Randomized controlled trial comparison of analgesic drugs for control of pain associated with induced lameness in lactating dairy cattle

摘要

Both the economic loss and welfare implications oflameness affect the dairy industry. Currently no analgesicdrugs are approved to alleviate lameness-associatedpain in lactating dairy cattle in the United States. Inthis randomized controlled trial, 48 lactating Holsteinswere enrolled to evaluate the effect of oral meloxicamand i.v. flunixin meglumine on induced lameness. Cowswere allocated to 1 of 4 treatment groups (n = 12per group): lameness and flunixin meglumine (LAME+ FLU); lameness and meloxicam (LAME + MEL);lameness and placebo (LAME + PLBO); or shaminduction and placebo (SHAM + PLBO). Six hoursbefore treatment, arthritis-synovitis was induced in thedistal interphalangeal joint with 20 mg of amphotericinB, whereas SHAM cows were given an intra-articularinjection of an equal volume (4 mL) of isotonic saline.Cows in LAME + FLU received 2.2 mg/kg flunixinmeglumine i.v. and whey protein placebo orally; LAME+ MEL were administered 1 mg/kg meloxicam orallyand 2 mL/45 kg sterile saline placebo i.v.; LAME +PLBO were administered 2 mL/45 kg sterile salineplacebo i.v. and whey protein placebo orally; andSHAM + PLBO received 2 mL/45 kg sterile salineplacebo i.v. and whey protein placebo orally. The initialtreatment of MEL, FLU, or PLBO was identifiedas time 0 h and followed by a second dose 24 h laterwith data collection for 120 h. The methods used toassess analgesic efficacy were electronic pressure mat,visual lameness assessment, visual analog score, plasmacortisol concentration, plasma substance P concentration,mechanical nociception threshold, and infraredthermography imaging. Linear mixed effect modelingwas the primary method of statistical analysis. Visuallameness scoring indicated a lower proportion of theFLU + LAME group was lame at the T2 h and T8h time points in comparison to the positive controls,whereas MEL therapy resulted in a lower proportionof lame cows at the T8 h time point. Cortisol areaunder the effect curve was lower following FLU therapycompared with LAME + PBLO for the 0–2 h (LSMdifference = 35.1 ng·h/mL, 95% CI: 6.8, 63.3 ng·h/mL), 2–8 h (LSM difference = 120.6 ng·h/mL, 95% CI:77.2, 164.0 ng·h/mL), and 0–24 h (LSM difference =226.0 ng·h/mL, 95% CI: 103.3, 348.8 ng·h/mL) timeintervals. Following MEL therapy, cortisol area underthe effect curve was lower than LAME + PLBO forboth the 2 to 8 h (LSM difference = 93.6 ng·h/mL, 95%CI: 50.2, 137.0 ng·h/mL) and 0 to 24 h time intervals(LSM difference = 187.6 ng·h/mL, 95% CI: 64.9, 310.4ng·h/mL). Analysis of data from other assessmentmodalities failed to discern biologically relevant differencesbetween treatment groups. We conclude thatmeaningful differences were evident for visual lamenessassessment and cortisol from MEL and FLU treatmentversus the positive control. Further clinical research isneeded toward development of a model that will createreproducible events that are more pronounced in severityand duration of lameness which can be validated asa substitute for naturally occurring lameness cases.