The Analgesic Effect of Two Different Extended-Release Meloxicam Formulations for Attenuation of Hypersensitivity in Rats (Rattus norvegicus)
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) frequently administered every 24 hours to control mild to moderate pain in rodents. Extended-release meloxicam offers a refinement of less frequent dosing and an extended therapeutic window compared with the standard daily-dosed meloxicam formulation. The aim of this study was to compare the analgesic efficacy of 2 different extended-release meloxicam formulations to a standard meloxicam formulation in a rat incisional pain model. Adult Long-Evans rats (n = 33) were randomly assigned into one of 4 treatment groups (n = 8-9 per group): (1) saline (0.9% NaCl, 5 mL/kg, SC, once); (2) meloxicam (Melox; 2 mg/kg, SC, every 24 hours); (3) meloxicam extended-release polymer (Melox-ER; 4 mg/kg, SC, once); or (4) meloxicam extended-release suspension (Melox-XR; 4 mg/kg, SC, once). Under isoflurane anesthesia, a 1-cm longitudinal skin incision was made on the plantar hind paw 5 minutes after drug administration. Mechanical and thermal hypersensitivity assessments were performed one day before surgery (−24 hour), 4 hours after surgery (4 hour), and 3 consecutive days following surgery (24, 48, and 72 hours). Mechanical (4-48 hours) and thermal (4-72 hours) hypersensitivity were observed in the saline group. Melox-ER did not attenuate mechanical or thermal hypersensitivity at any time point. Melox and Melox-XR attenuated mechanical hypersensitivity at the 48-hour time point. No abnormal clinical signs were noted, but injection site reactions were noted in the Melox, Melox-ER, and Melox-XR groups. Further research is needed to evaluate rat meloxicam analgesic dosages for incisional pain.
Introduction
Appropriate pain management is an essential component of laboratory animal care and use for regulatory, scientific, and ethical reasons.1,2 Rats are frequently used to study the pathophysiology of various conditions and to evaluate therapeutic interventions; for example, they have been used as surgical models for the study of heart disease and cardiac regeneration3 and as models to simulate chronic kidney disease since they closely mimic human physiologic responses.4 Commonly used analgesic drug classes to control postoperative pain in rats include opioids (buprenorphine),5 local anesthetics (lidocaine or bupivacaine),6 and NSAIDs (meloxicam and carprofen).7 Buprenorphine is chosen for rodent surgery for its potent, long-lasting analgesic effects on the CNS,8 whereas NSAIDs act on the peripheral nervous system9 to reduce inflammation and pain, and local anesthetics provide targeted, short-term peripheral nervous system pain relief without systemic effects.10 NSAIDs are frequently used to control mild to moderate pain or in conjunction with buprenorphine as part of a multimodal analgesic plan.11 The commonly used NSAIDs (meloxicam and carprofen) are frequently administered once every 24 hours in rats.12
Meloxicam is a cyclooxygenase-2 (COX-2)-specific NSAID that provides analgesic and anti-inflammatory effects.13 COX-2-specific NSAIDs are designed to selectively inhibit the COX-2 enzyme, offering advantages over nonspecific COX NSAIDs such as reduced gastrointestinal side effects, effective pain and inflammation control, and a lower risk of bleeding.14 These properties of meloxicam make it a widely used pain management drug in laboratory rodents.15,16 However, the frequent handling needed to provide every 24-hour dose administration can cause additional stress to both the animals and researchers.11,17,18 Recently, 2 new extended-release meloxicam formulations, meloxicam extended-release polymer (Melox-ER) and meloxicam extended-release suspension (Melox-XR), were developed. Melox-ER and Melox-XR are both injectable extended-release meloxicam formulations but rely on slightly different technologies. Melox-ER utilizes a liquid biodegradable polymer with biocompatible organic solvents in combination with meloxicam. Once administered, the polymer solution coagulates to form a sustained-release delivery matrix for the gradual release of meloxicam. Melox-XR is a suspension made from medium-chain triglyceride oil, which is degraded by lipase and esterase to also gradually release meloxicam over time. Both formulations were designed to provide a longer duration of effect, often covering several days from a single injection. These 2 new extended-release meloxicam formulations potentially offer a significant refinement by reducing the dosing frequency and extending the therapeutic window compared with the standard meloxicam formulation.19 However, little is known about the efficacy of these 2 formulations relative to standard meloxicam. There are no published reports specifically comparing the efficacy of extended-release meloxicam formulations for postoperative pain in rats.
The aim of this study was to compare the analgesic efficacy of 2 different extended-release meloxicam formulations (Melox-ER and Melox-XR) to the standard meloxicam formulation (Melox) using an incisional rat pain model. By assessing the mechanical and thermal hypersensitivity in postoperative rats, we hypothesize that meloxicam extended-release polymer (Melox-ER; 4 mg/kg, SC, once) and meloxicam extended-release suspension (Melox-XR; 4 mg/kg, SC, once) will provide similar analgesic effects as standard meloxicam (Melox; 2 mg/kg, SC, every 24 hours).
Ethical review.
This research was approved by Stanford University's Institutional Animal Care and Use Committee. All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals.1 Stanford University is accredited by AAALAC International.
Materials and Methods
Study design.
Rats (n = 18 males and n = 15 females) were randomly assigned into one of 4 treatment groups (n = 8 per group, except the Melox-ER group where n = 9): (1) saline (0.9% NaCl, 5 mL/kg, SC; once); (2) Melox (2 mg/kg, SC, once daily; Boehringer Ingelheim Animal Health, Duluth, GA); (3) Melox-ER (4 mg/kg, SC, once; Wedgewood Pharmacy, Swedesboro, NJ); or (4) Melox-XR (4 mg/kg, SC, once, an experimental formulation made by Fidelis Animal Health, North Brunswick, NJ). The stock solution of meloxicam was diluted with sterile water to make a 0.5-mg/mL concentration for Melox; therefore, the saline group and Melox treatment group were administered a similar approximate volume of 1 mL. Melox-ER and Melox-XR were administered based on their drug concentrations of 2 and 5 mg/L, which corresponded to approximate volumes of 0.6 and 0.3 mL, respectively. At 0 hour (surgery day), all drugs were administered 5 minutes before incision when the animals were under anesthesia with a 22-gauge needle and a 1-mL Luer-lock syringe, and the injection site was gently pinched for at least 5 seconds postadministration to minimize drug leakage. For the Melox group, drug administration was repeated every 24 hours, one hour before initiating behavioral testing (Figure 1). Melox at 2 mg/kg was selected based on standard dosing in rats.7 Melox-ER was administered at 4 mg/kg to replace 2 doses of 2 mg/kg standard meloxicam. In addition, a previous research indicated that Melox-ER at 4 mg/kg successfully attenuated mechanical hypersensitivity in a rat incisional model, which is the same model that was used in the current study.20 Therefore, 4 mg/kg was chosen for Melox-XR based on unpublished pharmacokinetics data suggesting that a 4-mg/kg dose of Melox-XR was comparable to Melox-ER of the same dosage.21
Citation: Journal of the American Association for Laboratory Animal Science 2025; 10.30802/AALAS-JAALAS-25-119
Sample size.
A total of 33 adult (18 males and 15 females) Long-Evans rats (weighing 220-355 g) from Charles River Laboratories (Wilmington, MA) were used in this study. A sample size of about 8 rats per group was established through power analysis, using an effect size of 0.5, a correlation of 0.25 among repeated measurements, a significance threshold of 0.05, and a statistical power of 95.2%.
Inclusion and exclusion criteria.
All data points were included in the analysis. Animals and data points were set to be excluded a priori only under conditions of procedural errors (eg, incorrect dosage and incorrect injections) or if animals experienced distress exceeding that anticipated from the procedure, such as persistent guarding, self-injury, severe lethargy, or significant loss of body weight (greater than 15%). None of these exclusion criteria occurred during this study; therefore, no data points or animals were excluded from analysis.
One rat in the Melox group was missing a single body weight data point at the 48-hour time point due to an oversight in data recording. All other data points and animals across all experimental groups were included in the analysis without exclusion.
Randomization.
Randomization was used to assign animals to treatment groups, with group allocation determined using a random number generator. Randomization aimed to achieve equal sex representation, targeting 4 males and 4 females per testing group. All groups met this target except for Melox-XR, which included 5 males and 3 females, and Melox-ER, which included 5 males and 4 females; all other groups contained 4 males and 4 females. While potential confounders such as order of treatment administration, measurement timing, or cage location were not explicitly controlled, animals were identified using a tail-marking system (based on the number of rings applied during the testing week) to ensure accurate tracking of each subject throughout the study.
Blinding.
The same experimenter was blinded to group allocations throughout the entire experimental period, including group formation, treatment administration, surgery, behavioral testing, and necropsy. All assessments and data collection were performed by the same blinded experimenter. Group identities were only revealed after data collection and the gross necropsy were complete.
Outcome measures.
The primary outcome measures assessed in this study were behavioral changes in response to mechanical and thermal stimuli, specifically mechanical hypersensitivity (measured by paw withdrawal frequency using the von Frey filaments) and thermal hypersensitivity (measured by paw withdrawal latency using the Hargreaves test). These tests were used to evaluate postoperative hypersensitivities in rats that had a plantar hind paw incision procedure as they provide specific, objective, and quantifiable values related to sensitivity at the incision site. The study’s primary hypothesis-testing outcome measures were the changes in mechanical and thermal sensitivity following administration of different meloxicam formulations. These outcomes were used to determine the sample size through power analysis, making them the basis for statistical comparison across treatment groups.
Statistical analysis.
Statistical analysis was performed using a 2-way repeated measures ANOVA with Bonferroni correction for multiple comparisons (R Development Core Team, 2015) to evaluate differences within and between groups over time for mean withdrawal responses. Data from all 4 groups were assessed for multivariate normality using the Anderson-Darling test, with P values of 0.719, 0.730, 0.934, and 0.976 for saline, Melox, Melox-ER, and Melox-XR, respectively, indicating no significant deviation from normality. Data are reported as mean ± SEM to indicate the precision of the sample mean rather than the variability of individual observations. Data are reported as mean ± SEM, and a P value of less than 0.05 was considered statistically significant. The main objective of this study was to examine the variability of the sample means22,23 and determine the probability of their deviation from the true population mean.
Animals.
Adult male and female Long-Evans rats (Rattus norvegicus), aged approximately 3-4 months and weighing between 220 and 355 g, were obtained from Charles River Laboratories (Wilmington, MA). According to the vendor, the rats were confirmed to be free of pathogens such as Theiler murine encephalomyelitis virus, reovirus type 3, Kilham rat virus, Sendai virus, murine adenovirus types 1 and 2, rat parvovirus, Toolan H1, Hantaan virus, pneumonia virus of mice, rat coronavirus, rat minute virus, lymphatic choriomeningitis virus, Mycoplasma pulmonis, and any endo- or ectoparasites. Rats were acclimated in the vivarium for 72 hours before the experiment. Animals were pair housed in reusable rat cages with Sani-Chips bedding (Envigo-7090 Teklad; Inōtiv, West Lafayette, IN) and provided shredded paper bedding (Enviro-dri; Shepherd Specialty Papers, Watertown, TN) as enrichment. The environment was maintained on a 12:12-hour dark:light cycle at 70-74 °F (21-23 °C) and 30%-70% relative humidity. Throughout the acclimation and experimental periods, the rats were given ad libitum access to a commercial rodent diet (Teklad Global 18% Protein Rodent Diet 2018; Inōtiv, West Lafayette, IN) and reverse osmosis purified water. All rats were weighed before surgery and every 24 hours. Thermal and mechanical hypersensitivity testing were conducted daily at approximately 10:00 am starting from 24 hours before surgery to 72 hours postsurgery. At the study’s conclusion, rats were euthanized by carbon dioxide asphyxiation, and a blinded researcher performed a gross examination to evaluate the animals for any gross abnormalities.
Surgery.
Anesthesia was induced using 5% isoflurane in 100% oxygen (1-2 L/min) delivered via an induction chamber. Once a surgical plane of anesthesia was achieved, rats were positioned in sternal recumbency on a warm water-circulating blanket set at 38 °C. Anesthesia was maintained using 2%-3% isoflurane with 100% oxygen via a nose cone. The left hind paw was positioned with the dorsal surface down, and the plantar surface was aseptically prepared. Cefazolin (20 mg/kg, SC) was administered preoperatively to prevent infection. A hind paw pinch confirmed the absence of withdrawal, ensuring sufficient anesthesia. After confirming stable breathing and pink mucous membranes, a 1-cm incision was made along the plantar surface of the left hind paw, starting 0.5 cm from the tibiotarsus and extending distally, using a no. 15 scalpel blade. The underlying plantaris muscle was carefully elevated with bent forceps and longitudinally transected. Saline was applied to the surgical site, and sterile gauze was used to achieve hemostasis. The incision was then closed with 2 interrupted horizontal mattress sutures using 5-0 polyglactin 910 (Ethicon, Raritan, NJ). Postoperatively, rats were monitored in a warm recovery cage lined with a paper towel and returned to their home cage after full recovery.
Behavioral testing.
Mechanical and thermal hypersensitivity testing was performed on both the ipsilateral (left) paw and contralateral (right) paw at −24 hours before surgery to collect baseline data, as well as at 4, 24, 48, and 72 hours postsurgery.
Mechanical hypersensitivity testing: von Frey test.
Each rat was placed individually in a transparent plastic chamber (23 × 13 × 13 cm) and given 15 minutes of acclimation time immediately before each day’s testing on an elevated mesh platform. No additional acclimation sessions were conducted on the days before testing. The right hind paw (contralateral) served as a control for the left hind paw (ipsilateral) of each rat. Calibrated 6.0-g Semmes-Weinstein von Frey filaments were applied 10 times to the plantar surface of both the ipsilateral (surgical site) and contralateral (control) hind paws, avoiding the heel and toes. The 6-g filament was selected based on results from pilot testing. The 6-g filaments produced a baseline withdrawal rate of 20%-30%, whereas 8- and 10-g filaments exceeded 30%, making it harder to distinguish pain-induced changes on subsequent testing days. Each filament was applied for 1-2 seconds with an interstimulus interval of approximately 5 seconds until a withdrawal response occurred. Mechanical hypersensitivity was defined as an increase in the frequency of paw withdrawal responses. The chamber was sanitized with 1% Virkon-S (Lanxess USA, Pittsburgh, PA) followed by 70% ethanol between testing sessions.
Thermal hypersensitivity testing: Hargreaves test.
Rats were individually placed in a transparent plastic chamber (23 × 13 × 13 cm) and allowed 15 minutes to acclimate immediately before each day’s testing on an elevated glass platform maintained at an average temperature of 30 °C. No additional acclimation sessions were conducted on the preceding days. Thermal stimuli were generated by a radiant heat source from a 50-W light bulb focused on the central plantar surface of each hind paw. To prevent tissue damage, exposure time did not exceed 20 seconds. Each hind paw was tested 4 times, with at least 4 minutes between trials. Withdrawal latency was determined by averaging the results of the last 3 trials. Thermal hypersensitivity was defined as a significant reduction in paw withdrawal latency following the application of thermal stimuli.
Clinical observations and gross pathology.
Body weight was measured daily at −24, 0, 24, 48, and 72 hours postsurgery, and rats were monitored for any abnormal behaviors, such as sedation, hyperactivity, greasy fur, pica, or skin reactions throughout the experiment. At 72 hours postoperatively, the study concluded with euthanizing the rats using CO2 inhalation, followed by gross necropsies performed by researchers blinded to the treatments administered.
Results
Body weight.
The starting body weights of rats in this study were 246.33 ± 76.1 g. Body weights in all groups were not significantly different throughout the study as compared with their −24 hour values.
Mechanical hypersensitivity.
Sex did not significantly affect mechanical hypersensitivity outcomes (P = 0.339), so data are presented combined for males and females. Responses to mechanical stimuli in ipsilateral (left) hind paws (Figure 2) showed no significant differences across all treatment groups before treatment (−24 hour). In the saline group, mechanical hypersensitivity was significantly increased at 4 hours (8.25 ± 0.73), 24 hours (6.88 ± 0.69), and 48 hours (5.38 ± 1.24) compared with baseline (−24 hours) (1.88 ± 0.58), with P values of less than 0.001, 0.001, and 0.04, respectively. Both Melox (P value is 0.257) and Melox-XR (P value is 0.102) groups attenuated mechanical hypersensitivity at 48 hours postoperatively compared with the baseline. The Melox group had a significantly decreased number of paw withdrawals compared with the saline group at 4 and 24 hours postoperatively (P values are 0.048 and 0.038, respectively). Melox-ER did not attenuate mechanical hypersensitivity at any time point (all P > 0.05). For the intact hind paw (control), contralateral mechanical hypersensitivity was not statistically different from the baseline (−24 hours) in saline or meloxicam treatment groups at any time point throughout the study, and no formal statistical analysis was performed.
Citation: Journal of the American Association for Laboratory Animal Science 2025; 10.30802/AALAS-JAALAS-25-119
Thermal hypersensitivity.
Sex did not significantly affect thermal hypersensitivity outcomes (P = 0.440), so data are presented combined for males and females. Thermal latencies in ipsilateral (left) hind paws (Figure 3) were not significantly different among treatment groups at −24 hours. In the saline group and all meloxicam drug treatment groups, thermal latencies were significantly lower at 4, 24, 48, and 72 hours with P values of less than 0.001 as compared with baseline values (−24 hour). When comparing thermal hypersensitivity to the saline group, Melox and Melox-XR groups did not significantly differ in their thermal latency at any time point (all P > 0.05). In contrast, Melox-ER significantly increased the thermal latency compared with the saline group at the 72-hour time point (P = 0.049). For the intact hind paw, contralateral thermal hypersensitivity was not statistically different from the baseline (−24 hour) in saline or meloxicam treatment groups at any time point throughout the study, and no formal statistical analysis was performed.
Citation: Journal of the American Association for Laboratory Animal Science 2025; 10.30802/AALAS-JAALAS-25-119
Clinical observations and gross pathology.
No abnormal behaviors were noted in any rats throughout the study period. Injection site reactions were noted in all meloxicam formulation groups upon gross pathologic evaluation. The injection site reactions were characterized by a marked increase in skin adherence to the underlying muscle (as compared with the saline group) and various sized subcutaneous injection site nodules (left shoulder) of rats given Melox-ER (37.5%; 3 of 9 rats; approximately 3-cm nodule), Melox-XR (37.5%; 3 of 8 rats; approximately 3-cm nodule), and Melox (12.5%; 1 of 8 rats; approximately 1.5 cm nodule). The nodules contained a demarcated oily substance that leaked out after the nodule was incised. These nodules may have been a source of discomfort that was not detected during our behavioral evaluation. No intervention for the nodules was required, and the nodules appeared to be self-limiting. No other gross pathologic abnormalities were noted.
Discussion
This study evaluated mechanical and thermal hypersensitivity in rats subjected to a paw incision model, using different meloxicam formulations to assess their postoperative pain management efficacy. The results show that the Melox and Melox-XR groups attenuated postoperative mechanical hypersensitivity only at the 48-hour time point, and that Melox-ER failed to attenuate mechanical hypersensitivity at all time points. None of the meloxicam formulations provided attenuation of thermal hypersensitivity. Melox-ER significantly increased the thermal latency responses compared with the saline group at the 72-hour time point. We recommend further evaluation of meloxicam dosing for incisional pain in rats.
Our laboratory has widely used the paw incisional model24 to evaluate analgesic effectiveness for managing mild to moderate postoperative hypersensitivity.25–29 By making an incision on the rat’s left (ipsilateral) hind paw plantar area coupled with manipulating and incising the plantaris, the model consistently induces mild to moderate pain, which can be assessed using mechanical and thermal hypersensitivity tests. In this study, mechanical hypersensitivity in the saline group lasted for 48 hours, while thermal hypersensitivity persisted over the entire 72-hour study period. Since the study concluded at 72 hours, thermal hypersensitivity may have persisted beyond this time point. These values are consistent with our previous research showing that the saline group’s mechanical hypersensitivity usually lasts 24-96 hours,24–26,28,30 and thermal hypersensitivity generally persists for 72-96 hours.25,26,28,30
Meloxicam is a widely used NSAID with potent analgesic and anti-inflammatory properties, primarily through selective inhibition of the COX-2 enzyme involved in prostaglandin synthesis.13,31 While meloxicam effectively manages pain and inflammation, its use in rats is associated with dose-dependent toxic effects, including gastrointestinal lesions,20,32,33 nephrotoxicity,34–36 and hepatotoxicity.34,37,38 These toxic effects are often accompanied by hematologic changes such as reduced hemoglobin and erythrocyte counts, leukocytosis, and elevated liver enzymes, as well as biochemical evidence of renal and hepatic impairment.37,38 Studies have also highlighted a potential antioxidant role to reduce oxidative stress and organ damage caused by meloxicam.34 Prolonged meloxicam administration or administration of higher dosages exacerbates these adverse outcomes,39 thus emphasizing the importance of careful dosing and patient monitoring to mitigate toxicity. Melox-ER and Melox-XR are innovative formulations designed to enhance meloxicam’s therapeutic profile by extending its duration of action and reducing dosing frequency.12,40–42 The polymer-based Melox-ER system can gradually release the active drug over time, maintaining consistent therapeutic levels while minimizing peaks and troughs.7 Similarly, the Melox-XR suspension-based delivery system achieves prolonged drug release, providing sustained analgesic and anti-inflammatory effects.41,43–45 These extended-release formulations aim to address the standard meloxicam’s limitations, such as the need for daily administration,18 minimizing handling stress, and reducing fluctuating plasma concentrations.20,46,47
Despite their potential benefits, research on Melox-ER and Melox-XR remains limited to rodents. A previous study11 from our group evaluated Melox-ER (4 mg/kg, SC) in male Sprague-Dawley rats also using the incisional pain model and found that Melox-ER attenuated mechanical, but not thermal, hypersensitivity. In this current study, only Melox and Melox-XR attenuated mechanical hypersensitivity at the 48-hour time point, and Melox-ER increased thermal latency response as compared with saline at 72 hours. Although Melox-ER showed an increase in thermal latency as compared with saline at 72 hours, this was not observed at earlier time points, closer to surgery, This suggests that the dosages of Melox-ER were not sufficient to attenuate thermal hypersensitivity for this model, particularly during the immediate postoperative period. There are several possible explanations for the difference seen in mechanical and thermal hypersensitivity attenuation between the 2 studies. This current study used a different rat strain (Sprague-Dawley compared with Long-Evans), a younger age of test subject, and both sexes. All of these factors potentially affected the analgesic efficacy and the model evaluation.
Although this study provided insight in comparing 2 new extended-release meloxicam formulations with the standard meloxicam formulation in a rat incisional pain model, several limitations are worth mentioning. First, there are few studies assessing optimal meloxicam dosing in rats toward establishing better safety and efficacy profiles. Higher dosages of the meloxicam formulations may provide improved mechanical and thermal hypersensitivity attenuation for this model. Previous research using mice indicated that higher NSAID doses are required to attenuate mechanical and thermal hypersensitivity. A higher meloxicam dose (10 mg/kg) resulted in better analgesic effect compared to a lower dosage (2.5 mg/kg).48 Second, the study only evaluated a select number of time points, thus potentially limiting our understanding of the duration of action for the meloxicam formulations. The time points selected may not have adequately captured the peak plasma concentration, which would have been during the first 12 hours following administration.49 Third, only the paw incisional model was employed and may not adequately reflect other forms of postoperative pain. It should be noted that NSAIDs are more effective at controlling sustained inflammatory pain, a feature that may limit their apparent efficacy in this acute model.50 Therefore, other models and assessment methods may help to more completely define meloxicam efficacy. Fourth, only one strain of rat was used, whereas different rat strains may demonstrate differences in efficacy. Similarly, only a single dose of each meloxicam formulation was administered, thereby not allowing a dose-response analysis. Thus, caution should be exercised when generalizing these findings to different rodent strains. Finally, mechanical and thermal assays primarily assess evoked pain and do not capture spontaneous or ongoing discomfort, which can be clinically relevant. Hypersensitivity testing was selected because our laboratory has extensive experience with this testing method, ensuring consistency and reliability in measurement. Humane monitoring and observations were conducted throughout the study, with defined criteria to euthanize any animal exhibiting pain or distress beyond the average expectation for this model. While no animals met these criteria, and overt behavioral signs of discomfort were not observed, subtle local discomfort associated with the subcutaneous nodules found upon necropsy cannot be fully ruled out. The local skin reactions, although self-limiting, represent a potential welfare consideration and may have influenced hypersensitivity measurements. Also, behavioral structured activity monitoring like the grimace scale was not performed could possibly have limited the assessment of spontaneous pain. Future studies using different animal models, dosing regimens, and multimodal analgesic approaches are necessary to further clarify the translational value of these findings.
In conclusion, Melox at 2 mg/kg and Melox-XR at 4 mg/kg attenuated mechanical hypersensitivity only at the 48-hour postoperative time point, and Melox at 2 mg/kg reduced mechanical hypersensitivity as compared with saline at 4 and 24 hours. Similarly, Melox at 2 mg/kg and Melox-XR groups failed to attenuate thermal hypersensitivity from 4 to 72 hours postoperatively, while Melox-ER at 4 mg/kg significantly attenuated thermal hypersensitivity only at the 72-hour time point. Future studies should investigate a wider range of dosages for different meloxicam formulations, including extended-release formulations, and the use of extended time points and additional pain models to provide a more complete understanding of meloxicam’s therapeutic potential and limitations. These results indicate that the incisional pain model, higher dosages of meloxicam formulations, and multimodal analgesia may be necessary to ameliorate both mechanical and thermal hypersensitivity.
Experiment Timeline.
Mechanical Hypersensitivity of the Ipsilateral (Left) Hind Paw. Mechanical hypersensitivity was assessed by measuring the number of paw withdrawals (in incidents; mean ± SEM) of the ipsilateral (left) hind paw to a mechanical stimulus. The x-axis represents time, while the y-axis represents number of paw withdrawals. A lower the number of paw withdrawals indicates lower hypersensitivity. The arrow marks surgery at 0-h time point. *Value that is significantly different (P < 0.05) compared with baseline (−24 h) value of the same treatment group. #Value that is significantly different (P < 0.05) when compared with the saline group.
Thermal Hypersensitivity of the Ipsilateral (Left) Hind Paw. Thermal hypersensitivity was assessed by measuring the thermal latency (in seconds; mean ± SEM) of the ipsilateral hind paw to a thermal stimulus. The x-axis represents time, while the y-axis represents the number of paw withdrawals. A shorter thermal latency indicates higher hypersensitivity. The arrow marks surgery at 0-h time point. *Value that is significantly different (P < 0.05) compared with baseline (−24 h) value of the same treatment group. #Value that is significantly different (P < 0.05) when compared with saline group.
Contributor Notes