subject to intervention more often than girls (N.=283 vs. N.=181). Analgesics were administered in case of 49 (10.56%) patients only. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the analgesics of choice, which were used in 25 patients (50%), while opioid analgesics were used in 10 patients (20.40%). Analgesia was mostly used in patients with lower limb (34.69%) and upper limb (30.61%) injuries. The lowest percentage of analgesic use was observed in patients with head and neck injuries (3.06%). There was a significant relationship demonstrated between the type of EMS and the use of analgesics (χ2=6.330; P=0.012). Analgesia with EMS in children with injuries is critically insufficient. NSAIDs are the most commonly administered drugs in pre-hospital conditions. Head and torso injuries reduce the percentage of drugs administered by EMS. The EMS teams with no doctors (BEMS) are significantly more likely to use anesthetics, compared to SEMS.

Esketamine use for primary intelligent analgesia in adults with severe burns: A double-blind randomized trial with effects on analgesic efficacy, gastrointestinal function and mental state

BackgroundOpioid consumption for analgesia in burn patients is enormous. Non-opioid analgesics for burn pain management may result in opioid sparing, reducing opioid-related adverse reactions and drug tolerance or addiction. MethodsA dual-center, randomized controlled trial assessed Esketamine for the perioperative period in patients with severe [20–50 % total body surface area (TBSA)] and extensive (≥ 50 % TBSA) burns, comparing analgesia with standard anesthesia. Sixty patients were randomly allocated (1:1 ratio) to two arms. In the Treatment Arm, patients received intra-operative Esketamine and postoperative intravenous primary intelligent analgesia pump with Esketamine. Patients in the Control Arm received the same intervention as Treatment Arm without Esketamine. The primary endpoint was subjective analgesic efficacy (SAE) evaluated on Day 28 or the day before hospital discharge. Secondary outcomes included the postoperative Numeric Pain Rating (NPR) Scale at rest (NPRr) and during movement (NPRm) and opioid consumption. Gastrointestinal dysfunction Scores (GIDS) and serum markers of intestinal injury [intestinal fatty acid-binding protein 2 (iFabp2) and apolipoproteinA2 (ApoA2)] were measured in the 1st and 4th post-injury weeks. Depression and sleep quality were assessed by relevant questionnaires. ResultsFifty-five patients were included in the analysis. Esketamine-treated Arm recorded a better analgesic efficacy than the Control Arm (proportion of patients with Grade 1 or 2 SAE scores, 67.9 % vs. 40.7 %, p = 0.022). Esketamine-treated patients had lower NPRm values (p = 0.033) and lower daily opioid consumption (p = 0.033) when compared with Controls. Esketamine-treated patients showed comparable gastrointestinal recovery to those in the Control Arm. The overall sleep quality might be improved in the Treatment Arm. ConclusionsEsketamine use is safe for perioperative primary intelligent analgesia of severe burns, resulting in improved resting pain control and lower opioid requirements. Trial registrationThe trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn/) (ChiCTR2000034069).

Access to care for patients with chronic pain receiving prescription opioids, cannabis, or other treatments

Abstract Changes in chronic noncancer pain treatment have led to decreases in prescribing of opioids and increases in the availability of medical cannabis, despite its federal prohibition. Patients may face barriers to establishing new care with a physician based on use of these treatments. We compared physician willingness to accept patients based on prescription opioid, cannabis, or other pain treatment use. This study of 36 states and Washington, DC, with active medical cannabis programs surveyed physicians who treat patients with chronic noncancer pain between July 13 and August 4, 2023. Of 1000 physician respondents (34.5% female, 63.2% White, 78.1% primary care), 852 reported accepting new patients with chronic pain. Among those accepting new patients with chronic pain, more physicians reported that they would not accept new patients taking prescription opioids (20.0%) or cannabis (12.7%) than those taking nonopioid prescription analgesics (0.1%). In contrast, 68.1% reported willingness to accept new patients using prescribed opioids on a daily basis. For cannabis, physicians were more likely to accept new patients accessing cannabis through medical programs (81.6%) than from other sources (60.2%). Access to care for persons with chronic noncancer pain appears to be the most restricted among those taking prescription opioids, although patients taking cannabis may also encounter reduced access.

Discovery of a CCR2-targeting pepducin therapy for chronic pain

Targeting the CCL2/CCR2 chemokine axis has been shown to be effective at relieving pain in rodent models of inflammatory and neuropathic pain, therefore representing a promising avenue for the development of non-opioid analgesics. However, clinical trials targeting this receptor for inflammatory conditions and painful neuropathies have failed to meet expectations and have all been discontinued due to lack of efficacy. To overcome the poor selectivity of CCR2 chemokine receptor antagonists, we generated and characterized the function of intracellular cell-penetrating allosteric modulators targeting CCR2, namely pepducins. In vivo, chronic intrathecal administration of the CCR2-selective pepducin PP101 was effective in alleviating neuropathic and bone cancer pain. In the setting of bone metastases, we found that T cells infiltrate dorsal root ganglia (DRG) and induce long-lasting pain hypersensitivity. By acting on CCR2-expressing DRG neurons, PP101 attenuated the altered phenotype of sensory neurons as well as the neuroinflammatory milieu of DRGs, and reduced bone cancer pain by blocking CD4+ and CD8+ T cell infiltration. Notably, PP101 demonstrated its efficacy in targeting the neuropathic component of bone cancer pain, as evidenced by its anti-nociceptive effects in a model of chronic constriction injury of the sciatic nerve. Importantly, PP101-induced reduction of CCR2 signaling in DRGs did not result in deleterious tumor progression or adverse behavioral effects. Thus, targeting neuroimmune crosstalk through allosteric inhibition of CCR2 could represent an effective and safe avenue for the management of chronic pain.

Opioid metabolism and drug-drug interaction in cancer.

Concomitant use of multiple drugs in most patients with cancer may result in drug-drug interactions (DDIs), potentially causing serious adverse effects. These patients often experience unrelieved cancer-related pain (CRP) during and after cancer treatment, which can lead to a reduced quality of life. Opioids can be used as part of a multimodal pain management strategy when non-opioid analgesics are not providing adequate pain relief, not tolerated, or are contraindicated. However, due to their narrow therapeutic window, opioids are more susceptible to adverse events when a DDI occurs. Clinically relevant DDIs with opioids are usually pharmacokinetic, mainly occurring via metabolism by cytochrome P450 (CYP). This article aims to provide an overview of potential DDIs with opioids often used in the treatment of moderate-to-severe CRP and commonly used anticancer drugs such as chemotherapeutics, tyrosine kinase inhibitors (TKIs), or biologics. A DDI-checker tool was used to contextualize the tool-informed DDI assessment outcomes with clinical implications and practice. The findings were compared to observations from a literature search conducted in Embase and PubMed to identify clinical evidence for these potential DDIs. The limited results mainly included case studies and retrospective reviews. Some potential DDIs on the DDI-checker were aligned with literature findings, while others were contradictory. In conclusion, while DDI-checkers are useful tools in identifying potential DDIs, it is necessary to incorporate literature verification and comprehensive clinical assessment of the patient before implementing tool-informed decisions in clinical practice.

Robotic living donor nephrectomy is associated with reduced post-operative opioid use compared to hand-assisted laparoscopic approach.

Robotic donor nephrectomy (RDN) has emerged as a safe alternative to laparoscopic donor nephrectomy (LDN). Having previously demonstrated comparable efficacy, this study aims to examine postoperative analgesia use (opioid and non-opioid) in the two groups. We conducted a retrospective review of 300 living donor nephrectomies performed at our center, comparing 150 RDN's with a contemporary cohort of 150 hand-assisted LDN's. In addition to clinical and demographic information, data on postoperative inpatient opioid and non-opioid analgesia (from patient's arrival to the surgical floor after surgery till the time of discharge) was collected. Opioid dosages were standardized by conversion to morphine milligram equivalents (MME). All patients were managed post-operatively under a standardized ERAS pathway for living donor nephrectomy patients. There were no significant differences in donor age, gender, and BMI between RDN and LDN groups. Total post-operative opioid use (MME's) was significantly lower in RDN patients (RDN 27.1 vs. LDN 46.3; P < 0.0001). Breakdown of opioid use with post-operative (POD) day demonstrated significantly lower use in RDN group on POD1 (RDN 8.6 vs. LDN 17.0; P < 0.05), and POD2 (RDN 3.9 vs LDN 10; P < 0.05). RDN patients had a shorter post-operative length of stay (LOS) (RDN 1.69days vs. LDN 1.98; P = 0.0003). There were no differences between groups in non-opioid medication use, complications, and readmission rates. RDN has comparable safety to hand-assist LDN and offers additional benefits of lower postoperative opioid requirement and a shorter hospital LOS.

Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries.

NaV1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that NaV1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed NaV1.7 mRNA, with NaV1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV1.7 inhibitors. Two highly selective NaV1.7 blockers, GNE8493 and PF05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P<0.01), with residual activity being blocked by the NaV1.3 inhibitor, ICA121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV1 blocker tetrodotoxin. Our results demonstrated that blocking NaV1.7 with GNE8493, PF05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV1.7 mRNA. NaV1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. NaV1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking NaV1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV1.7 mutations on autonomic nerve activity.