Flunixin meglumine: An efficient and cost-effective drug

Flunixin meglumine is a potent, non-narcotic, nonsteroidal, analgesic agent with anti-inflammatory and antipyretic activity. It is significantly more potent than pentazocine, meperidine, and codeine as an analgesic in the rat yeast paw test.

Synthesis of Flunixin meglumine

Reacting the flunixin obtained in the step (1) with N-methylglucamine in isopropanol, the molar ratio of flunixin to N-methylglucamine is 2:1; fluorine Nisin has a mass ratio to isopropanol of 1:11; and simultaneously added maltodextrin; the molar ratio of the maltodextrin to 2-methyl-3-trifluoromethylaniline is 1:2.5; heating Reflux, filtration, cooling, stirring and crystallization, stirring is continued until the temperature of the system drops below 25 ° C, and the crystals are filtered with suction to obtain flunixin meglumine.[1]

Flunixin Meglumine for Providing Analgesia

Farm animals are exposed to various painful procedures during their productive lives, making it necessary to implement anesthetic and analgesic protocols. However, there are few studies evaluating the effectiveness of these drugs in domestic species. We evaluated the effects of meloxicam and flunixin meglumine in pain sensitivity of goat kids subjected to surgical castration with local anesthesia. The von Frey monofilament test was used to evaluate pain sensitivity in three body regions: four points of the scrotum (dorsal and ventral; left and right lateral); medial region of the pelvic limb, gracilis muscle; and hypogastric region of the abdomen. Reactions were recorded before castration, immediately after castration, and once-daily for three consecutive days after castration. Meloxicam-treated goats experience increased pain sensitivity in the scrotal region and gracilis, particularly at 1 day after castration. However, flunixin meglumine resulted in lower pain reactions, indicating more effective pain relief.[2]

Additionally, in goat kids given local lidocaine anesthesia and dehorned, those also given flunixin meglumine spent more time in activity behaviors (e.g., exploring, playing, and feeding) than a saline-treated control. It was recently reported that goats receiving transdermal flunixin after surgical castration might have pain mitigated, but authors suggested that a single dose may not be sufficient to reduce the physiological indicators of pain. Therefore, both NSAIDs (meloxicam and flunixin meglumine) efficiently controlled pain in goat kids. However, to our knowledge, a contemporaneous comparison of these two products for pain control after castration of goat kids has not been reported. Goats that received flunixin meglumine did not have increased postoperative pain sensitivity, whereas those that received meloxicam exhibited pain soon after the surgery, presenting higher sensitivity than the flunixin meglumine-treated goats until 72 h post-surgery. This was partially in agreement with Shukla et al., who reported that plasma meloxicam concentrations in goats were low at 48 h after intravenous application, and not detectable at 72 h after drug administration. Conversely, flunixin meglumine was detected in plasma samples after transdermal administration in goats up to 96 h after administration

The efficacy of flunixin meglumine plus lidocaine for pain relief in goat kids partially corroborated previous results. Park et al. compared not castrated and castrated Korean cattle bull calves, receiving or not receiving lidocaine combined with flunixin meglumine, to determine the effects of this combination on various indicators of pain and inflammation. In that study, the combination of both drugs did not reduce elevated pain but tended to decrease elevated inflammation in castrated animals, suggesting that additional treatment may be required to alleviate pain. Similarly, Webster et al. reported a positive effect of a combination of lidocaine and flunixin meglumine on post-castration performance, plasma cortisol concentrations, and behavior of dairy calves, with attenuation of signs of pain and stress. However, we are not aware of published studies comparing the effects of meloxicam and flunixin meglumine as pain relief for goat kids.

Pharmacokinetics and pharmacodynamics of flunixin meglumine

Selection of drugs for use in South American Camelids (SAC, llamas and alpacas) is challenging. There are no approved products for use in SAC in the United States (US). Veterinarians select and administer drugs based off limited published data or extrapolate from other species. Intravenous (IV) drugs are particularly difficult to administer due to limited venous access and unique anatomic features of the SAC cervical region. Furthermore, jugular venipuncture can be stressful for an unshorn poorly restrained alpaca. Pharmaceuticals that can be administered by routes other than IV are attractive for use in SAC practice. There are several drugs that can be administered via the transdermal route including fentanyl and more recently flunixin meglumine. A recent study evaluating the pharmacokinetics of transdermal (TD) fentanyl in alpacas found absorption of the drug to be variable. To date, there have been no studies evaluating flunixin meglumine in alpacas. The pharmacokinetics of flunixin meglumine has been evaluated in llamas. Flunixin meglumine administered at 2.2 mg/kg IV to llamas resulted in a short half-life, low volume of distribution and prolonged clearance compared to other large animal species.[3]

Flunixin meglumine, a nonsteroidal anti-inflammatory drug (NSAID), is used for its antipyretic, analgesic and anti-inflammatory properties. Common side effects of flunixin meglumine administered in other species include gastrointestinal ulceration and renal papillary necrosis . A new TD formulation of flunixin meglumine has been developed for use in cattle and has recently been released for use in the US. Recent studies have evaluated TD flunixin meglumine in Holstein calves and goats (Kleinhenz et al., 2016; Reppert et al., 2019). In Holstein calves, TD flunixin meglumine was rapidly absorbed and had a longer half-life than IV administration of the drug (Kleinhenz et al., 2016). However, in goats, TD flunixin meglumine had prolonged absorption and lower bioavailability compared to cattle (Reppert et al., 2019). The new TD formulation of flunixin meglumine would provide a less stressful means to administer an anti-inflammatory in a species that can be difficult to restrain and treat. The purpose of this study was to determine the pharmacokinetic and pharmacodynamic properties of IV and TD flunixin meglumine in alpacas.

Prostaglandin E2 inhibition has been used as a measure to determine efficacy of flunixin meglumine in several species. In this study, PGE2 inhibition was quantified for both IV and TD flunixin meglumine formulations. Intravenous flunixin meglumine resulted in 100% suppression of PGE2. The level of suppression suggested IV flunixin meglumine (administered at 2.2 mg/kg) might be clinically effective in alpacas. Further studies in sick alpacas are needed to support this hypothesis. Transdermal flunixin meglumine did not result in measurable suppression of PGE2 at any time point in any of the alpacas. The observed Cmax did not meet the calculated IC80, which is the target concentration suggested for clinical effects (Warner et al., 1999). Such findings indicate that TD flunixin meglumine used in this study would not be clinically effective in healthy alpacas. These findings are not surprising given the limited amount of TD exposures of flunixin meglumine and 5-OH-FLU as reflected by the very low mean AUCs of 6.315 µg/ml × hr and 0.262 µg/ml × hr, respectively, in alpacas.

In summary, IV and TD flunixin meglumine administered to healthy adult alpacas did not result in any adverse effects. The pharmacokinetics of IV flunixin (2.2 mg/kg) was characterized by rapid clearance, short elimination half-life, and large volume of distribution and produced 100% PGE2 suppression. The pharmacokinetic properties of TD flunixin were slow absorption, poor distribution and long elimination half-life, and rapid clearance from the plasma. Poor bioavailability and inability to suppress PGE2 indicates that TD flunixin administered at 3.3 mg/kg is not recommended for use in alpacas.

References

[1] INSTITUTE OF SUBTROPICAL AGRICULTURE CAS - CN109206365, 2019, A

[2] Brusin V, Ceballos MC, Trindade PHE, Rocha Góis KC, Conde G, Tessarine Barbosa V, Rosa GDS, Paranhos da Costa MJR. Flunixin Meglumine Is Superior to Meloxicam for Providing Analgesia after Surgical Castration in 2-Month-Old Goats. Animals (Basel). 2022 Dec 6;12(23):3437.

[3] Reppert EJ, Kleinhenz MD, Montgomery SR, Heiman J, Sura A, Bornheim HN, Magnin G, Sidhu PK, Zhang Y, Joo H, Coetzee JF. Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in alpacas. J Vet Pharmacol Ther. 2019 Sep;42(5):572-579.

You may like