improving analgesia: dose determination of ketorolac ...€¦ · 2017-09-12 · dubin ae &...
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Improving Analgesia: dose determination of ketorolac tromethamine in horsesSHANNON GRADY, PHARMD, FSVHPVETERINARY CLINICAL PHARMACY RESIDENTPURDUE UNIVERSITY VETERINARY TEACHING HOSPITAL
Outline Pathophysiology of pain and inflammation
Review of analgesic agents used in veterinary medicine
Use of ketorolac tromethamine in human and veterinary medicine
Current research in equine medicine and future studies
Learning Objectives Identify drug targets within the arachidonic acid cascade.
Describe the significance of non-steroidal anti-inflammatory drugs in the pain management of veterinary patients.
Describe the use of ketorolac tromethamine in human medicine and how its use can be translated to veterinary medicine.
Disclosures I have no actual or potential conflict of interest in relation to this
presentation.
I will be discussing off-label uses for the following medications:◦ Ketorolac tromethamine
Nociceptive Pain Neuropathic vs. nociceptive vs. inflammatory
Dubin AE & Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest . 2010;120(11):3760-3772
Nociceptive Pain Neuropathic vs. nociceptive vs. inflammatory
Caused by noxious stimuli◦ Chemical, thermal, mechanical◦ Pressures and temperatures large enough to
cause tissue damage
Dubin AE & Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest . 2010;120(11):3760-3772
Nociceptive Pain Neuropathic vs. nociceptive vs. inflammatory
Caused by noxious stimuli◦ Chemical, thermal, mechanical◦ Pressures and temperatures large enough to
cause tissue damage
Chemical mediators bind to nociceptors
Signal sent to dorsal horn of spinal cord
Transmitted to brain where pain is perceived
Reaction and inflammatory pain
Dubin AE & Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest . 2010;120(11):3760-3772
Nociceptive Pain Neuropathic vs. nociceptive vs. inflammatory
Caused by noxious stimuli◦ Chemical, thermal, mechanical◦ Pressures and temperatures large enough to
cause tissue damage
Chemical mediators bind to nociceptors
Signal sent to dorsal horn of spinal cord
Transmitted to brain where pain is perceived
Reaction and inflammatory pain
Dubin AE & Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest . 2010;120(11):3760-3772
Inflammatory Pain Tissue Damage◦ Inflammatory response
◦ Protective and healing mechanism◦ Acute vs. chronic pain
◦ Drug targets
Zhang J & An J. Cytokines, Inflammation and Pain. Int Anesthesiol Clin. 2007; 45(2): 27-37
Pain Management in Veterinary Medicine Local anesthetics◦ Lidocaine, mepivacaine
Alpha-2 adrenergic agonists◦ Dexmedetomidine, detomidine
Corticosteroids◦ Prednisone, prednisolone
Opioids◦ Fentanyl, morphine, hydromorphone, oxymorphone
Non-steroidal anti-inflammatory drugs (NSAIDs)
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Mechanism of action◦ Inhibition of cyclooxygenase enzymes (COX-1 and COX-2)◦ Prevents formation of prostaglandins
Why NSAIDs?◦ Non-narcotic (opioids)
◦ Not controlled by DEA◦ Fewer, less severe adverse effects
◦ Analgesic and anti-inflammatory properties
Non-selective:
Carprofen (Rimadyl®)
Meloxicam (Metacam®)
Etodolac (EtoGesic®)
Flunixin (Banamine®)
Phenylbutazone
Ketoprofen (Ketofen®)
COX-2 selective:
Deracoxib (Deramaxx®)
Robenacoxib (Onsior®)
Firocoxib (Previcox®, Equioxx®)
Arachidonic Acid CascadeCELL
MEMBRANE
PhospholipidsPhospholipase Arachidonic
Acid
Riviere JE & Papich MG. Veterinary Pharmacology and Therapeutics, 9 th Edition. Ames, IA: Wiley-Blackwell, 2009.
Arachidonic Acid CascadeCELL
MEMBRANE
PhospholipidsPhospholipase Arachidonic
Acid
Riviere JE & Papich MG. Veterinary Pharmacology and Therapeutics, 9 th Edition. Ames, IA: Wiley-Blackwell, 2009.
Leukotrienes
Thromboxane A2
Prostaglandins (PGE2)
Cyclooxygenase-1 & 2
Lipoxygenase
Cyclooxygenase-1
Prostaglandins Primary mediators of inflammatory pain◦ PGE2
Nociceptors contain EP4 receptors
Drug target
PGE2
EP4 Receptor
Dorsal Root Ganglion
Riviere JE & Papich MG. Veterinary Pharmacology and Therapeutics, 9 th Edition. Ames, IA: Wiley-Blackwell, 2009.
Arachidonic Acid CascadeCELL
MEMBRANE
PhospholipidsPhospholipase Arachidonic
Acid
Riviere JE & Papich MG. Veterinary Pharmacology and Therapeutics, 9 th Edition. Ames, IA: Wiley-Blackwell, 2009.
Leukotrienes
Thromboxane A2
Prostaglandins (PGE2)
Cyclooxygenase-1 & 2
Lipoxygenase
Cyclooxygenase-1
Drug Target
Novel NSAID: ketorolac tromethamine 1970s
Extremely potent anti-inflammatory and analgesic◦ Rats: 500-800x more potent than aspirin
FDA-approved in humans◦ Short-term management of moderate-severe pain in
patients requiring opioid-level analgesia◦ Usually post-operative pain
“Opioid-sparing”
Rooks, et al. The pharmacologic activity of ketorolac tromethamine. Pharmacotherapy . 1990;10*6 Pt 2): 30S-32S.
Ketorolac: human studies 60 patient undergoing elective hysterectomy
Continuous-rate infusion of ketorolac or placebo◦ Total daily dosage: 120 mg◦ 0.6 – 1.3 mg/kg/day
Outcomes:◦ Frequency of supplementary analgesia use
◦ Morphine via patient-controlled analgesia (PCA)
◦ Pain score at 24 hours post-procedure
Results:◦ Morphine consumption significantly lower in ketorolac group than placebo group (21.5% less)◦ Patient-reported pain significantly lower in ketorolac group after 24 hours
Blackburn A et al. Balanced Analgesia with Intravenous Ketorolac and Patient-Controlled Morphine Following Lower Abdominal Surgery. J Clin Anesth. 1995;7:103-108
Ketorolac: human studies 191 human patients undergoing major abdominal surgeries
Maximum ketorolac dosage: 150 mg per 24 hours◦ 0.8 to 1.7 mg/kg/day
Results:◦ Both ketorolac groups required less total morphine◦ No differences in adverse events between groups
All received supplemental morphine as
needed
O’Hara DA et al. Evaluation of the Safety and Efficacy of Ketorolac versus Morphine by Patient-Controlled Analgesia for Postoperative Pain. Pharmacotherapy . 1997;17(5):891-899.
Pain Management in Equine Medicine NSAIDs◦ Flunixin (Banamine®)◦ Phenylbutazone◦ Ketoprofen (Anafen®)◦ Firocoxib (Equioxx®)
Opioids◦ Butorphanol
Local anesthetics◦ Mepivacaine, Lidocaine
Corticosteroids◦ Dexamethasone
What’s missing?Lack of efficacy in certain clinical situations
OsteoarthritisPost-operative musculoskeletal pain (i.e. arthrodesis)LaminitisPleuritis
Ketorolac: equine studies Ferraresi et al, 2014
Pharmacokinetic study in 6 colts undergoing orchiectomy
0.5 mg/kg single IV injection after intubation, approximately 10 minutes prior to surgery◦ Dose derived from previous canine and feline studies
Results:◦ No adverse effects, however:
◦ Did not specify parameters for NSAID◦ No placebo control for comparison
◦ Rapid distribution◦ Short half-life (0.7 hours)
Ferraresi C et al. Pharmacokinetics of IV Ketorolac in Horses Undergoing Orchiectomy. J Equine Vet Sci . 2014;34:870-875.
Ketorolac: equine studies Bianco AW et al, 2015
Randomized, cross-over study of 9 healthy, adult horses
0.5 mg/kg ketorolac given IV, IM and PO
Monitoring of adverse events◦ Changes in behavior, appetite, fecal consistency
Results◦ Rapid absorption after IM and PO administration◦ Bioavailability 71% (IM) and 57% (PO)◦ IV half-life: mean 8.7 hours (range 1.2 – 21.9 hours)
Bianco AW et al. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular and oral single-dose administration. J Vet Pharmacol Therap. 2015;39,167-75.
Ketorolac: literature recap Ketorolac is “opioid-sparing”◦ Less opioid needed to control pain in humans◦ Fewer side effects from opioids
Dosage◦ Large dosage range seen in human studies◦ Only 0.5 mg/kg studied in horses◦ Up to 2 mg/kg studied in goats, sheep, calves
Horses◦ Pharmacokinetic profile has been established◦ No studies comparing placebo/control group to assess efficacy or safety◦ No studies comparing ketorolac to other analgesic agents
Pilot Study How does ketorolac compare to other NSAIDs commonly used in horses?
Establish a dose of ketorolac to use in a cross-over study◦ Is ketorolac effective at higher doses than previously studied?◦ Are there any adverse effects seen at higher doses?
Pilot Study Objective: determine appropriate dosage of ketorolac to use in a study comparing ketorolac to other NSAIDs in horses
◦ 0.5, 1 and 2 mg/kg
Efficacy Endpoints Analgesia Heart rateSubjective lameness scoreObjective lameness score
Safety Endpoints Nephrotoxicity Serum creatinineUrine specific gravityProteinuria
Gastrointestinal toxicity Fecal occult blood test
Hematologic toxicity Platelet countWhite blood cell count with differential
Foot Lameness Model Developed by JH Foreman (University of Illinois)
Customized heart bar shoe placed on left front foot◦ Counterbalanced bar shoe on right front foot
At least 1 week of rest in pasture
Screw inserted into screw and tightened at beginning of each trial
Temporary, reversible lameness
Foreman JH & Lawrence LM (1987) Lameness and heart rate elevation in the exercising horse. Proceedings of the Equine Nutrition & Physiology Symposium,10,345.
Foot Lameness Model
Video here
Foot Lameness Model
Evaluation of Foot Pain Heart rate◦ Elevated when mammals are in pain
Lameness evaluation◦ Subjective lameness score (0 to 5)
◦ Assigned by large animal surgeons◦ Equinosis® Lameness Locator Score
◦ Distance measured in millimeters
Timeline of Trials 1. Customized shoes made and placed on horses
2. At least 1 week of rest on pasture to acclimate to shoe
3. Return to VTH for trial
4. Baseline data collected◦ Physical exam, bloodwork, urinalysis, fecal occult blood testing◦ Baseline lameness
5. Trial (4 days)
6. Horses returned to pasture for at least 2 week washout period
7. Returned to VTH for next trial
Timeline of Trials Trial Days:◦ Drug given on day 0 at 8:00am◦ Lameness evaluated throughout the day until horse returned to baseline lameness score
◦ Heart rate, subjective lameness score, objective lameness score◦ t = 30 mins, t = 1h, t = 1.5h, t = 2h, t = 3h, t = 4h, t = 5h, t = 6h, t = 7h, t = 8h, t = 9h, t = 10h, t = 11h, t = 12h
◦ Lameness alleviated (screw removed from shoe) once horse returned to baseline
◦ Bloodwork, urinalysis, FOBT performed every 24 hours after drug given (day 1, day 2, day 3)◦ Physical exams performed every 12 hours
Results Study population from Purdue University Teaching Herd (n = 4)
◦ Horse 1: 14 y/o Thoroughbred mare◦ Horse 2: 14 y/o Thoroughbred mare◦ Horse 3: 6 y/o Thoroughbred gelding◦ Horse 4: 16 y/o Thoroughbred mare
Inclusion criteria◦ Sound (0/5 lameness score)◦ No NSAID administration within the past 2 months◦ Otherwise healthy
Results – Horse 1, Baseline
Video here
Results – Horse 1, Lameness Grade 4
Video here
Results – Horse 1 – 2h after ketorolac
Video here
Results – Lameness Scores
Results – Lameness Scores
Baseline Peak Effect Percent Improvement = (Difference / Baseline)
Results – Lameness Scores
Results – Percentage Improvement in Lameness Locator Score
Results – Changes in Serum Creatinine Over Time
Limitations and Lessons Learned Grade 4 lameness translates to different Lameness Locator numbers depending on the horse
Difficulties with customized shoes◦ Broken screws◦ Cracked frog◦ Lost on pasture
Distractions during lameness evaluations in hospital
◦ Horse #3
Disparity between objective and subjective lameness evaluations
Horse #4◦ Grand mal seizure & subsequent euthanasia◦ 7 hours after receiving ketorolac at 0.5 mg/kg◦ Had already reached baseline lameness
◦ Did not lose data
◦ Necropsy unremarkable◦ Likely not attributable to ketorolac
Current Research Ketorolac 2 mg/kg◦ More consistent response in percentage reduction in lameness◦ No adverse effects◦ Doses of other NSAIDs on high end of dosing range
◦ Pleuritis, laminitis, osteoarthritis, post-operative musculoskeletal pain
Same lameness model as pilot study
Same inclusion criteria
Same efficacy and safety parameters
Current Research Randomized Latin Square cross-over design (n = 12 horses)◦ Ketorolac 2 mg/kg◦ Phenylbutazone 4.4 mg/kg◦ Flunixin 1.1 mg/kg◦ NaCl 0.9% (placebo)
Dosing interval extended to 5 days with every 12 hour doses
Washout period of >2 weeks between trials
Current Research Analgesia vs. anti-inflammatory action◦ Inflammatory marker in cephalic vein blood
◦ Serum Amyloid A, cytokines◦ Baseline, immediately after lameness induction, immediately prior to first dose, 2h, 12h
◦ Thermography◦ Visual representation of inflammation◦ Baseline, immediately after lameness induction, immediately prior to first dose, 2h, 12h
Pharmacokinetic comparison◦ Pharmacokinetics of ketorolac, phenylbutazone, flunixin
◦ 5 min, 2h, 4h, 8h, 12h
Current Research 2 of 4 trials complete
Improvement seen within placebo group◦ Horses become acclimated to screw?
Different surface used for lameness evaluations
◦ Minimize distractions
Horses ◦ Horse 1: 14 y/o Thoroughbred mare◦ Horse 2: 15 y/o Thoroughbred mare◦ Horse 3: 6 y/o Thoroughbred gelding◦ Horse 4: 11 y/o Arabian mare◦ Horse 5: 22 y/o Thoroughbred mare◦ Horse 6: 13 y/o Thoroughbred mare◦ Horse 7 : 16 y/o Thoroughbred mare◦ Horse 8: 6 y/o Mixed Breed mare◦ Horse 9: 15 y/o Standardbred mare◦ Horse 10: 11 y/o Standardbred mare◦ Horse 11: 4 y/o Thoroughbred mare◦ Horse 12: 12 y/o Standardbred gelding
Excluded
Future Research Inflammatory markers◦ Lipopolysaccharide-induced synovitis model
Continuous-rate infusion◦ Common in human medicine◦ Combination with other analgesics
Comparison to commonly used equine opioids◦ Butorphanol, Morphine
Take Home Points The arachidonic acid cascade is a primary drug target for reducing pain in inflammatory diseases
Ketorolac is a potent NSAID that is commonly used in human medicine for pain requiring opioid-level analgesia
Ketorolac appears to be effective in reducing analgesia in horses with experimentally-induced lameness
Ketorolac may have a role in controlling painful inflammatory diseases in horses
Questions? Acknowledgements:◦ Co-Investigators:
◦ Sandra Taylor, DVM, PhD, DACVIM (LA)◦ Timothy Lescun, BVSc, MS◦ Alec Davern, DVM
◦ Statistics:◦ George Moore, DVM, PhD
◦ Others:◦ Wil Gwin, RPh, DICVP◦ Alex Bianco, DVM, MS, DACVIM (LA)◦ John Foreman, DVM, MS, DACVIM (LA)◦ Jeff Ko, DVM, MS, DACVA◦ Molly Cripe-Birt (large animal technician)◦ Jordan Keehn (veterinary technology student)