Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Cannabidiol as an Alternative Analgesic for Acute Dental Pain.

Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (P < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (P < 0.05) but not in the placebo group (P > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (P < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (P < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.

A pilot randomized, placebo-controlled, double-blind study of omega-3 fatty acids to prevent paclitaxel-associated acute pain syndrome in breast cancer patients: Alliance A22_Pilot2.

PURPOSE: Paclitaxel is associated with an acute pain syndrome (P-APS- and chronic chemotherapy-induced peripheral neuropathy (CIPN). P-APS is associated with higher risk of CIPN. Omega-3 fatty acids have well-established anti-inflammatory and neuroprotective properties. The primary purpose of this pilot study was to assess whether omega-3 fatty acids could decrease P-APS and thus CIPN. METHODS: Patients scheduled to receive weekly paclitaxel for breast cancer were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior and continued until paclitaxel was stopped. Patients completed acute pain questionnaires at baseline, daily after each treatment, and 1 month after completion of therapy. RESULTS: Sixty patients (49 evaluable) were randomized to treatment versus placebo. Seventeen (68.0%) patients receiving the omega-3 fatty acids intervention experienced P-APS, compared to 15 (62.5%) of those receiving placebo during the first week of treatment (p = 0.77). Over the full 12-week study, 21 (84.0%) patients receiving the omega-3 fatty acid intervention experienced P-APS, compared to 21 (87.5%) of those receiving placebo (p = 1.0). Secondary outcomes suggested that those in the intervention arm used more over-the-counter analgesics (OR: 1.65, 95% CI: 0.72-3.78, p = 0.23), used more opiates (OR: 2.06, 95% CI: 0.55-7.75, p = 0.28), and experienced higher levels of CIPN (12.8, 95% CI: 7.6-19.4 vs. 8.4, 95% CI: 4.6-13.2, p = 0.21). CONCLUSIONS: The results of this pilot study do not support further study of the use of omega-3 fatty acids for the prevention of the P-APS and CIPN. TRIAL REGISTRATION: Number: NCT01821833.

An Appraisal of Using Opioids in Patients with Opioid Use Disorder.

Podiatric physicians have come to realize that opioid use disorder (OUD) is a public health crisis causing morbidity, mortality, lost productivity, and legal cost in the United States. Opioid analgesics are efficient first-line pain relievers for acute and chronic lower-extremity pain syndrome. Perioperative pain management strategies have been proposed using opioid stewardship, but there are few standardized protocols to guide podiatric medical providers treating patients with OUD. First, we describe the pharmacology of therapeutic agents used as medications for addiction treatment for OUD and substance use disorder (SUD). Second, we offer criteria for selecting acute pain and perioperative management in patients with OUD and SUD per current medical literature. Finally, we review the literature applying opioid stewardship in the context of prescribing opioid analgesics in the presence of OUD and SUD. Three hypothetical clinical scenarios grounded in clinical-based literature are described with congruent data and founded guidelines. The first and second scenarios describe acute pain and perioperative management in patients with OUD receiving methadone and buprenorphine-naloxone, respectively. The third scenario describes acute pain and perioperative management in a patient with SUD receiving intravenous naltrexone. We hope that the lower-extremity specialist will appreciate that thoughtful management of acute perioperative pain among patients who receive medications for addiction treatment for OUD is critically important given the risks of destabilization during the perioperative period. The literature reveals the lack of rigorous evidence on acute pain management in patients who receive medication for OUD; however, some clinical evidence supports the practice of continuing methadone or buprenorphine for most patients during acute pain episodes.

Dexamethasone dose-dependently prevents taxane-associated acute pain syndrome in breast cancer treatment.

PURPOSE: Taxane-associated acute pain syndrome (T-APS) is one of the most bothersome adverse effects caused by taxanes. We have previously reported the attenuating effect of dexamethasone (DEX) on T-APS and its risk factors under DEX prophylaxis. However, the appropriate DEX dosage administration remains unclear. Therefore, this study aimed to investigate whether DEX dose-dependently prevents T-APS in breast cancer patients. METHODS: We retrospectively evaluated patients with breast cancer who received docetaxel (75 mg/m2)-containing chemotherapy without pegfilgrastim and regular non-steroidal anti-inflammatory drugs. The patients were divided into 4 mg/day and 8 mg/day DEX groups, with each DEX dosage on days 2-4 (n = 68 for each group). Primary endpoint was the comparison of all-grade T-APS incidence between the groups. Propensity score-matching was performed to adjust the baseline factors between the groups, and outcomes in the matched-population were also assessed. RESULTS: The incidence of all-grade T-APS was 72.1% in 4 mg/day group and 48.5% in 8 mg/day group, which was significantly lowered by higher DEX dosage (P = 0.008). The severity of T-APS was also significantly reduced in 8 mg/day group (P = 0.02). These results were confirmed in the propensity score matching. Multivariate logistic analysis showed that higher DEX dosage was an independent T-APS preventive factor, whereas age < 55 years was a risk factor. Moreover, DEX-dosage-associated adverse effects similarly appeared in both groups. CONCLUSION: Our study suggested that DEX dose-dependently prevents T-APS in breast cancer treatment. As understanding of the nature of T-APS and its appropriate management can significantly contribute to less onerous chemotherapy provision, further studies are required.

An Open-label, Prospective, Multicentric, Cohort Study of Nimesulide/Paracetamol Fixed Drug Combination for Acute Pain Management: Sub-group Analysis.

OBJECTIVE: Nimesulide has been evaluated in numerous clinical studies in the management of a variety of acute painful conditions. However, there is limited Indian data available on the nimesulide/paracetamol fixed drug combination (FDC). Hence, an open-label prospective multicentric study was conducted to evaluate the safety and efficacy of this FDC in the management of acute painful conditions in real-world settings. MATERIALS AND METHODS: A prospective, open-label, and multicenter study conducted at 24 centers across Indian patients with acute painful conditions due to trauma, tendinitis, myalgia, low backache, sprains, pulled muscle, soft tissue injury, dental pain, and dental procedure/surgery. Nimesulide/paracetamol FDC was prescribed by clinicians as a part of routine practice. The effectiveness was evaluated on the numerical rating scale (NRS), that is, pain intensity at rest and movement, and the physician/patient global assessment scale (GAS) among the subgroups of acute painful conditions like myalgia, dental pain, low backache, etc. Hepatic safety was also evaluated among the subgroups at the end of treatment. RESULT: A total of 464 patients were included in the study. The reduction in NRS score at rest and movement during treatment duration across different types of pain was statistically significant (p < 0.001). Pain reduction was evident as per patient and physician GAS at the end of treatment in all indications. No clinically significant difference was found in liver parameters at the end of the study. Nimesulide/paracetamol (FDC) was well tolerated across all the subgroups. CONCLUSION: Nimesulide/paracetamol FDC was found to be well-tolerated and effective in pain management across all acute painful conditions in a real-world setting without any hepatic safety concerns.

Association of OPRM1, MIR23B, and MIR107 genetic variability with acute pain, chronic pain and adverse effects after postoperative tramadol and paracetamol treatment in breast cancer.

BACKGROUND: Tramadol is an opioid analgesic often used for pain management after breast cancer surgery. Its analgesic activity is due to the activation of the µ-opioid receptor, encoded by the OPRM1 gene. This study investigated the association of genetic variability in OPRM1 and its regulatory miRNA genes with outcomes of tramadol/paracetamol treatment after breast cancer surgery with axillary lymphadenectomy. PATIENTS AND METHODS: The study included 113 breast cancer patients after breast cancer surgery with axillary lymphadenectomy treated with either 75/650 mg or 37.5/325 mg of tramadol with paracetamol for pain relief within the randomized clinical trial KCT 04/2015-DORETAonko/si at the Institute of Oncology Ljubljana. All patients were genotyped for OPRM1 rs1799971 and rs677830, MIR23B rs1011784, and MIR107 rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain as well as adverse effects of tramadol treatment was evaluated using logistic regression, Fisher's exact test, and Mann-Whitney test. RESULTS: The investigated OPRM1 related polymorphisms were not associated with acute pain assessed with the VAS scale within four weeks after surgery (all P > 0.05). Carriers of at least one polymorphic OPRM1 rs1799971 allele had a higher risk of constipation in the first four weeks after surgery compared to non-carriers (OR = 4.5, 95% CI = 1.6-12.64, P = 0.004). Carriers of at least one polymorphic OPRM1 rs677830 allele had a higher risk of constipation after third week of tramadol treatment (OR = 3.11, 95% CI = 1.08-8.89, P = 0.035). Furthermore, carriers of two polymorphic MIR23B rs1011784 alleles had a higher risk of nausea after 28 days of tramadol treatment (OR = 7.35, 95% CI = 1.27-42.6, P = 0.026), while heterozygotes for MIR107 rs2296616 allele had a lower risk of nausea after 21 days of tramadol treatment (OR = 0.21, 95% CI = 0.05-0.87, P = 0.031). In carriers of two polymorphic MIR107 rs2296616 alleles, chronic pain was significantly more common than in carriers of two wild-type alleles (P = 0.004). Carriers of at least one polymorphic MIR23B rs1011784 allele experienced more neuropathic pain after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036), while carriers of at least one polymorphic OPRM1 rs677830 allele experienced less neuropathic pain compared to carriers of two wild-type alleles (OR = 0.38, 95% CI = 0.15-0.99, P = 0.047). CONCLUSIONS: Genetic variability of OPRM1 and genes coding for miRNAs that could affect OPRM1 expression may be associated with adverse effects of tramadol/paracetamol treatment as well as with chronic and neuropathic pain after breast cancer surgery with axillary lymphadenectomy.

Comparison of the prevalence of opioid use among U.S. adults with cardiac conditions before and during the COVID-19 pandemic.

Limited data are available on the prevalence of prescription opioid use among patients with cardiac conditions who were exposed to increased risks of cardiac events including myocardial failure and cardiac arrest. According to the U.S. National Health Interview Survey, we evaluated the prevalence of opioid use in patients with cardiac conditions who reported prescription opioid use in the past 12 months and 3 months in 2019 and 2020, respectively, and further estimated the prevalence of opioid use for acute pain or chronic pain. We also analyzed the stratified prevalence by demographical characteristics. Our results showed that there was no statistically significant change in the prevalence of opioid use in the past 12 months (26.5% in 2019 vs. 25.7% in 2020) or the past 3 months (66.6% in 2019 vs. 62.5% in 2020) before and during the COVID-19 pandemic. However, there was a significant decline in the prevalence of opioid use for acute pain, from 64.2% (95% confidence interval [CI] 57.6% to 70.3%) in 2019 to 49.6% (95% CI 40.1% to 59.0%) in 2020 (P = 0.012), particularly in the subgroups of men, non-Hispanic white people, adults with education below high school, those with an income-to-poverty ratio ranging from 1.0 to 1.9, and those covered with health insurance. Our findings suggest that monitoring opioid use in the era of living with COVID-19 is important, which will help inform healthcare providers to develop care strategies to reduce health loss for vulnerable individuals.

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.

BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. RESULTS: Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (Pfrom 0 <0.001) and -0.92 mL/min/1.73 m2/year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2/year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. CONCLUSIONS: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.

Management of surgical patients on opioid replacement therapy: An audit of current practice.

Patients on opioid replacement therapy hospitalised with acute pain represent a clinical challenge and have poorer perioperative outcomes. There is limited evidence relating to acute pain management of this complex cohort. The primary objectives of this retrospective audit was to establish the number of patients who are admitted on opioid replacement therapy with an acute pain condition under surgical services and evaluate the management of these patients to determine consistency of pain management practices. Secondarily, we aimed to evaluate the documentation of opioid replacement therapy in clinical notes to determine adherence to operational protocols and record clinically relevant outcomes including infection or postoperative complication rates. Forty-four episodes of care for buprenorphine patients and 19 episodes of care for methadone patients were included. There was significant variability in inpatient opioid prescribing, including practice of dose modification, and there was high utilisation of additional opioids, although agent choice varied. Multimodal analgesia was utilised, especially following acute pain service review. There was an 11% readmission rate for complications of the initial presentation. Documentation at transitions of care was poor. There is a need for further clinical studies into specific acute pain management strategies, and their effect on clinically relevant outcomes, to guide consistent management practices.

Implementing an intravenous ketamine protocol for acute pain in the medical-surgical setting.

ABSTRACT: A subanesthetic intravenous ketamine infusion is a safe and effective acute pain management modality for moderate to severely painful surgical procedures and may be useful in patients who are at increased risk for opioid-related adverse events. Despite its safety profile, intravenous ketamine is often restricted to the intensive care unit, which results in decreased patient access to this effective therapy. For clinicians who wish to implement an intravenous ketamine protocol in the medical-surgical setting, there are few resources available. In this brief report, we present our ketamine infusion protocol for acute pain and the clinical and financial outcomes 1 year after implementation. In our experience, ketamine infusions on the medical-surgical ward are safe and cost-effective when an established acute pain service protocol is followed. Nurse practitioners play an essential role in increasing patient access to intravenous ketamine infusions and leading change by collaborating with stakeholders to develop a protocol, training nurses and interdisciplinary team members, and providing ongoing support to nursing staff.

The Use of Intravenous Lidocaine as an Analgesic Modality in the Austere Environment: Two Cases.

Providing effective analgesia for trauma in austere settings is particularly difficult and often complicated by equipment and medication limitations and harsh environmental conditions. Common modalities that are employed in conventional clinical practices may not be available or pragmatic in austere environments. Furthermore, side effects such as sedation, altered mentation, or hypoxemia require additional resources and attention. We report 2 cases that demonstrate the use of intravenous lidocaine for the management of acute pain, secondary to trauma, in an austere environment. In the first, the administration of intravenous lidocaine reduced pain, secondary to a tibia fracture, thereby facilitating splinting. In the second, a patient, who had sustained rib fractures, was also treated with intravenous lidocaine. In this case, the analgesic effects of the medication resulted in reduction in pain and improvement in pulmonary function. Of note, the narrow therapeutic window of this modality was made evident as both patients transiently experienced tinnitus following the initial lidocaine bolus. This report describes 2 cases in which intravenous lidocaine was used to manage acute pain, in an austere environment, while avoiding many of the detrimental effects that accompany alternative analgesics.

Prevention of taxane-associated acute pain syndrome with etoricoxib for patients with breast cancer: A phase II randomised trial.

BACKGROUND: For patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer. MATERIALS AND METHODS: We conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0-10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events. RESULTS: The overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P < 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P < 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79-107.24) was significantly higher than that of the control group (93.88-96.71) (P = 0.001 at cycle 1 and P < 0.001 at cycles 2-4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63-39.29; 34.59, 95% CI: 33.73-35.45, respectively; P < 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group. CONCLUSION: Prophylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04565600.

A critical review of oliceridine injection as an IV opioid analgesic for the management of severe acute pain.

INTRODUCTION: Oliceridine is a G protein-selective (biased) agonist at the µ-opioid receptor, with less recruitment of ß-arrestin-2, a signaling pathway associated with opioid-related adverse events. Nonclinical evidence showed that oliceridine elicits a rapid systemic analgesic effect while attenuating opioid-related adverse events. AREAS COVERED: Three pivotal studies in patients with moderate-to-severe acute pain, including two randomized, double-blind, placebo- and morphine-controlled efficacy studies following either orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty; and an open-label safety study following a surgical procedure or due to a medical condition. EXPERT OPINION: Poorly controlled acute postoperative pain is associated with poorer recovery, longer hospitalization, increased complications, and worse healthcare outcomes. Recently, oliceridine intravenous injection was approved for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Introduction of this new IV opioid provides a valuable option to manage postoperative pain.

Disparities in Opioid Prescribing for Long-Term Chronic and Short-Term Acute Pain: Findings from the 2019 National Health Interview Survey.

The CDC cautioned against prescribing opioids for long-term chronic pain because opioid use disorder (OUD) risk was greater compared to short-term use for acute pain. The study objective was to describe rates and characteristics of respondents prescribed opioids for long-term chronic and short-term acute pain. National Health Interview Survey respondents for 2019 aged 18 years and over were examined (n = 31,997). Bivariate and multivariable models demonstrated opioid use for long-term and acute pain relative to sociodemographic characteristics. About 12.3% of US adults took opioids in the last 12 months, and among those with chronic pain who had been prescribed opioids in the last 3 months, over half took opioids every day. The odds of taking opioids for long-term chronic pain decreased with increasing income and increased with advancing age. Opioid prescribing diverged from CDC recommendations. Less affluent older adults may be at increased risk for OUD.

Non-inferiority of intranasal ketamine compared to intravenous morphine for musculoskeletal pain relief among older adults in an emergency department: a randomised controlled trial.

OBJECTIVES: ketamine has potential advantages over morphine for musculoskeletal pain relief. The aim of this study was to compare the analgesic efficacy and safety of intranasal (IN) ketamine to intravenous (IV) morphine for older adults with musculoskeletal pain in the emergency department (ED). METHODS: this was a non-inferiority, double-blind, randomised controlled trial of ED patients aged of 65 and older presenting with acute moderate to severe musculoskeletal pain defined as a score ≥5 on an 11-point numeric rating scale (NRS). Patients were randomly assigned to receive IN ketamine or IV morphine. The primary outcome was comparative reduction of NRS pain scores between ketamine and morphine groups at 30 min post-treatment. Secondary outcomes were incidence of adverse events and requirement for rescue therapy. RESULTS: seventy-four patients were eligible for analysis (37 in the IN ketamine and 37 in the IV morphine group). Mean pain score at 30 min did not differ significantly between IN ketamine and IV morphine groups (6.03 versus 5.81). Similarly, the difference in mean NRS change from baseline between IN ketamine and IV morphine groups [(-2.14, 95% CI: -2.79 to -1.48) and (-0.81, 95% CI: -2.36 to -1.26) = -0.32, 95% CI: -1.17 to -0.52] did not reach the non-inferiority margin of 1.3. Adverse events and incidence of rescue therapy also did not differ between groups. CONCLUSIONS: intranasal ketamine can provide a non-inferior analgesic effect compared to intravenous morphine for acute musculoskeletal pain in older adults with mild adverse effects and low incidence of rescue analgesic treatment.

α1-Antitrypsin derived SP16 peptide demonstrates efficacy in rodent models of acute and neuropathic pain.

SP16 is an innovative peptide derived from the carboxyl-terminus of α1-Antitrypsin (AAT), corresponding to residues 364-380, and contains recognition sequences for the low-density lipoprotein receptor-related protein-1 (LRP1). LRP1 is an endocytic and cell-signaling receptor that regulates inflammation. Deletion of Lrp1 in Schwann cells increases neuropathic pain; however, the role of LRP1 activation in nociceptive and neuropathic pain regulation remains unknown. Herein, we show that SP16 is bioactive in sensory neurons in vitro. Neurite length and regenerative gene expression were increased by SP16. In PC12 cells, SP16 activated Akt and ERK1/2 cell-signaling in an LRP1-dependent manner. When formalin was injected into mouse hind paws, to model inflammatory pain, SP16 dose-dependently attenuated nociceptive pain behaviors in the early and late phases. In a second model of acute pain using capsaicin, SP16 significantly reduced paw licking in both male and female mice (p < .01) similarly to enzymatically inactive tissue plasminogen activator, a known LRP1 interactor. SP16 also prevented development of tactile allodynia after partial nerve ligation and this response was sustained for nine days (p < .01). Immunoblot analysis of the injured nerve revealed decreased CD11b (p < .01) and Toll-like receptor-4 (p < .005). In injured dorsal root ganglia SP16 reduced CD11b+ cells (p < .05) and GFAP (p < .005), indicating that inflammatory cell recruitment and satellite cell activation were inhibited. In conclusion, administration of SP16 blocked pain-related responses in three distinct pain models, suggesting efficacy against acute nociceptive, inflammatory, and neuropathic pain. SP16 also attenuated innate immunity in the PNS. These studies identify SP16 as a potentially effective treatment for pain.

Further exploration of the structure-activity relationship of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors.

Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, and its inhibition produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs have anti-inflammatory and inflammation resolving properties, thus inhibition of sEH consequently reduces inflammation. Concurrent inhibition of both enzymes may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and a decrease in side effects compared to ligands with single targets. Previously, microwave-assisted methodologies were employed to synthesize libraries of benzothiazole analogs from which high affinity dual inhibitors (e.g. 3, sEH IC50 = 9.6 nM; FAAH IC50 = 7 nM) were identified. Here, our structure-activity relationship studies revealed that the 4-phenylthiazole moiety is well tolerated by both enzymes, producing excellent inhibition potencies in the low nanomolar range (e.g. 6o, sEH IC50 = 2.5 nM; FAAH IC50 = 9.8 nM). Docking experiments show that the new class of dual inhibitors bind within the catalytic sites of both enzymes. Prediction of several pharmacokinetic/pharmacodynamic properties suggest that these new dual inhibitors are good candidates for further in vivo evaluation. Finally, dual inhibitor 3 was tested in the Formalin Test, a rat model of acute inflammatory pain. The data indicate that 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by 3 is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. The results presented here will help toward the long-term goal of developing novel non-opioid therapeutics for pain management.

Acute Visceral Pain in Rats: Vagal Nerve Block Compared to Bupivacaine Administered Intramuscularly.

BACKGROUND: Visceral and parietal peritoneum layers have different sensory innervations. Most visceral peritoneum sensory information is conveyed via the vagus nerve to the nucleus of the solitary tract (NTS). We already showed in animal models that intramuscular (i.m.) injection of local anesthetics decreases acute somatic and visceral pain and general inflammation induced by aseptic peritonitis. The goal of the study was to compare the effects of parietal block, i.m. bupivacaine, and vagotomy on spinal cord and NTS stimulation induced by a chemical peritonitis. METHODS: We induced peritonitis in rats using carrageenan and measured cellular activation in spinal cord and NTS under the following conditions, that is, a parietal nerve block with bupivacaine, a chemical right vagotomy, and i.m. microspheres loaded with bupivacaine. Proto-oncogene c-Fos (c-Fos), cluster of differentiation protein 11b (CD11b), and tumor necrosis factor alpha (TNF-α) expression in cord and NTS were studied. RESULTS: c-Fos activation in the cord was inhibited by nerve block 2 hours after peritoneal insult. Vagotomy and i.m. bupivacaine similarly inhibited c-Fos activation in NTS. Forty-eight hours after peritoneal insult, the number of cells expressing CD11b significantly increased in the cord (P = .010). The median difference in the effect of peritonitis compared to control was 30 cells (CI95, 13.5-55). TNF-α colocalized with CD11b. Vagotomy inhibited this microglial activation in the NTS, but not in the cord. This activation was inhibited by i.m. bupivacaine both in cord and in NTS. The median difference in the effect of i.m. bupivacaine added to peritonitis was 29 cells (80% increase) in the cord and 18 cells (75% increase) in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli by inhibiting c-Fos and microglia activation. CONCLUSIONS: In rats receiving intraperitoneal carrageenan, i.m. bupivacaine similarly inhibited c-Fos and microglial activation both in cord and in the NTS. Vagal block inhibited activation only in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli. This emphasizes the effects of systemic local anesthetics on inflammation and visceral pain.

Risk factor analysis for taxane-associated acute pain syndrome under the dexamethasone prophylaxis.

PURPOSE: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. METHODS: In total, 143 patients with breast cancer who received docetaxel (75 mg/m2) or paclitaxel (175 mg/m2)-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. RESULTS: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. CONCLUSION: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.