Postoperative Pain Model Research Articles

An Injectable Oil-Based Depot Formulation of N-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation.

Objectives: The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST) and to investigate the pharmacokinetics and pharmacodynamics after injectable administration. Methods: A novel N-acyloxymethyl prodrug of ROP, i.e., ROP-ST, was synthesized and its physicochemical properties such as log P, solubility and stability characterized. A soybean oil-based depot of ROP-ST was prepared, and the in-vitro release of ROP-ST was evaluated using an "inverted-cup" method. Pharmacokinetic profiles and tissue retention properties were investigated after intramuscular administration of the formulation in rats. The analgesic efficacy was assessed via a von Frey monofilaments test by measuring the paw withdrawal thresholds. Results: The structure of ROP-ST was ascertained with clear 1H NMR assignment and accurate mass-to-charge ratio. The high Log P value of ROP-ST (9.16) demonstrated extremely low aqueous solubility, but the prodrug is biolabile when in contact with plasma or liver esterase. Intramuscular injection of ROP-ST oil solution in rats provided a significantly higher mean residence time without a very clear plasma peak of ROP. In a postoperative pain model of rats, the injection of ROP-ST oil solution into the vicinity of the sciatic nerve in the right ankle effectively controlled the postoperative pain for at least 72 h. Conclusions: The injectable oil-based depot formulation of N-acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain.

Select terpenes from Cannabis sativa are antinociceptive in mouse models of post-operative pain and fibromyalgia via adenosine A2a receptors.

Terpenes from Cannabis show promise for pain management. Our lab found that the terpenes geraniol, linalool, β-caryophyllene, and α-humulene relieve chemotherapy-induced peripheral neuropathy via Adenosine A2a receptors (A2aR). This suggests terpenes as potential non-opioid, non-cannabinoid therapeutics. In this study, we investigated post-operative and fibromyalgia pain, expanding potential terpene applications to different pain types. Male and female CD-1 mice had their baseline mechanical sensitivity measured via von Frey filaments and underwent either paw incision surgery or reserpine-induced fibromyalgia (0.32mg/kg, sc). After pain was established, the mice received 200mg/kg ip of a terpene, and their mechanical sensitivity was measured over three hours. To determine the potential mechanism of action, mice were given the A2aR antagonist istradefylline (3.2mg/kg, ip) 10min before terpene, with mechanical sensitivity measured after. Hot plate pain testing was performed as a control. Terpene treatment caused time-dependent elevation of the mechanical thresholds of the mice from both pain models, strongest for geraniol, then linalool or α-humulene, indicating that these four terpenes are anti-nociceptive in post-surgical and fibromyalgia pain. Pretreatment with istradefylline blocked antinociception, suggesting the terpenes act via the A2aR in these pain models. Terpenes had no effect on hot plate latencies, ruling out non-specific motor effects. These results demonstrate that the terpenes geraniol, linalool, β-caryophyllene, and α-humulene may be a viable medication for post-operative and fibromyalgia pain relief. Their mechanism of action via the A2aR furthers our knowledge of its importance in pain processing and as a target of terpene drugs.

Comparative study of the effects of ibuprofen, acetaminophen, and codeine in a model of orofacial postoperative pain in male and female rats.

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100mg/kg), acetaminophen (100 and 300mg/kg) and codeine (3 and 10mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control.

Related Factors and Risk Prediction of Chronic Pain after Knee Replacement.

This study aimed to explore potential risk factors associated with chronic pain after total knee arthroplasty (TKA) and to establish the risk prediction model of chronic postoperative pain (CPSP). This study retrospectively analyzed the clinical data of 160 patients who underwent TKA in our hospital between January 2021 and January 2024. Relevant data such as the baseline characteristics, past medical history, CPSP condition, and pain numerical rating scale (NRS) were retrieved from the medical information system. Logistic regression analysis was performed on the risk factors affecting the postoperative CPSP of the patients. The identified risk factors were incorporated to develop a risk-prediction model. Among the 160 patients, 67 (41.88%) had CPSP at or around the operation incision. The NRS pain score was significantly higher in the CPSP group than in the non-CPSP group during exercise preoperative and 3 months post-operation. Furthermore, the CPSP group had a higher NRS score than the non-CPSP group at rest 3 months after the procedure (p < 0.05). We observed that the preoperative NRS score, preoperative hospital for special surgery (HSS) score, postoperative functional training, and postoperative adverse events were the independent factors influencing the occurrence of CPSP after TKA (p < 0.05). Additionally, there was a significant positive correlation between preoperative NRS score, postoperative adverse events, and CPSP pain severity, and a significant negative correlation between preoperative HSS score, postoperative functional training, and CPSP pain severity (p < 0.05). The receiver operating characteristic (ROC) curve had excellent calibration and prediction capabilities for the predictive model of CPSP after TKA, with the area under the curve (AUC) of 0.868 (95% CI: 0.811-0.925). In this study, the predictive model of CPSP risk for patients after TKA surgery was initially constructed, which can help medical staff predict the risk of CPSP in patients after surgery individually, thereby preventing the occurrence of CPSP.

Sustainable release artifact in PLGA microspheres for prolonged local aesthetics in postoperative pain management.

The challenge of effectively managing long-term pain after surgery remains a significant issue in clinical settings. Although local anesthetics are preferred for their effective pain relief and few side effects, their short-lasting effect does not fully meet the pain relief needs after surgery. Articaine, widely used for postoperative pain relief as a local anesthetic, is pharmacologically limited by its short half-life, which reduces the duration of its pain-relieving effects. To overcome this issue, this study presents a new approach using poly (lactic-co-glycolic acid) (PLGA) microspheres for controlled articaine release, aiming to extend its analgesic effect while reducing potential toxicity. The PLGA microspheres were shown to extend the release of articaine for at least 72h in lab tests, displaying excellent biocompatibility and low toxicity. When used in a rodent model for postoperative pain, the microspheres provided significantly prolonged pain relief, effectively reducing pain for up to 3days post-surgery, without causing inflammation or tissue damage for over 72h after being administered. The extended release and high safety profile of these PLGA microspheres highlight their promise as a new method for delivering local anesthetics, opening up new possibilities for pain management in the future.

Low level laser therapy alleviates mechanical allodynia in a postoperative and neuropathic pain model and alters the levels of inflammatory factors in rats.

This study aimed to investigate the analgesic and preventive effect of low-level laser therapy (LLLT) on the incisional pain model and spinal nerve ligation (SNL) model in rats and identify the possible mechanisms of action. Male Sprague-Dawley rats were used, divided into different treatment groups. The single application group received LLLT before or after skin incision or SNL. The consecutive application group received LLLT for six consecutive days post-incision, three days pre-incision, or three consecutive days pre-SNL. The control group underwent skin incision or SNL without LLLT. The von Frey test was used to quantify the pain associated with mechanical allodynia. Pro-inflammatory cytokine level and alterations in nerve growth factor (NGF) expression were measured by using ELISA and immunohistochemistry, respectively in the skin, muscle of the paw, and spinal cord dorsal horn (SCDH). In the incisional pain model, LLLT showed significant analgesic and preventive effect. LLLT ameliorated SNL-induced mechanical allodynia but LLLT had no preventive effect. LLLT decreased interleukin-1β (IL-1β) expression levels in the skin, muscle, and SCDH and reduced the optical density of skin and spinal cord NGF in the incisional pain model. LLLT alleviated incisional pain and neuropathic pain caused by SNL in rats, and reduced the levels of IL-1β and NGF in the peripheral tissue and SCDH in the incisional pain model. LLLT might be effective in patients with post-operative pain and peripheral neuropathic pain.

Postoperative Pain at Discharge From the Post-anesthesia Care Unit: A Case-Control Study.

Despite advancements in postoperative pain management, approximately 20% of patients still experience severe pain within the first 24 hours post-surgery. Previous studies utilizing machine learning have shown promise in predicting postoperative pain with various models. This study investigates postoperative pain predictors using a machine learning approach based on physiological indicators and demographic factors in a Mexican cohort. We conducted a retrospective case-control study to assess pain determinants at Post-anesthesia Care Unit (PACU) discharge at Hospital Ángeles Lomas in Mexico City. Data were collected from 550 patients discharged from the PACU, including 292 cases and 258 controls, covering a range of surgical procedures and illnesses. Machine learning techniques were employed to develop a predictive model for postoperative pain. Physiological responses, such as blood pressure, heart rate, respiratory rate, and anesthesia type, were recorded prior to PACU admission. Significant differences were found between cases and controls, with factors such as sex, anesthesia type, and physiological responses influencing postoperative pain. Visual analog scale (VAS) scores at PACU admission were predictive of pain at discharge. Our findings reinforce existing literature by highlighting sex-based disparities in pain experiences and the influence of anesthesia type on pain levels. The logistic regression model developed, incorporating physiological responses and sex, shows potential for refining pain management strategies. Limitations include the lack of detailed surgical data and psychological factors, and validation in a prospective cohort. Future research should focus on more comprehensive predictive models and longitudinal studies to further improve postoperative pain management.

Pain mechanistic networks: the development using supervised multivariate data analysis and implications for chronic pain

Abstract Chronic postoperative pain is present in approximately 20% of patients undergoing total knee arthroplasty. Studies indicate that pain mechanisms are associated with development and maintenance of chronic postoperative pain. The current study assessed pain sensitivity, inflammation, microRNAs, and psychological factors and combined these in a network to describe chronic postoperative pain. This study involved 75 patients with and without chronic postoperative pain after total knee arthroplasty. Clinical pain intensity, Oxford Knee Score, and pain catastrophizing were assessed as clinical parameters. Quantitative sensory testing was assessed to evaluate pain sensitivity and microRNAs, and inflammatory markers were likewise analyzed. Supervised multivariate data analysis with “Data Integration Analysis for Biomarker Discovery” using Latent cOmponents (DIABLO) was used to describe the chronic postoperative pain intensity. Two DIABLO models were constructed by dividing the patients into 3 groups or 2 defined by clinical pain intensities. Data Integration Analysis for Biomarker discovery using Latent cOmponents model explained chronic postoperative pain and identified factors involved in pain mechanistic networks among assessments included in the analysis. Developing models of 3 or 2 patient groups using the assessments and the networks could explain 81% and 69% of the variability in clinical postoperative pain intensity. The reduction of the number of parameters stabilized the models and reduced the explanatory value to 69% and 51%. This is the first study to use the DIABLO model for chronic postoperative pain and to demonstrate how different pain mechanisms form a pain mechanistic network. The complex model explained 81% of the variability of clinical pain intensity, whereas the less complex model explained 51% of the variability of clinical pain intensity.

Monnieriside A from Evolvulus linarioides promotes antinociceptive effects in models of inflammatory and postoperative pain in male mice

Monnieriside A (MoA) is a chromone isolated from Evolvulus linarioides. This study investigated the antinociceptive potential of MoA in mice. MoA (0.01–100 mg/kg, i.p.) inhibited nociception in the inflammatory phase of the formalin test without causing motor impairment. MoA (0.1–100 mg/kg, i.p.) also reduced hindpaw mechanical allodynia caused by either intraplantar injection of Complete Freund’s Adjuvant (CFA) or surgical paw incision to simulate postoperative pain. Postoperative antinociception was accompanied by reduced IL-1β levels in the incised paw, assessed by ELISA. The antinociceptive action of MoA (100 mg/kg, i.p.) was preserved in IL-10 knockout mice submitted to paw incision, indicating that IL-10 is not essential to the antinociceptive effect. Interestingly, MoA (100 mg/kg, i.p.) increased the expression of TGF-β in IL-10 knockout mice, which could be a compensation mechanism leading to an antinociceptive effect in the absence of IL-10.

Patient-related predictors of post-operative pain following root canal treatment: A structural model analysis.

The pathways to post-operative pain are complex and encompass factors that extend beyond the treatment protocol employed. This study aimed to identify patient-related predictors of post-operative pain following root canal treatment. A total of 154 patients received a single-visit root canal treatment for asymptomatic necrotic mandibular molars. Before treatment, dental anxiety, dental fear and sense of coherence (SOC) were measured as predictors for each patient using validated questionnaires. Other measured predictors included gender, age, previous negative experiences at the dental offices and prior root canal treatment. Post-operative pain was assessed using the Numeric Rating Scale at multiple time-points over 30 days. Structural equation analysis was employed to evaluate the direct and indirect effects of patient-related predictors on a theoretical model of post-operative pain. The irrigant solution was also included in the model, as it was the only aspect that varied in the treatment protocol (sodium hypochlorite 2.5% and 8.25%). Dental anxiety (coefficient 0.028; p < .01), dental fear (coefficient 0.007; p = .02) and irrigant solution (coefficient 0.004; p = .03) exerted a direct effect on post-operative pain. SOC exerted an indirect effect on post-operative (coefficient 0.006; p = .01) through dental anxiety and dental fear. Moreover, previous negative experiences (coefficient 0.048; p = .04) exerted an indirect effect on post-operative pain through dental anxiety. Dental anxiety, dental fear, previous negative experiences and SOC are patient-related predictors of post-operative pain following root canal treatment. These factors should be taken into consideration in clinical practice, as patients with these characteristics may be at an increased risk of experiencing post-operative pain.

Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

An injectable oleogel-based bupivacaine formulation for prolonged non-opioid post-operative analgesia.

Opioid-based medications remain the mainstay of post-operative pain management, even though they are associated with a plethora of adverse effects including addiction, nausea, constipation, cognitive impairment, respiratory depression, and accidental death due to overdose. Local anesthetics are effective at controlling the intense pain after surgery but their short duration of effect limits their clinical utility in post-operative pain management. In this manuscript, an optimized injectable oleogel-based formulation of bupivacaine for multi-day post-operative pain management was characterized on the benchtop and assessed in two clinically-relevant porcine post-operative pain models. Benchtop characterization verified the optimized oleogel-based bupivacaine formulation design, demonstrating a homogenous stable oleogel with sufficient injectability due to shear-thinning properties, high drug loading capacity and first-order drug release kinetics over 5days. In vivo assessment in two pig post-operative pain models demonstrated that the oleogel-based bupivacaine formulation can provide statistically significant multi-day analgesia in two routes of administration: local instillation directly into a surgical site and ultrasound-guided peripheral nerve block injection. Pharmacokinetic assessment of ALX005 found that Cmax values were not statistically different from the bupivacaine HCl control, with no clinical signs of local anesthetic systemic toxicity observed, when administering up to 2.7 and 8.1 times the control dose of bupivacaine HCl. This study demonstrates the pre-clinical safety and efficacy of an injectable oleogel-based bupivacaine formulation and explores its utility as a single-administration long-acting local anesthetic product for post-operative pain management that can be used in both local and regional anesthetic applications.

Analgesic Effect of Sulforaphane: A New Application for Poloxamer-Hyaluronic Acid Hydrogels.

Sulforaphane (SFN) has shown potential as an antioxidant and anti-inflammatory agent. To improve its druggability, we developed new analgesic formulations with sulforaphane-loaded hyaluronic acid (HA)-poloxamer (PL) hydrogel. This study evaluated the pre-clinical safety and effectiveness of these formulations. Effectiveness was tested on Wistar rats divided into groups (n = 15) receiving (IM, 10 mg/kg) SFN formulations or control groups (without SFN). This study used a hind paw incision postoperative pain model to evaluate mechanical hypersensitivity with von Frey filaments. TNF-α, IL-1β, substance P, and CGRP levels verified anti-inflammatory activity in the hind paw tissue. Histopathology of tissues surrounding the injection site was assessed after 2 and 7 days post-treatment. To corroborate drug safety, cell viability of 3T3 and RAW 264.7 cultures was assessed. Additionally, RAW 264.7 cultures primed with carrageenan evaluated nitric oxide (NO) levels. All animals exhibited post-incisional hypersensitivity, and F2 (PL 407/338 (18/2%) + HA 1% + SFN 0.1%) showed a longer analgesic effect (p < 0.05). F2 reduced TNF-α, IL-1β, and CGRP levels (p < 0.05). Histopathological evaluation showed mild to moderate inflammatory reactions after the formulations' injections. F2 produced no significant difference in cell viability (p > 0.05) but reduced NO production (p < 0.05). Thus, our results highlight the biocompatibility and effectiveness of F2.

Extended Release of Bupivacaine from Temperature-Responsive PNDJ Hydrogels Improves Postoperative Weight-Bearing in Rabbits Following Knee Surgery.

Effective treatment of postoperative pain lasting for multiple days without opioids is an important clinical need. We previously reported analgesia lasting up to 96 h in a porcine soft tissue model of postoperative pain using SBG004, an extended-release formulation of bupivacaine based on the temperature-responsive polymer poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ]. Orthopaedic surgical sites such as the knee can involve complex sensory innervation which presents a distinct challenge to local anesthetic delivery. The purpose of this work was to evaluate the pharmacokinetics and efficacy of SBG004 in an orthopaedic surgical model in comparison to currently available local anesthetics. Pharmacokinetics following periarticular (PA) or intraarticular (IA) injection of SBG004 were compared against liposomal bupivacaine (Lip-Bupi) PA in New Zealand White rabbits (all doses 14.5 mg/kg). Analgesic efficacy of SBG004 (IA, PA, or IA + PA), three active comparators, and saline was evaluated following knee surgery in New Zealand White rabbits. Analgesia was assessed via weight-bearing on the operated limb during spontaneous large steps in video recordings. Systemic bupivacaine exposure lasted at least 7 days for SBG004 PA, 4 days for SBG004 IA, and 2 days for Lip-Bupi PA. In the analgesia study, weight-bearing in all active groups except SBG004 IA was more frequent versus saline through 8 h postoperatively (p < 0.05). Only SBG004 IA + PA resulted in a higher proportion of weight-bearing rabbits at 24 h versus saline (6/7 versus 2/10, p = 0.015). Analysis of pooled data from 24-72 h showed significantly greater frequency of weight-bearing in rabbits receiving SBG004 IA + PA (71%) versus saline (37%), ropivacaine cocktail (41%), and Lip-Bupi PA (36%). The results indicate that the release profile from SBG004 PA or IA coincides reasonably with the time course of postoperative pain, and SBG004 may produce longer duration of analgesia than local anesthetics currently used in knee surgery, including during the period of 24-72 h recognized as a target for extended-release local anesthetics.

Pronociceptive role of spinal Cav2.3 (R-type) calcium channels in a mouse model of postoperative pain.

More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Cav2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Cav2.3 as a potential target to treat postoperative pain and to reduce opioid-related side effects. A plantar incision model was established in adult male and female C57BL/6 mice. Cav2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Cav2.3 blocker-alone or together with morphine-was also assessed after surgery. Paw incision in female and male mice caused acute nociception and increased Cav2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Cav2.3, but not with a scrambled siRNA, prevented the development of surgery-induced nociception in both male and female mice, with female mice experiencing long-lasting effects. High doses of i.t. SNX-482, a Cav2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX-482 mediated a long-lasting reversal of postsurgical pain in female and male mice. Our results demonstrate that Cav2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.

Analgesic effects of oral Yokukansan on acute postoperative pain and involvement of the serotonin nervous system: a mouse model study.

Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia.

Development of opioid analgesic tolerance in rat to extended-release buprenorphine formulated for laboratory subjects.

Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.

Efficient microwave synthesis of flurbiprofen derivatives and their enhancement of efficacy in chronic inflammatory pain models and gastro-protective potential in post-operative model

Present research was designed to synthesize and characterize the flurbiprofen derivatives and to evaluate their analgesic, anti-inflammatory and gastro-protective activities in post-operative and chronic inflammatory pain models. Flurbiprofen derivatives were produced by using three-step processes involving esterification, hydrazide production, and schiff base, each of which modified a different carboxyl group. All the newly synthesized flurbiprofen derivatives (NS5-NS8) were characterized by 1H NMR,13C NMR,19F NMR and HR-ESI-MS, and the post-operative, inflammatory pain and ulcerogenic activities were determined in well-established in-vivo animal models. To evaluate post-operative and inflammatory pain, various doses of compounds [1, 3, 10, and 30 mg/kg (bwt)] were used, while their ulcerogenic potential was assessed at doses of 100 and 150 mg/kg (bwt). The incisional damage linked pain was significantly (p < 0.001) reduced by derivatives at different doses in both the acute and repeated tests with decreased response of phologistic agent-induced inflammation. The stomach histology and biochemical features demonstrate that the synthesized derivatives have no potential to cause ulcerogenicity as compared to aspirin and flurbiprofen. Furthermore, docking shows that the hydrazide moiety of these compounds is crucial in interacting within COX-2 binding site. Therefore, the synthesized compounds exhibit strong analgesic and anti-inflammatory effects and a low risk of causing ulcers. These attributes render them potentially valuable therapeutic agents for the treatment of pathological disorders associated with inflammation and pain. Communicated by Ramaswamy H. Sarma

Chiral S-flurbiprofen axetil-loaded lipid microspheres for improved analgesic effects: Preparation, characterization, and preclinical evaluation

Flurbiprofen axetil (FPA) is a non-steroidal anti-inflammatory drug commonly used for managing post-surgical and cancer-related pain. However, FPA consists of two enantiomers, namely S-flurbiprofen axetil (S-FPA) and R-flurbiprofen axetil (R-FPA), with distinct inhibitory activities on cyclooxygenase (COX). This study focused on utilizing chiral S-FPA as the active pharmaceutical ingredient for the first time, and developed S-FPA-loaded lipid microspheres (S-FPA@LMs). The average particle size and zeta potential of S-FPA@LMs were 217.33 ± 6.66 nm and −36 ± 3.46 mV, respectively. S-FPA@LMs exhibited excellent stability for at least 6 months when stored at 5 ± 3 °C. COX activity inhibition assay revealed that S-FPA selectively inhibited COX-1, exhibiting a more potent inhibitory effect than the racemic form of FPA. In a rat model of postoperative incision pain, S-FPA@LMs demonstrated dose-dependent analgesic effects with superior efficacy compared to equimolar doses of FPA@LMs. Pharmacokinetic studies revealed comparable profiles for the metabolites, including S-flurbiprofen (S-FP) and R-flurbiprofen (R–FP), when S-FPA@LMs and FPA@LMs were administered in equimolar doses. Additionally, continuous administration for 7 days showed no significant accumulation of S-FP and R–FP. The inversion from S-FP to R–FP after S-FPA@LMs administration was also negligible. In terms of safety, S-FPA@LMs did not induce any signs of hemolysis or coagulation in rabbit erythrocytes. Moreover, no immediate allergic reactions were observed in the active systemic anaphylaxis test. The sub-acute toxicity study indicated dose-dependent adverse reactions primarily related to the gastrointestinal system, with recovery observed after a 2-week recovery period. Notably, S-FPA@LMs displayed a lower mortality rate and less severe pathological changes in the deceased rats compared to FPA@LMs. Overall, our findings highlight the potential of S-FPA@LMs as a promising candidate for acute pain management with satisfactory stability, enhanced analgesic efficacy, reduced dosage, and reduced toxicity compared to the racemic mixture. In summary, the introduction of S-FPA@LMs presents an innovative approach to managing acute pain, warranting further exploration and development in the field of pain therapeutics.

Bunionectomy as an Acute Postoperative Pain Model: Overview of Common Experimental Methods, and Insights from Past Clinical Trials.

To obtain broad regulatory approval for a new analgesic agent in acute postoperative pain, US and European regulatory authorities require pivotal studies in both hard (bony) tissue pain and soft tissue pain. Bunionectomy is by far the most common hard tissue pivotal trial model, in spite of the fact that the model has limited relevance to clinicians prescribing pain drugs (pain from bunionectomy is not extreme or long-lasting, and is adequately treated by existing drugs). The authors outline the experimental characteristics that make bunionectomy an appealing study model for researchers despite its lack of clinical relevance compared to larger surgeries. These include bunionectomy's high signal-to-noise ratio (secondary to the ability to standardize surgical procedures, anesthesia and perioperative care) and relative operational simplicity (including relatively easy subject enrollment). They present an overview of the surgical and anesthetic protocols typical to modern bunionectomy studies, as well as common design paradigms, common endpoints, and other key design features of bunionectomy trials. They also provide an informal qualitative review of bunionectomy acute pain studies performed in the past 15 years, and a master table of acute pain bunionectomy trials performed from 2006-2023. Drawing from their informal review of past studies, the authors discuss trends in rescue medication, study enrollment rates, subject demographics, and the advantages and disadvantages of bunionectomy compared with another common acute pain model, dental impaction pain (third molar extraction).