19/3/218 MDVMA 3.3.18 Pain and Inflammation Management After Parturition in Dairy Cattle Adrian A. Barragan, DVM, MS, PhD Department of Veterinary and Biomedical Science Penn State University Outline Stress and Inflammation Around Parturition Effects of Stress and Inflammation on Cow Health and Performance Pain in Cattle Overview Pain and Inflammation Management Alternatives Final Notes 1
µg/ml ng/ml 19/3/218 Inflammation During the Post-Partum Leblanc et al., 214 Stress and Inflammation at Parturition Comline et al., 1974; adapted from Uchida et al., 1993 35 3 25 2 15 Effects of Stress and Inflammation on Cow Health and Performance Haptoglobin Healthy >1 Case of Disease P Value <.5 1 5 5 12 12 24 24 36 36 48 48 6 6 72 72 84 84 96 96 18 12 132 144 156 168 18 5 Hour relative to calving 4 3 Cortisol Healthy >1 Case of Disease 2 1 12 24 36 48 6 72 84 96 181213214415616818 Hour relative to calving Barragan et al., 218 (In preparation) 2
19/3/218 Effects of Stress and Inflammation on Cow Health and Performance Goff and Horst, 1997; Huzzey et al., 29 Negative energy Balance (NEB) Metabolic Stress Around Calving Adapted from Grummer, 1993 Metabolic Stress Around Calving DMI Direct activation of inflammatory cells (toll-like receptors) Fat tissue mobilization (NEFA) Insulin resistance Pro-inflammatory molecules Immune system functions Risk of metabolic and infectious diseases Leblanc et al., 214 3
19/3/218 Metabolic Stress Around Calving NEFA (>.5) Pre-partum: 3.6x DA BHBA (>12) Post-partum: 8x DA LeBlanc et al., 25 Pain International Association for the Study of Pain (I) An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (I, 211) The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment (I, 211) (http://www.iasp-pain.org/education/content.aspx?itemnumber=1698) Cattle used to be prey animals that lived in large groups, and evolved to express subtle pain-related behavior (Johnson, 216) Pain Around Parturition Several behaviors associated with pain and discomfort have been reported in dairy cows around parturition: o Decreased feeding and drinking frequency (Miedema et al., 211; Jensen, 212) o Looking back at the flank region (Berglund et al., 1987) o Restless behavior (Miedema et al., 211; Schuenemann et al., 211) 4
Adapted from synapse. Dictionary.com 19/3/218 Pain in Dystocic Births Adult Cattle Calves Median Range First Quartile Third Quartile Mode Claw amputation 1 2-1 9 1 1 Dystocia 7 2-1 5 8 8 Metritis 4 1-1 3 6 3 LDA 3 1-1 2 5 3 Castration (Burdizzo) 7 2-1 5 8 8 Disbudding 7 2-1 6 9 8 Pneumonia 6 1-1 4 7 5 Umbilical abscess 5 1-1 4 6 4 Adapted from Huxley and Whay, 215 Pain in Dystocic Births Median Range First Quartile Third Quartile Mode Adult Cattle Claw amputation 1 2-1 9 1 1 Dystocia 7 2-1 5 8 8 Metritis 4 1-1 3 6 3 LDA 3 1-1 2 5 3 Calves Castration (Burdizzo) 7 2-1 5 8 8 Only 34 % of veterinarians provide analgesia following dystocia (Hewson et al., 27) Disbudding 7 2-1 6 9 8 Pneumonia 6 1-1 4 7 5 Umbilical abscess 5 1-1 4 6 4 Adapted from Huxley and Whay, 215 Substance P Projection Dorsal horn (Spinal Cord) Substance P release Pain transmission Pain modulation Transmission Adapted from Anderson et al., 25 5
ng/ml Adapted from synapse. Dictionary.com 19/3/218 Substance P Projection Substance P release Pain transmission Pain modulation Dorsal horn (Spinal Cord) Substance P is a neuropeptide produced by neurons in the dorsal horn of the spinal cord that is involved in the transmission and modulation of pain (DeVane, 21) Transmission Adapted from Anderson et al., 25 Substance P After Calving 1 9 8 7 6 5 4 3 2 1 DYS n = 76 EUT n = 76 DYS EUT 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hours relative to calving P <.5 Barragan et al., 217 Pain Treatment in Cattle Currently there are no drugs approved for the treatment of pain in cattle Available drugs can be used in extralabel (ELDU) manner under AMDUCA regulations o Different species o Different diseases or conditions o Different dose, frequency and route of administration Some drugs are prohibited or have specific restrictions CFR, 218; FARAD, 218 6
19/3/218 ELDU Conditions Active veterinarian-client-patient relationship (VCPR) Provide proper rationale for the lack of efficacy/existence of approved drugs and the need of using a drug in ELDU manner Ensure and maintain identification of treated animals Determine and ensure proper withdrawal time (WDT) If not possible, ensure that the animal does not enter into the human food supply CFR, 218; FARAD, 218 Pain Treatment After Calving The drugs that have been proposed to treat pain and inflammation after parturition are non-steroid anti-inflammatory drugs (NSAIDs) Carprofen Flunixin meglumine (FM) Meloxicam Aspirin Carprofen FDA approved for the treatment of pain associated with osteoarthritis in dogs Can be used in ELDU manner WDT (single dose) = 21 d meat, d milk Provide justification for the lack of effectiveness of the approved drug in cattle (FM) Smith et al., 28; FDA, 218 7
19/3/218 Carprofen after Calving Study Description A total of 639 cows (PRIM = 134; MULT = 55) Control (n = 221): No treatment Early (n = 214): Carprofen on d 1, 3 and 5 after calving Late (n = 24): Carprofen treatment on d 19, 21 and 23 after calving Measures: Performance: Milk yield, health events and reproduction Meier et al., 214 Carprofen After Calving Meier et al., 214 Carprofen After Calving No differences in milk production, health and reproduction parameters Meier et al., 214 8
19/3/218 Flunixin Meglumine (FM) Commonly used in dairy cattle FDA approved in dairy cattle o Fever associated with bovine respiratory diseases o Inflammation associated with endotoxemia WDT = 4 d meat, 36 h milk Can be used in ELDU manner (strictly IV) Smith et al., 28; FDA, 218 First FDA Approved Pain Killer First FDA approved pain killer for use in food producing animals Topical transdermal FM solution Not allowed for use in: o Beef bulls intended for breeding o Dairy bulls o Female dairy cattle 2 months of age or older o Suckling beef calves, dairy calves, and veal calves. FDA, 218 Flunixin Meglumine After Calving Study Description Study 1: Pre-calving (TRT = 34; = 38) TRT: Two IV administrations of FM when moved to calving pen and 18 to 36 h later : Sterile saline Study 2: Post-calving (TRT = 633; = 632) TRT: Two IV administrations of FM immediately after calving and 24 h later : Sterile saline Measures: Performance: Milk production and health events Newby et al., 217 9
19/3/218 Flunixin Meglumine After Calving Risk for stillbirth (Pre-calving study) Odds of having: o Retained placenta o High temperature o Metritis Milk production Newby et al., 217 Meloxicam FDA approved for the treatment of pain associated with osteoarthritis in dogs Can be used in ELDU manner WDT (single dose) = 15 d meat, 5 d milk Provide justification for the lack of effectiveness of the approved drug in cattle (FM) Effective in treating pain associated with dehorning and castration Smith et al., 28; Coetzee et al., 213; Stock et al., 213 Meloxicam After Calving Study Description A total of 13 dairy cows that experienced dystocia (1 = Mild; and 2 = Severe) o C-section and fetotomy excluded TRT (n = 51): One dose (SC) of meloxicam (.5 mg/kg of body weight) 24 h after calving Placebo (n = 52): One dose (SC) of medication vehicle solution 24 h after calving Measures: Metabolic status: Blood metabolites (e.g.,nefa, BHB, haptoglobin) Performance: Dry matter intake, milk production Newby et al., 213 1
19/3/218 Meloxicam After Calving No differences in dry matter intake, milk production, blood metabolites (NEFA, BHB, Haptoglobin) or health events Newby et al., 213 Acetylsalicylic Acid (Aspirin) Not an FDA approved drug Cannot be used in ELDU manner Attractive option o Easy administration o Short milk and meat WDT (24 h) o Low cost Smith et al., 28 Aspirin After Calving Study Description A total of 78 cows (PRIM =39; MULT = 39) TRT: Aspirin (1.95 g/l) in drinking water with molasses (221 mg/l) during the first 7 days after parturition CONT: Water with molasses during the first 7 days after parturition Measures: Metabolic status: Blood metabolites (e.g.,nefa, BHB) Performance: Milk and milk component production Farney et al., 213 11
19/3/218 Aspirin After Calving Farney et al., 213 Aspirin After Calving Study Description A total of 22 cows (all MULT cows) LAS: Injectable aspirin (1.95 g/l) during the first 5 days after parturition (15 g/d the first 3 d; 7.5 g/d the last 2 d) CONT: Untreated Measures: Metabolic status: Blood metabolites (e.g.,nefa) and BCS Performance: Milk, incidence of diseases and reproductive Bertoni et al., 24 Aspirin After Calving Results: More prolonged and marked BCS reduction Metritis incidence Pregnancy rate after 1 st AI Service per conception Bertoni et al., 24 12
19/3/218 Aspirin After Calving Study Description A total of 153 cows (all MULT cows) within 12 h to 36 h after calving SAL: One placebo bolus on day 1 and a drench with aspirin (125 g/d aspirin, 375 ml f water) for 3 days MEL: One bolus with meloxicam (675 mg/d) on day 1 and a drench with water (375 ml) for 3 days CONT: One placebo bolus on day 1 and a drench with water (375 ml) for 3 days Measures: Metabolic status: Blood metabolites (e.g.,nefa, BHB, Haptoglobin) and BCS Performance: Milk, incidence of diseases and reproduction Carpenter et al., 216 Aspirin After Calving Results: Milk protein No difference in [BHB], BCS, or reproductive performance Carpenter et al., 216 Aspirin After Calving: New Strategy Shorter treatment period (2 d) o Simple o Less labor involved Individual treatment (oral boluses) o Accurate dose administration May fit in better with the logistic of large modern dairy operations (TRT every 12 h) 13
ng/ml 19/3/218 Aspirin After Calving: New Strategy Study Description A total of 563 organic dairy cows within 12 h after calving (n=278): 4 consecutive oral treatments with acetylsalicylic acid (aspirin; 1 mg/kg) every 12 h (n=285): 4 consecutive oral treatments with gelatin capsules filled with water every 12 h Measures: Pain, inflammation, stress and metabolic status Performance: Milk and milk components, incidence of diseases, mortality and culling rate Barragan et al., 217 New Strategy: Study Design Treatment groups = 2 boluses of aspirin (1 mg/kg) every 12 h P.O. = 2 gelatin capsules every 12 h P.O. Calving n = 278 ~ 12 h 24 h 36 h 48 h n = 285 Daily Milk Yields 7 DIM Blood samples: SP HP Cortisol 3 DIM 6 DIM ~15 DIM Health events First 5 DHIA Tests Milk yield Somatic cell count Milk fat and protein 8 7 6 5 4 3 2 Substance P Concentrations P <.5 1 n = 76 n = 76 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hour relative to calving 14
ng/ml µg/ml ng/ml ng/ml µg/ml 19/3/218 Haptoglobin Concentrations P >.5 <.1 P <.5 25 2 15 1 5 n = 76 n = 76 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hour relative to calving Cortisol Concentrations P <.5 6 5 4 3 2 1 n = 76 n = 76 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hour relative to calving Biomarkers in Cows with Dystocia 6 CORTISOL 25 HAPTOGLOBIN P <.5 5 4 3 2 2 15 1 1 5 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hour relative to calving 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hours relative to calving 1 9 8 7 6 5 4 3 2 1 SUBSTANCE P 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hours relative to calving DYS n = 76 EUT n = 76 15
ng/ml ng/ml ng/ml ng/ml µg/ml μg/ml μg/ml 19/3/218 Biomarkers in Cows with Dystocia 6 5 4 3 CORTISOL 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hour relative to calving 1 9 8 7 6 5 4 3 2 1 25 2 15 1 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hours relative to calving HAPTOGLOBIN P <.5 2 Overall, cows that experienced dystocia had 1 5 haptoglobin concentrations compared to eutocic cows 12 24 36 48 6 72 84 96 18 12 132 144 156 168 18 Hours relative to calving Cows with dystocia had substance P concentrations at 168 h (7 d) after parturition SUBSTANCE compared P to eutocic cows DYS n = 76 EUT n = 76 Biomarkers by Parity 7 6 5 4 3 2 1 5 1 15 2 HP-PRIM SP-PRIM HP-MULT SP-MULT P.5 -.1 P <.5 35 3 25 2 15 1 5 PRIM n = 47 MULT n = 15 Biomarkers by Parity 7 35 Overall, primiparous cows (PRIM) had substance P and 6 3 haptoglobin concentrations compared to multiparous cows (MULT) 5 CORTISOL 25 4 2 3 2 1 5 1 15 2 HP-PRIM SP-PRIM HP-MULT SP-MULT P.5 -.1 P <.5 15 1 5 PRIM n = 47 MULT n = 15 16
Milk yield (kg/d) kg/d kg/d 19/3/218 Daily Milk Yield in Cows Treated with Aspirin 4 35 3 25 2 15 1 5 n = 114 n = 129 3 6 9 12 15 18 21 24 27 3 Day relative to calving P >.5 <.1 P <.5 Daily Milk Yield in Cows Treated with Aspirin 4 35 3 25 2 15 1 5 n = 114 n = 129 3 6 9 12 15 18 21 24 27 3 Day relative to calving Overall, cows that received produced P >.5 <.1 P <.5 1.82 kg/d more than cows in the group during the first 3 DIM Daily Milk Yield in Cows with Dystocia 45 4 35 3 25 2 15 1 n = 12 5 n = 16 3 6 9 12 15 18 21 24 27 3 P >.5 <.1 P <.5 17
Milk yield (kg/d) SC Linear Score SC Linear Score 19/3/218 Daily Milk Yield in Cows with Dystocia 45 4 35 3 Overall, cows that experienced DYS and received 25 produced 4.48 kg/d more milk compared to DYS cows 2 that received during the first 3 DIM 15 1 n = 12 5 n = 16 3 6 9 12 15 18 21 24 27 3 P >.5 <.1 P <.5 Somatic Cell Counts 2.5 2 P >.5 <.1 P <.5 1.5 1.5 n = 21 n = 222 1 2 3 4 5 DHIA test relative to calving Somatic Cell Counts 2.5 2 1 P >.5 <.1 P <.5 Overall, cows treated with at calving 1.5 tended to have lower SCC during the first 5 DHIA tests compared to cows.5 n = 21 n = 222 1 2 3 4 5 DHIA test relative to calving 18
19/3/218 Final Remarks NEB, pain, inflammation and stress during the periparturient period can negatively affect animal well-being and performance Different alternatives have been proposed to treat pain and inflammation in dairy cows after calving However, controversy still exists regarding the type of drug use, route of administration and length of treatment Recent research showed promising results regarding the use of a short-term treatment with aspirin for pain and inflammation after calving, improving cows wellbeing and performance Final Remarks NSAID treatment should be used as a temporary strategy Further efforts should be aimed at identifying preventive strategies (e.g., dry cow comfort, nutrition) to improve cow comfort ( NEB, stress and inflammation) at calving, thus improving animal well-being and performance during early lactation Adrian A. Barragan, DVM, MS, PhD Assistant Clinical Professor Tel: 814.863.5849 Email: axb779@psu.edu Thank you Department of Veterinary and Biomedical Sciences College of Agricultural Sciences Penn State University 19