The Fourth Vital Sign in All Creatures Great and Small

All things bright and beautiful, All creatures great and small, All things wise and wonderful, The Lord God made them all. Cecil Frances Alexander (1818-1895 / England) During this past year, members from the International Veterinary Academy of Pain Management have been providing articles about techniques and modalities to enhance the level of analgesia your practice provides. Today, we will discuss the fact that pain management needs to be applied to All Creatures Great and Small, including Laboratory Animals. Lets first name what species can be included in laboratory animals. Certainly, rats and mice would be recognized, as would rabbits. But, did you know laboratory animals includes, dogs, cats, ferrets, primates, guinea pigs, hamsters, gerbils, sheep, goats, cows, horses, pigs, birds, reptiles, amphibians, fish, and invertebrates? Not only these species, but others are classified as non-traditional laboratory animals. So, as you can see providing analgesia for laboratory animals is a large task. While this article will briefly touch on certain topics involved in laboratory animal analgesia, it is not meant as an in-depth piece. Careful study of specifics for each species must be taken into account before proceeding with any analgesic therapy. Pain has been called the fourth vital sign after body temperature, heart rate, and respiratory rate, and its potential presence should be evaluated in patients just as the other vital signs are. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. 1 Pain motivates us to withdraw from potentially damaging situations, protect a damaged body part while it heals, and avoid those situations in the future. 2 It is initiated by stimulation of nociceptors in the peripheral nervous system, or by damage to or malfunction of the peripheral or central nervous systems.3 Most pain resolves promptly once the painful stimulus is removed and the body has healed, but sometimes pain persists despite removal of the stimulus and apparent healing of the body; and sometimes pain arises in the absence of any detectable stimulus, damage or pathology. 4 For the purpose of this article we will describe pain as acute, chronic or neuropathic (maladaptive). Acute pain is a normal physiologic and usually time-limited response to an adverse (noxious) chemical, thermal or mechanical stimulus, associated with surgery, trauma, and acute illness and historically responsive to opioid therapy.5 Chronic pain is defined by the IASP (International Association for the Study of Pain) as pain without apparent biological value that has persisted beyond the normal tissue healing time usually taken to be 3 months. 6 The classic example of chronic pain is osteoarthritis. Neuropathic pain is a type of pain which is caused by damage to or dysfunction of the nervous system. 7 Neuropathic pain cannot be explained by a single disease process or a single specific location of damage. Examples of neuropathic pain are phantom limb pain (e.g., onychectomy complications), complex regional pain syndrome, prolonged intervertebral disc disease, cancer, and chronic ear pain. Pain scoring for laboratory animals has evolved since 1985 when a behavioral paper was published by Morton and Griffiths. 8 Pain rating scales should include at least three requirements 9: 1. Minimal Interobserver variability and observer bias. 2. Ability to distinguish varying levels of pain intensity in a particular species and situation 3. Ability to detect the degree of importance of pain to the subject. Pain Scales can be visual analog scales (VAS); numerical rating scales (NRS) and simple descriptive scales (SDS). VAS a line with no markings is used, numbers are at each end 0 being no pain and 100 being worst. NRS a number line with individual numerical markings (1-10) which are chosen as the score. SDS numbers used to assign to descriptions that categorize different levels of pain intensity.

Assessment of pain or distress may be based on many different criteria including: Decreased activity Abnormal postures, hunched back, muscle flaccidity or rigidity Poor grooming Decreased food or water consumption Decreased fecal or urine output Weight loss (generally 20-25% of baseline), failure to grow, or loss of body condition (cachexia) Dehydration Decrease or increase in body temperature Decrease or increase in pulse or respiratory rate Physical response to touch (withdrawal, lameness, abnormal aggression, vocalizing, abdominal splinting, increase in pulse or respiration) Teeth grinding (seen in rabbits and farm animals) Self-aggression Inflammation Photophobia Vomiting or diarrhea Objective criteria of organ failure demonstrated by hematological or blood chemistry values, imaging, biopsy, or gross dysfunction

SPECIES-SPECIFIC BEHAVIORAL SIGNS OF PAIN

Species Dog Vocalizing Whimpers, howls, growls Generally silent; may growl or hiss Screams, grunts, moans Squeaks, squeals Piercing squeal on acute pain Urgent repetitive squeals Grunting, nicker Posture Cowers, Crouches; Recumbent Stiff, hunched in sternal recumbency; limbs tucked under body Head forward, arms across body; huddled crouching Dormouse posture; rounded back; head tilted; back rigid Hunched; faces back of cage Hunched Rigid; head lowered Locomotion Reluctant to move; awkward, shuffles Reluctant to move limb, carry limb Favors area in pain Temperament Varies from chronic to acute; can be subdued or vicious; quiet or restless Reclusive

Cat

Primate

Docile to aggressive

Mice, rats, hamsters Rabbits

Ataxia; running in circles Inactive; drags hind legs Drags hind legs Reluctant to move; walk in circles "up & down" movement None Limp; reluctant to move the painful area Limp; reluctant to move the painful area

Guinea Pig Horses

Docile or aggressive depending on severity of pain, eats neonates Apprehensive, dull, sometimes aggressive depending on severity of pain; eats neonates Docile, quiet, terrified, agitated Restless, depressed

Chickens Cows, calves, goats Sheep

Gasping Grunting; grinding teeth Grunting; teeth grinding

Stand on one foot, hunched huddled Rigid; head lowered; back humped Rigid; head down

Lethargic, allows handling Dull, depressed; act violent when handled Disinterested in surroundings; dull, depressed

Pigs

Birds

From excessive squealing to no sound at all Chirping

All four feet close together under body Huddled, hunched

Unwilling to move; unable to stand From excessive movement to tonic immobility depending on severity of pain None unless forced; if a schooling fish; will separate itself from others Immobility; lameness

From passive to aggressive depending on severity of pain Inactive; drooping, miserable appearance

Fish

None

Clamped fins; pale color; hiding; anorexia Closed eyes; color changes; rapid respirations Hunched; hiding; color change

First sign to occur is anorexia; lethargic; stressed easily Anorexia; aggressive;

Amphibians

None

Reptiles

Hiss; grunting

immobility unless forced

Anorexia; aggressive; lethargic; avoidance

This chart is meant to display some of the different signs species may exhibit if in pain. Individuals may not show any of these signs or they show signs not listed. This is meant as a general guide.

When determining which analgesics should be used several factors need to be considered10: What is the likely severity of pain, and what is its anticipated duration? Which drug or drugs should be administered, and at what dose rates? Are there any special factors that will influence the choice of analgesic, for example, the species of animal, any potential interactions with the particular research project, or any particular features of the current condition and the type of pain? What facilities are available for management of the animal? What level of nursing care and monitoring of the animal is available? Can staff attend throughout a 24 hour period? Are there facilities for continuous infusion of analgesics?

Mechanism-Specific Definitions11 Clifford Woolf has proposed a clinically useful method of classifying pain that is based on the underlying physiology and pathophysiology of the specific type of pain: Nociceptive pain: transient pain in response to a noxious stimulus. Inflammatory pain: spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation. Neuropathic pain: spontaneous pain and hypersensitivity to pain in association with damage to or a lesion in the nervous system. Functional pain: hypersensitivity to pain resulting from abnormal processing of normal input. The mechanism-specific definitions of pain highlight the fact that the sensation of pain can represent normal protective mechanisms (nociceptive, inflammatory) to abnormal sensory processing (neuropathic, functional) in which pain itself becomes a disease. In veterinary medicine, inflammatory pain is routinely observed acutely (surgery, trauma) and chronically (osteoarthritis, cancer). Severe acute and chronic pains have components of neuropathic pain. The role of functional (central) pain in veterinary patients is less clear. Dr. Woolf further classified pain as Adaptive pain, which is defined as an appropriate hypersensitive response to a potentially damaging stimulus that is responsive to medication or Maladaptive pain (commonly referred to as windup pain), defined as spontaneous hypersensitivity resulting from abnormal processing of a stimulus by the central nervous system (CNS), does not respond to treatment. 12 Multimodal Analgesia Multimodal analgesia uses more than one method of pain management. Multiple methods can actually reduce the amount of medications necessary to relieve pain, and can minimize uncomfortable side-effects. Benefits include13 1. More effective analgesia

2. Possible reduction of doses of one or more individual drugs 3. Fewer incidences of breakthrough pain Using combinations of different classes of analgesics may override some of the problems that can occur from differences in the speed of onset of action or duration of analgesia from various agents. Medications like opioids, NSAIDS, local anesthetics, alpha-2-agonists, ketamine, tramadol, gabapentin, amantadine and amitriptyline have shown synergistic effects when used in combinations. The following tables are to be used as guidelines. It is always best to begin a medication at the lowest dose possible unless you have proven knowledge of how a certain species will react. Multimodal Analgesic Drugs for Dogs and Cats Drug Morphine Dose 0.5-1.0 mg/kg 0.05-0.1 mg/kg 0.2 mg/kg: loading, IM 0.1-0.5 mg/kg/hr 0.05-0.1 mg/kg/hr 0.1 mg/kg preservative free 1-5 mg in 5-10 ml saline 3-5 mg/kg 0.1-0.5 mg/kg 0.05-0.2 mg/kg 0.03-0.05 mg/kg 0.1-0.2 mg/kg 5g/kg + 3-6 g/kg/hr 2-3 g/kg + 2-3 g/kg/hr 25 g/hr 50g/hr 75 g/hr 100g/hr 25-50 g/hr Butorphanol 10 mg/ml 0.1-0.2 mg/kg 0.2-0.4 mg/kg IV; then 0.1-0.2 mg/kg/hr Species Canine (K-9) Feline Canine: Feline: K-9/feline Canine K-9/feline K-9/feline K-9 Feline K-9/feline K-9 Feline K-9: 3-10 kg K-9: 10-20 kg K-9:20-30 kg K-9:> 30 kg Feline K-9/feline K-9/feline IM,IV,SC CRI Route IM, SC, IV IM, SC IM then continuous rate infusion (CRI) IV Epidural Intraarticular IM,SC IM,SC,IV IM,IV,SC IM,SC IM,IV,SC IV IV Dose Interval q3-4 hr q3-4 hr Comments Caution with IV administration: histamine release-give slowly

q12-24 hr

Meperidine Methadone Oxymorphone Hydromorphone Fentanyl

q1-2 hr q2-4 hr q3-4 hr q3-4 hr q2-4 hr Infusion Infusion q1-3 days q1-3 days q1-3 days q1-3 days 6 days K-9: q1 hr Feline: q2-4 hr

DO NOT GIVE IV (Histamine release) NMDA antagonist activity Minimal histamine release Minimal histamine release. Hyperthermia may occur in cats

Fentanyl Patch

12-24 hr to reach peak concentrations. Must supplement analgesia until blood levels are reached

6 hr to reach peak concentrations Low oral bioavailability

Pentazocine Nalbuphine Buprenorphine Tramadol

1-3 mg/kg 0.03-0.1 mg/kg 10-30g/kg 2-10 mg/kg start at 2-3mg/kg

K-9/feline K-9/feline k-9/feline K-9 feline

IM,IV,SC IM,IV,SC IM,IV,SC PO

q2-4 hr q2-4 hr q4-10 hr q4-6hr

15-30 minute onset. Excellent buccal mucosa absorption in cats and dogs
Nonscheduled agonist activity. Serotonin and norepinephrine reuptake inhibitor. NMDA antagonist at lower doses, GABA receptor inhibitor at high concentrations.

Codeine Medetomidine Dexmedetomidine 1.0 mg/ml

1-2 mg/kg 2-15 g/kg 5-20 g/kg 1 g/kg IV, then 1-2 g/kg/hr 1-5 g/kg 2-5 g/kg 0.1-0.5 g/kg 0.1 mg/kg IV; 0.3-0.5 mg/kg IM 0.05-0.2 mg/kg IV 0.5 mg/kg; IV then 0.1-0.5 mg/kg/hr 3-5 mg/kg 1.0 mg/kg 0.5-1.0 mg/kg 5-10 mg/kg

K-9 K-9 Feline K-9/feline K-9/feline K-9/feline K-9/feline K-9/feline K-9/feline K-9/feline K-9/feline K-9 Feline K-9/Feline

PO IM,IV IM,IV CRI Epidural Intraarticular IM,IV IM,IV

q0.5-1.5 hr q0.5-1.5 hr

Sedation, mild analgesia, bradycardia, vomition

Xylazine Yohimbine (Antagonist) Atipamezol (Antagonist) Ketamine Amantadine Amitriptyline Gabapentin

q0.5-1.0 hr 2-4 times the medetomidinedexmedetomidine dose Excellent for intraoperative CRI analgesia Neuropathic pain Enhanced noradrenergic activity VDCC inhibitor; excellent for neuropathic pain or in addition as preanesthetic/postoperative analgesic 3 mg maximum total dose; used to potentiate or prolong analgesic drug effect. No analgesic benefit alone. Used to potentiate or prolong analgesic drug effect Onset: Onset: 10-15 minutes. Maximum dose: 12 mg/kg (K-9); 6 mg/kg (feline) Excellent intra-operative CRI analgesia for both K-9

CRI PO PO PO PO q24 hr q12-24 hr q12-24 hr q12-24 hr

Acepromazine

0.025-0.05 mg/kg

K-9

IM,SC,IV

q8-12 hr

Diazepam

0.05-0.2 mg/kg 0.1-0.2 mg/kg 0.25-1.0 mg/kg 6.0 mg/kg

Feline K-9/feline K-9/feline K-9

IM,SC IV PO Perineural

q8-12 hr q2-4 hr q12-24 hr q1-2 hr

Lidocaine (1-2%)

3.0 mg/kg 2-4 mg/kg IV, then 25-80 g/kg/min

Feline K-9

Perineural IV: CRI

q1-2 hr

0.25-0.75 mg/kg slow IV, then 10-40 g/kg/min Bupivacaine (0.250.5%) Mepivacaine (12%) References 2.0 mg/kg 1.0 mg/kg 6.0 mg/kg 3.0 mg/kg

Feline

IV: CRI

and feline

K-9 Feline K-9 Feline

Perineural Perineural Perineural Perineural

q2-6 hr q2-6 hr q2-2.5 hr q2-2.5 hr

Onset: 20-30 minutes. Maximum dose: 2 mg/kg (K-9 or feline)

Fish RE, Brown MJ, Danneman PJ and Karas AZ. Anesthesia and Analgesia in Laboratory Animals, Academic Press, London, UK, 2008 Gaynor, JS, Muir, WW. Handbook of Veterinary Pain Management, Mosby/Elsevier Publishing, St. Louis, MO., 2009. Short, C.E. (Ed), Principles and Practice of Veterinary Anesthesia, Williams and Wilkins, Baltimore, 1987. Tranquilli, WJ, Thurmon, JC, Grimm, KA. Lumb and Jones Veterinary Anesthesia and Analgesia, Blackwell Publishing, 4th Edition, Ames, Iowa, 2007. Fox, SM. Chronic Pain in Small Animal Medicine, Manson Publishing LTD, London, UK. 2010. Spelts, K and Gaynor, J. Pain Management Strategies in Anesthesia for veterinary Technicians Editor Susan Bryant, Wiley-Blackwell Publishing, Ames, Iowa, 2010. Mathews, KA. Veterinary Clinics of North America: Small Animal Practice Update on Pain Management 38(6) Nov, Elsevier/Saunders Publishing, Philadelphia, PA. 2008. Tranquilli, WJ, Grimm, KA, Lamont, LA. Pain Management for the Small Animal Practitioner 2nd Edition Teton NewMedia, Jackson, WY 2004. Short, CE and Poznak, AV. Animal Pain Churchill Livingstone Inc. New York, NY, 1992 Hellebrekers, LJ. Animal Pain: A Practice-Oriented Approach to Effective Pain Control in Animals Van der Wees Uitgeverij, Utrecht, The Netherlands. 2000. Sawyer, DC. The Practice of Veterinary Anesthesia: Small Animals, Birds, Fish and Reptiles. Teton NewMedia, Jackson, WY. 2008 Carroll, GL. Small Animal Anesthesia and Analgesia, Blackwell Publishing, Ames, Iowa. 2008 Multimodal Analgesia in Primates Drug Morphine Fentanyl Dose (mg/kg) 1-2 1-2g/kg 2-10 g/kg 10-25 g/kg/h 50-70 g/kg/h to 70Route IM, SC IV IV IV-CRI IV-CRI Dose Interval q4h q30 min Comments for analgesia adjunct for inhalant anesthesia neurosurgical

Fentanyl Transdermal Patch Alfentanil Remifentanil Sufentanil Oxymorphone

100 g/kg/h 4g/kg/h or 25 g/kg/h times 2 patches 3-32 g/kg 3.2-5.6 g/kg 6-30 /kg/h Macaca: 0.15 Papio: 0.15 Saimiri sciureus: 0.075 Macaca: 0.15 Papio: 0.15 Saimiri sciureus: 0.075 Macaca: 0.01 Papio: 0.01-0.03 S. sciureus: 0.015 Macaca: 0.06 Papio: 0.06 28 mg 42 mg 56 mg 0.58-1.0 0.1-1.0 0.1-0.2 Macaca: 0.05 S. sciureus: 0.02 10 g/kg/min 0.5-1.0 g/kg 0.05-0.1 0.5-2.0 5-10 15-20 Macaca: 325 mg or 125 mg/5kg Papio: 325 mg or 125 mg/5kg 7 20 1% solution 15-30 5 2-4 0.1-0.2 0.3-1.0 1-2 100 mg

procedures transdermal drug delivery-topical IV IV IV-CRI IM IM IM IM IM IM IM IM IM SC SC Topical transdermal patch IM IM, SC, PO IM, IV IM SC IV-CRI IM, IV IM IM PO Suppository PO Suppository PO Suppository PO PO subgingival irrigation IM IM PO, SC, IV PO, SC, IM SC, IV SC, IM continuous delivery q4-6h q4-6h q4-6h q4-6h q4-6h q4-6h q6-8h q12h q6-8h q72h q72h q72h q8-12h q8-12h q3-4h q8h q6h for intraop and postop analgesia analgesia q30 min-1.5 hrs 30 min q6h q72h q15 min Ultra short acting < q15 min

best as CRI in 5% dextrose solution

Hydromorphone

Buprenorphine Buprenorphine SR Buprenorphine Transdermal Patch Methadone Butorphanol Ketamine Dexmedetomidine Medetomidine Xylazine Acetominophen Aspirin-Enteric Coated Ibuprofen

manufactured at ZooPharm Buprederm 2.4mg/cm2

used to treat fever and mild pain

q24h periodontitis

Ketorolac tromethamine Ketoprofen Carprofen Meloxicam Flunixin meglumine Topical Ketoprofen Patch

q6-8h q8-12h q24h q12-24h q6-12h q72h

Made in Japan

Bupivacaine 0.5% = 5mg/ml Lidocaine 2%=20 mg/ml Gabapentin Amitriptyline Amantadine Tramadol Tapentadol Dexamethasone References:

0.25%-1 mg/kg 0.50% - 1.2 mg/kg 2.5-5 mg/kg 25-50 2.0 3-5 1-2 50-100 mg tablet 0.25-1.0

local infiltration epidural local infiltration PO IM PO PO PO PO, IM, IV

q3-6h q1-2h q12h q12-24h q24h q8-12h q4-6h q6-8h

nerve blocks toxic dose is 4mg/kg nerve blocks toxic dose is 10 mg/kg excellent analgesic adjuvant analgesic adjuvant analgesic adjuvant opioid like new inflammation

Adams, Richard (ed.), Veterinary Pharmacology and Therapeutics, Iowa State University Press, Ames, Iowa, 8th edition 2001. Amass KD and Drew M. Safe-Capture International Chemical Immobilization of Animals Technical Field Notes, Safe-Capture International, Inc, Mt. Horeb, WI, 2006 Carpenter, JW. Exotic Animal Formulary, Elsevier/Saunders, St. Louis, MO, 2005 Fish RE, Brown MJ, Danneman PJ and Karas AZ. Anesthesia and Analgesia in Laboratory Animals, Academic Press, London, UK, 2008 Fortman JD, Hewett TA and Bennett BA. The Laboratory Non-Human Primate, CRC Press, Boca Raton, FL, 2002 Gaynor, JS, Muir, WW. Handbook of Veterinary Pain Management, Mosby/Elsevier Publishing, St. Louis, MO., 2009. Heard, DJ (Ed) The Veterinary Clinics of North America Exotic Animal Practice: Horne WA. , Primate Anesthesia, W.B. Saunders, Philadelphia, PA, 2001 Pg. 239-266 Longley L., Anaesthesia of Exotic Pets, Saunders/Elsevier , London, UK, 2008 Marx, K.L.and Roston, M.A., The Exotic Animal Drug Compendium An International Formulary, Veterinary Learning Systems, Trenton, N.J., 1996. Plumb D.C., Plumbs Veterinary Drug Handbook, Blackwell Publishing, Ames, Iowa, 2008. Reinhart V et.al. Making Lives Easier for Animals in research Labs, Animal Welfare Institute, Washington, DC, 2007. Reinhardt, Viktor and Annie. Environmental Enrichment and Refinement for Nonhuman Primates Kept in Research Laboratories, Animal welfare Institute, Washington DC, 2008. Short, C.E. (Ed), Principles and Practice of Veterinary Anesthesia, Williams and Wilkins, Baltimore, 1987. Stedmans Medical Dictionary 27th edition, Lippincott William & Wilkins, Philadelphia, PA, 2000 Tranquilli, WJ, Thurmon, JC, Grimm, KA. Lumb and Jones Veterinary Anesthesia and Analgesia, Blackwell Publishing, 4th Edition, Ames, Iowa, 2007. West G, Heard D and Caulkett. Zoo Animal & Wildlife Immobilization and Anesthesia, Blackwell Publishing, Ames, Iowa, 2007

Multimodal Analgesics for Rabbits Drug Butorphanol Dose (mg/kg) 0.1-0.5 Route SC, IM, IV Dose Interval q2-4h Comments May be slow to return to normal activity and selffeeding

0.1-0.3 mg/kg/h Buprenorphine Fentanyl 0.01-0.05 0.0074 20-30g/kg/h

IV CRI (continuous rate infusion) SC, IM, IV IV IV-CRI

q6-10h q2-4h

Morphine

1-4 g/kg/h 25g/h 0.5-5 0.1 0.05-0.2 0.05-0.2 5-10 1 1-2 5-10 1 ml drug/100 ml drinking water 100 5 1.5 1.1 1-3 0.6- 1.0 0.2 0.5 10g/kg/min 2/kg/min <2 < 1.5

IV-CRI transcutaneous patch IM single dose preoperatively epidurally IV, IM, SC IV, IM, SC SC, IM IV IV PO PO PO SC PO SC SC PO or SC PO IV IV-CRI IV-CRI SC local infiltration SC local infiltration

Can be used to reverse fentanyl after Hypnorm sedation Dose related respiratory depression during anesthesia to reduce volatile inhalant concentrations for analgesia May affect gastrointestinal motility

q72h q2-3h

Hydromorphone Oxymorphone Meperidine Methadone Nalbuphine Tramadol Acetaminophen (with or without codeine) Aspirin Carprofen Flunixin Ketoprofen Meloxicam Piroxicam Ketamine

q6-8h q6-8h q2-3h q4-5h q12-24h

q24h q12h q12h q24h q8h before surgery during surgery for 24 hours postoperatively

Lidocaine Bupivacaine

References Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, Elsevier/Academic Press, London, UK 160-174, 2009 Longley, L Rabbit Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 93. Lipman, NS, Marini, RP, Flecknell PA. Anesthesia and Analgesia in Rabbits in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 325. Johnston, M. (2009) Clinical Approaches to Analgesia in Ferrets and Rabbits in Handbook of Veterinary Pain Management 2nd Edition Gaynor, JS and Muir WW. Mosby/Elsevier, St. Louis, MO Pg 494-506. Multimodal Analgesics in Rodents Drug Buprenorphine Butorphanol Morphine Nalbuphine Oxymorphone Pentazocine Meperidine Methadone Tramadol Fentanyl Lidocaine/morphine Mouse 0.05-0.1 mg/kg SC q12h 1.1 mM in DMSO topically 1-2 mg/kg SC q4h 2.5 mg/kg SC q2-4h 6.1 mM in DMSO topically 2-4 mg/kg IM q4h 0.2-0.5 mg/kg SC q4h 5-10 mg/kg SC q3-4h 10-20 mg/kg SC, IM q23h 5 mg/kg SC, IP q24h 0.025-0.6 mg/kg SC 0.032 mg/kg SC 0.85mM Lidocaine 1.7 mM Morphine in DMSO Local infiltration 0.44mM Lidocaine 0.18 buprenorphine in DMSO topical application local infiltration SC 120 mg/kg PO 20 mg/kg SC 100-120 mg/kg IP 200 mg/kg PO 5 mg/kg SC q24h Rat 0.01-0.05 mg/kg SC, IV q8-12h 0.1-0.25 mg/kg PO q8-12h 1-2 mg/kg SC q4h 2.5 mg/kg SC q2-4h 1-2 mg/kg IM q3h 0.2-0.5 mg/kg SC q4h 0.03 mg/kg/h IV-CRI 5-10 mg/kg SC q3-4h 10-20 mg/kg SC, IM q23h 0.5-3 mg/kg SC 5 mg/kg SC, IP q24h 0.01-1.0 mg/kg SC 2.0-4.0 g/day PO Guinea Pig 0.05 mg/kg SC q8-12h 1-2 mg/kg SC q4h 2-5 mg/kg SC, IM q4h 1-2 mg/kg IV, IP, IM 0.2-0.5 mg/kg SC q4h 10-20 mg/kg SC, IM q2-3h

Lidocaine/buprenorphine

Lidocaine Bupivacaine Aspirin Acetominophen Carprofen Celecoxib

0.67-1.3 mg/kg/h CRI SCpump local infiltration SC 100 mg/kg PO 20 mg/kg SC 100-120 mg/kg IP 200 mg/kg PO 5-15 mg/kg SC q24h 10-20 mg/kg PO q24h

local infiltration SC 87 mg/kg PO 20 mg/kg SC 100-120 mg/kg IP 4 mg/kg SC q24h

Diclofenac Dipyrone Dipyrone/morphine Flunixin meglumine Ibuprofen Ibuprofen/ hydrocodone Ibuprofen/methadone Ibuprofen/oxycodone Ketoprofen Ketoprofen Meloxicam Meloxicam/tizanidine Meloxicam/clonidine Naproxen/hydrocodone Tizanidine Tizanidine/nimesulide Clonidine/nimesulide Gabapentin References

8 mg/kg PO q24h

2.5 mg/kg SC, IM q12h 4.0-11 mg/kg IV 30 mg/kg PO

10 mg/kg PO q24h 50-600 mg/kg SC, IP, IV 177-600 dipyrone 3.1-3.2 morphine SC, IV 2.5 mg/kg SC, IM q12h 15 mg/kg PO 200 mg/kg Ibuprofen 2.3 mg/kg hydrocodone SC 200 mg/kg Ibuprofen 1.7 mg/kg methadone SC 200 mg/kg Ibuprofen 0.5 mg/kg oxycodone SC 5 mg/kg SC q24h 5-15 % SC 10-20% IP 1 mg/kg SC, PO q24h

2.1 mg/kg PO q24h

2.5 mg/kg SC, IM q12h 10 mg/kg IM q4h

5 mg/kg SC q24h 5 mg/kg SC, PO q24h 0.5 mg/kg meloxicam 0.25 mg/kg tizanidine PO 0.5 mg/kg meloxicam 0.25 mg/kg clonidine PO

0.1-0.3 mg/kg SC, PO q24h

200 mg/kg naproxen 1.3 mg/kg hydrocodone SC 0.25-1.0 mg/kg PO 0.25 tizanidine mg/kg 1.0 nimesulide mg/kg PO 0.25 clonidine mg/kg 1.0 nimesulide mg/kg PO 10 mg/kg PO

10 mg/kg PO

10 mg/kg PO

Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, Elsevier/Academic Press, London, UK 160-174, 2009 Longley, L Rodent Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 93. Gaertner, DJ, Hallman, TM, Hankenson, FC, Batchelder, MA. Anesthesia and Analgesia for laboratory Rodents in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 241-243. Multimodal Analgesia in Ferrets Drug Dose Route Dose Interval Comments

Butorphanol Morphine

0.2-0.8 0.1-0.2 mg/kg/hr 0.2-2.0 0.25-1

SC, IM, IV CRI IM IM, SC, IV

q2-4h single dose q3-4h May vomit; bradycardia may occur with doses higher than 0.5 mg/kg Occasional vomit; bradycardia and respiratory depression may occur bradycardia and respiratory depression may occur during anesthesia to reduce volatile inhalant concentrations for analgesia

Hydromorphone

0.1 0.025-0.1

epidurally SC, IM, IV

q6-8h

Fentanyl

4-10g/kg

IM, IV

q30 minutes

20-30 g/kg/hr IV

CRI

1-4 g/kg/hr IV Oxymorphone Meperidine Buprenorphine Tramadol Medetomidine Dexmedetomidine Xylazine Ketamine 0.05-0.2 5-10 0.01-0.02 0.01-0.03 5 0.02-0.04 0.01-0.03 1-2 0.5 10 g/kg/min 2 g/kg/min Ketoprofen Carprofen Meloxicam Lidocaine Bupivacaine Mepivacaine References 1-2 2-4 0.2 2 4.4 1 1.1 2

CRI SC, IM, IV IM, SC SC, IM, IV IV, IM, SC, Transmucosal (TM) PO IM, SC, IV SC, IM, IV IM IV before surgery IV CRI during surgery IV CRI SC, IM, IV, PO SC, IM, IV, PO SC, IM, IV, PO locally Epidurally local infiltration epidurally local infiltration q6-8h q2-4h q6-8h q6-10h q12h 30-60 minutes 30-60 minutes 30-50 minutes

for 24 hours postoperatively q24h q24h q24h 60 minutes q4-6h q2-3h

Flecknell PA: Analgesia of small mammals. Vet Clin North Am Exot Anim Pract 4:47-56, 2001 Flecknell PA: Analgesia in small mammals. Semin Avian Exot Pet Med 7:41-47, 1998

Flecknell PA: Pain relief in laboratory animals. Lab Anim 18:147-160, 1984 Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, Elsevier/Academic Press, London, UK 160-174, 2009 Longley, L Ferret Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 93. Ko, J and Marini, RP Anesthesia and Analgesia in Ferrets in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 453. Johnston, M. (2009) Clinical Approaches to Analgesia in Ferrets and Rabbits in Handbook of Veterinary Pain Management 2nd Edition Gaynor, JS and Muir WW. Mosby/Elsevier, St. Louis, MO Pg 494-506. Multimodal Analgesia in Swine Drug Buprenorphine Butorphanol Morphine Oxymorphone Pentazocine Meperidine Fentanyl Fentanyl Patch Dose (mg/kg) 0.01-0.05 0.005-0.010 0.05-0.1 0.1-0.3 0.1-0.3 0.2-1.0 0.15 2 2-5 2 2.0-10.0 0.05 50-100 g/kg/h appropriate to weight probably 50 g/h Route IM, IV IM, IV IM, SC IM, IV IM, IV, SC IM IM IM, IV IM IM, IV IM, SC IM, SC IV-CRI transdermal Dose Interval q6-12h q8-12h q8-12h q4h q8-12h q4h q4h q4h q4h q2-4h q4h q2h q72h Comment

Intraoperative and postop infusion Dose related respiratory depression during anesthesia to reduce volatile inhalant concentrations for analgesia Intraoperative and postop infusion

Sufentanil Tramadol Ketamine Aspirin Carprofen Meloxicam Ketoprofen Flunixin Phenylbutazone Lidocaine 2%

0.005-0.001 15-30g/kg/h 5 3-5 mg/kg/h 10-20 2-4 0.4 1-3 1-2 10-20 Never exceed 20 mls

IM, SC IV-CRI PO CRI (continuous rate infusion) PO IM, IV, SC, PO SC IM, SC, PO, IV IV, SC IM, SC, PO local infiltration epidural

q2h q12h intraoperatively or postoperatively q4-6h q24h q24h q12h q24h q12h 90-180 minutes 4.0 ml for 100 kg 6 ml for 200 kg 8 ml for 300 kg

25-50k/kg/min Prilocaine 5% Bupivacaine 2-15 ml Never exceed 5 mg/kg Toxic signs may be seen a 2 mg/kg

IV-CRI SC or local infiltration Local infiltration

for castrations infusion for analgesia intra and postop 0.25% for infiltration 0.5% for nerve block 0.75% for epidural block

References Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, (2009) Elsevier/Academic Press, London, UK 160-174, Longley, L. Fancy Pig Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 124. Smith, AC and Swindle, MM. Anesthesia and Analgesia in Swine in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 434-435. Ivany, JM, and Muir, WW. Farm Animal Anesthesia in Farm Animal Surgery (2004) Editors: Fubini, SL and Ducharme, NG. Saunders/Elsevier St. Louis, MO Pg108-109. Multimodal Analgesics for Ruminants Drug Morphine Dose (mg/kg) 0.05-0.5 0.5 10 mg total dose 0.1 Route IM,IV IM, IV IM Epidural Dose Interval (hours) q6h q4-6h q4-6h q6-12h Species Cattle Goat Sheep Cattle (diluted to 510 ml with sterile saline), sheep/goat (diluted 3-5 ml with sterile saline or 1.5 mg/kg bupivacaine) Sheep, cattle Sheep, goat, cattle sheep, goats cattle sheep, goats, cattle Sheep, goats sheep, goat, cattle cattle (diluted to 5 ml with sterile saline sheep, goat (diluted to 2-3 ml with sterile saline) sheep, goat, cattle cattle ( diluted with 5 ml sterile saline)

Meperidine Butorphanol Buprenorphine Oxymorphone Fentanyl Xylazine

5 0.05-0.2 0.005 0.0015-0.006 0.005 0.01 0.05-0.2 0.05 0.05-0.1

IM IM, IV IM,IV IM,IV IM IV IM,IV Epidural Epidural/intrathecal IM, IV Epidural

q0.25-0.5h q1-3h q12h q4-6h q4h q1-2h q2-4h q2h q1-2h q2-4h q3h

Detomidine

0.003-0.01 0.04

0.01 Medetomidine 0.005-0.01 0.015

Intrathecal IM, IV Epidural

q1h q2-4h q3-7h

Romifidine

0.003-0.02 0.05 2.5 0.2-0.4 0.4-2.0 1.5-1.8 0.05 10 1.0 2.0 2.5 mg/kg 5-8 mg/kg

IM, IV intrathecal IV Epidural Epidural Epidural Epidural PO IM IV PO PO

q2-4h q1-2h q1h q1-2h q1-2h q2-3h q2-3h

Lidocaine

Bupivacaine Phenylbutazone Flunixin meglumine Ketoprofen Gabapentin References

TID TID

sheep, goats (diluted to 2 ml sterile saline) sheep, goat, cattle cattle ( diluted to 5 ml with sterile saline) goat (diluted 3-5 ml with sterile saline) sheep, goat, cattle goat (diluted to 3-5 ml with sterile saline) goat (CRI at 0.05-0.1 mg/kg/min) cattle sheep, goat sheep, goat cattle sheep, goat cattle, sheep, goat cattle sheep, goats cattle

Ivany, JM, and Muir, WW. Farm Animal Anesthesia in Farm Animal Surgery Editors: Fubini, SL and Ducharme, NG. Saunders/Elsevier St. Louis, MO 2004 Pugh, DG. Sheep and Goat Medicine Saunders/Elsevier Philadelphia, PA 2002 Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, Elsevier/Academic Press, London, UK 2009 Gaynor, JS, Muir, WW. Handbook of Veterinary Pain Management, Mosby/Elsevier Publishing, St. Louis, MO., 2009. Fish RE, Brown MJ, Danneman PJ and Karas AZ. Anesthesia and Analgesia in Laboratory Animals, Academic Press, London, UK, 2008 Short, C.E. (Ed), Principles and Practice of Veterinary Anesthesia, Williams and Wilkins, Baltimore, 1987. Tranquilli, WJ, Thurmon, JC, Grimm, KA. Lumb and Jones Veterinary Anesthesia and Analgesia, Blackwell Publishing, 4th Edition, Ames, Iowa, 2007. Multimodal Analgesics for Horses Drug Hydrocortisone sodium succinate Dexamethasone isonicotinate Methylprednisolone Prednisolone Intravenous Route mg/kg 1-4 0.015-0.050 0.1-0.5 0.25-1.0 Dosing Interval

Phenylbutazone Dipyrone Flunixin Ketoprofen Carprofen Butorphanol Buprenorphine Morphine Oxymorphone Methadone Meperidine Fentanyl Xylazine Detomidine Medetomidine Romifidine Acepromazine Butorphanol + Acepromazine Buprenorphine + Acepromazine Xylazine + Butorphanol Xylazine + Morphine Gabapentin Tramadol

2.2-4.4 5-22 1.1 2.2 0.5 0.01-0.04 0.01-0.04 0.05-0.1 0.001-0.02 0.05-0.10 0.2-1.0 0.01-0.1 0.5-1.0 0.03-0.04 0.01-0.02 0.04-0.08 0.05-1.0 0.05-0.1 + 0.02-0.05 0.005-0.01 + 0.02-.05 0.2-0.5 + 0.01-0.05 0.5-1.0 + 0.1-0.5 2-5 mg/kg PO 1-2 mg/kg IM, IV

Sid-bid Sid-bid Sid-bid Sid-bid q2-4h q10h q4h q2-4h q2-4h single injection 30 minutes 0.5-1.0 hr 0.5-1.5 hr 8-12 hr

bid bid

Loading Doses and Infusion Rates of Analgesic Drugs for Horses Drug Lidocaine Butorphanol Fentanyl Detomidine Medetomidine Dexmedetomidine Ketamine Ketamine + lidocaine Loading Dose (mg/kg) 1.3-2.0 0.01-0.02 0.002-0.005 0.005-0.01 0.005-0.01 5-20 g/kg IV IM 0.100-0.200 1 mg/kg IV bolus + 1.52.0 mg/kg over 30 min Infusion Rate (mg/kg/hr) 1.5-3 0.01-0.02 0.005-0.01 0.01-0.03 0.001-0.003 3.5 g/kg/hr 0.5-1.0 0.2 mg/kg/h + 3 mg/kg/h CRI Side Effects muscle fasciculations; if severe, seizures, coma & death GI motility locomotor activity Ataxia; sedation Ataxia; sedation muscle fasciculations, locomotor activity, apprehension for acute pain

References Doherty, T and Valverde A Manual of Equine Anesthesia and Analgesia Blackwell Publishing Ltd. Oxford, UK 2006. Muir, WW and Hubbell, JAE Equine Anesthesia Monitoring and Emergency Therapy Saunders/Elsevier St. Louis, MO 2009.

Tranquilli, WJ, Thurmon, JC, Grimm, KA. Lumb and Jones Veterinary Anesthesia and Analgesia, Blackwell Publishing, 4th Edition, Ames, Iowa, 2007. Riebold, TW. The Veterinary Clinics of North America: Equine Practice. Principles and Techniques of Equine Anesthesia Dec. 6(3). 1990. Multimodal Analgesics in Reptiles Drug Butorphanol Buprenorphine Morphine Dose (mg/kg) 0.4-2.0 0.02-0.2 0.05-4.0 (crocodiles) 1.5-6.5 (turtles) 1.0 (green iguanas) Route SC, IM, IV SC, IM Intracoelomic (IC) or IM Dosing Interval q12-24h q12-24h q12-24h Comment

Meperidine

1-4

IC

q4h

Ketamine

10-100

IM, IV, SC

Ceiling effect seen at 0.3 mg/kg in Nile crocodiles (Crocodylus niloticus africana) Duration of action may persist up to 24 hrs in turtles. Ceiling effect seen at 2.0 mg/kg in Nile crocodiles (Crocodylus niloticus africana) High doses associated with anesthesia. Low doses 10 mg/kg likely associated with analgesia without sedation. Lower doses may be effective for analgesia

Xylazine Medetomidine

Meloxicam Carprofen Ketoprofen Flunixin meglumine Lidocaine 2%

1.0-1.25 50-100g/kg (tortoises) 150-300 g/kg (aquatic) 150 g/kg (snakes and lizards) 0.1-0.2 1-4 2 0.5-2 2-5

IM IM, IV Intraosseous (IO)

IM, IV, PO IM, IV, SC IM, IV, SC IM local infiltration

q24-48h q24-72h q24-72h q24-48h Recommend to keep it < 5 mg/kg. Dilute to 0.5% to increase volume. Recommend < 2mg mg/kg Dilute to 0.25% to increase volume.

Bupivacaine 0.5%

1-2 (snakes, lizards, turtles) 2-5 (crocodiles)

Local infiltration

References Mosley, C. (2009) Clinical Approaches to Analgesia in Reptiles in Handbook of Veterinary Pain Management 2nd Edition Gaynor, JS and Muir WW. Mosby/Elsevier, St. Louis, MO Pg 488-489.

ORourke, DP and Jenkins, AL Anesthesia and Analgesia in Reptiles in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 508. Schumacher, J and Yelen T (2006) Anesthesia and analgesia. In Reptile Medicine and Surgery (D.R. Mader, ed) pp 442-452. W.B. Saunders, St. Louis, MO. Longley, L Reptile Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 206. Multimodal Analgesia in Avians Drug Butorphanol Buprenorphine Fentanyl Morphine Dexamethasone Carprofen Flunixin meglumine Ketoprofen Meloxicam Piroxicam Phenylbutazone Lidocaine Bupivacaine All Studies in ducks and chickens Species All All Cockatoos chickens All All All All Psittacines, raptors All Dose (mg/kg) 0.5-0.75 0.01-0.05 0.2 5-30 0.2-4.0 2.0-4.0 0.5 2.0 0.1-0.2 0.5 0.5 1.0-3.0 2 Route IM, IV IM SC IM IM, IV PO, IM, SC, IV IM PO, SC, IM PO, IM PO, IM PO Local infiltration SC, intraarticular, topical, IM, SC Dosing Interval (hours) q12h q8-12h q4h q12-24h q8-12h q24h q8-24h q12h q12h q8-12h Comment

Ensure hydrated to prevent nephrotoxicity Ensure hydrated to prevent nephrotoxicity. Ensure hydrated to prevent nephrotoxicity. Ensure hydrated to prevent nephrotoxicity. chronic pain, osteoarthritis anecdotal clinical application Do not exceed 4 mg/kg Dilute 1:10 before administration. Toxicosis occurs at 2.5 mg/kg.

References Clyde VL, Paul-Murphy J: Avian analgesia, in Fowler ME, Miller RE (eds): Zoo and Wild Animal Medicine: Current Therapy 4. Philadelphia, WB Saunders, 1999, pp 309314. Paul-Murphy JR, Brunson DB, Miletic V: Analgesic effects of butorphanol and buprenorphine in conscious African grey parrots (Psittacus erithacus erithacus and Psittacus erithacus timneh). Am J Vet Res 60:12181221, 1999.

Concannon KT, Dodam JR, Hellyer PW: Influence of a mu- and kappa-opioid agonist on isoflurane minimal anesthetic concentration in chickens. Am J Vet Res 56:806811, 1995. McGeown D, Danbury TC, Waterman-Pearson AE, Kestin SC: Effect of carprofen on lameness in broiler chickens. Vet Rec 144:668671, 1999. Multimodal Analgesia in Amphibians Drug Buprenorphine Butorphanol Fentanyl Morphine Nalorphine Lidocaine 1-2% Ketorolac Dexmedetomidine Xylazine Dose (mg/kg) 0.075 38 0.2-0.4 25 0.5 30-100 38-42 122 26 120 10 Route Dorsal Lymph Sac SC IM Intracoelomic SC IM, SC, topically SC SC Local infiltration Dorsal Lymph Sac Dorsal Lymph Sac Intracoelomic Dose Interval > 4 hr Comment ED50 in leopard frog (Rana pipiens) q12 hr > 4 hr 60-90 minutes > 4 hr > 4 hr Local anesthetic; use with caution ED50 in leopard frog (Rana pipiens) Little effect on feeding behavior

q12-24 hr

Sedation and depression of motor reflexes associated with administration of opioids and alpha-2-adrenergic agonists in mammals has not been observed in amphibians. References: Stevens, CW., Maciver, DN, Newman, LC. (2001) Testing and comparison of non-opioid analgesics in amphibians. Contemporary Topics 40, 23. Brenner, GM, Klopp, AJ, Keason, LL and Stevens, CW. (1994) Analgesic potency of alpha adrenergic agents after systemic administration in amphibians Journal of Pharmacological ExperimentalTtherapy 270 pg 540-545 Machin, KL. (2001) Fish, amphibian and reptile analgesia. In Analgesia and Anesthesia Veterinary Clinics of North America Exotic Animal Practice 4, P19-33. Terril-Robb, LA, Suckow, MA, Grigdesby, CF. (1996) Evaluation of the analgesic effects of butorphanol tartrate, xylazine hydrochloride, and flunixin meglumine in leopard frogs (Rana pipiens) Contemporary Topics 35, 54. Longley, L Amphibian Anaesthesia in Anaesthesia of Exotic Pets (2008) Saunders/Elsevier, Edinburgh, Scotland pg 257. Multimodal Analgesia for Fish Drug Butorphanol Carprofen Flunixin meglumine Ketoprofen Dose (mg/kg) 0.1-0.4 2-4 0.25-0.5 2 Route IM IM IM IM Comments q3-5days q3-5days

Meloxicam Morphine Lidocaine References

0.1-0.2 0.3 do not exceed 1-2 mg/kg total dose

IM IM local anesthesia

Stoskopf, M and Posner, LP. Anesthesia and Analgesia of Laboratory Fish in Anesthesia and Analgesia in Laboratory Animals 2nd Edition, (2008) Editors: Fish RE, Brown MJ, Danneman PJ and Karas AZ. Academic Press/Elsevier San Diego, CA pg 531. Longley, L Fish Anaesthesia in Anaesthesia of Exotic Pets, (2008) Saunders/Elsevier, Edinburgh, Scotland pg 276. Roberts, HE. Anesthesia, Analgesia, and Euthanasia in Fundamentals of Ornamental Fish Health, (2010) Editor: Roberts, HE. Wiley-Blackwell Publishing Ames, Iowa, 168-171. Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, (2009) Elsevier/Academic Press, London, UK pg. 240. Multimodal Analgesia for Miscellaneous Species Species Hamsters Drug morphine aspirin buprenorphine butorphanol carprofen flunixin ketoprofen nalbuphine oxymorphone meperidine aspirin butorphanol carprofen flunixin ketoprofen morphine nalbuphine oxymorphone meperidine buprenorphine aspirin buprenorphine butorphanol carprofen flunixin ketoprofen oxymorphone meperidine butorphanol carprofen ketoprofen Dose (mg/kg) 2-5 100 0.05-0.1 1-5 5 2.5 5 4-8 0.2-0.5 20 100 1-5 5 2.5 5 2-5 4-8 0.2-0.5 20 0.05-0.1 100 0.05-0.1 0.2-2.0 4 1-3 1 0.2-0.5 1-2 0.1-0.4 1 1-3 Route SC, IM, PO SC SC SC SC SC IM SC, IM SC, IM PO SC SC SC SC SC, IM IM SC, IM SC, IM SC PO SC SC, IM, IP SC SC SC, IM SC, IM SC, IM SC, IM PO SC, IM Dose Interval q2-4h q4-8h q6-12h q4h q24h q12-24h q12-24h q3h q6-12h q2-4h q4-8h q4h q24h q12-24h q2-4h q3h q6-12h q2-4h q6-12h q4-8h q6-12h q2-4h Q24h q12-24h q12-24h q6-12h q2-4h q8h q12-24h

Gerbil

Chinchilla

Prairie Dog

Degus

Duprasi (Fat-Tailed Gerbil)

buprenorphine meperidine morphine oxymorphone meloxicam aspirin butorphanol flunixin meperidine aspirin buprenorphine butorphanol flunixin meperidine buprenorphine butorphanol flunixin Use same dosages Use same dosages

0.01-0.05 10-20 2-5 0.2-0.5 0.1-0.2 50-100 0.2 2.5 10-20 150 0.1-0.2 1-5 2.5 20 0.01 0.1-0.5 1 as prairie dogs as prairie dogs

SC, IP SC SC SC, IM PO PO IM SC IM, SC PO SC SC SC SC, IM SC, IM, slow IV SC, IM SC, IM

q6-12h q2-3h q4h q6-12h q24h q4h q4h q12-24h q3-4h q4-6h q8h q2-4h q12-24h q3-4h q8-12h q4-6h q12-24h

Herbivorous Marsupials

Woodchuck Ground squirrels Invertebrates

There is little literature to document the use of analgesics in invertebrate species such as: Mollusks Gastropods, cephalopods, Bivalves Annelids Ploychaetes, Oligochaetes, Hirudineans (leeches) Arachnida Spiders, Scorpions, Horseshoe Crabs Crustaceans crabs, crayfish, hermit crabs, lobsters, shrimp Insects Nematodes Echinoderms Nociceptive cells have been found in invertebrates and opioid systems are functional in invertebrate nociception. Local anesthetics will block the nociceptive pathway and decrease stimulus. Opioids provide good analgesia. As of this time, we are urged to carefully extrapolate dosing information from what has been published on lower vertebrates (fishes, amphibians, reptiles). Centipedes only reports of 5% isoflurane and 100% oxygen Cephalopods Magnesium chloride (MgCl2) for anesthesia is reported, but no analgesics. Chaetognaths - Arrowworms no reports of surgery or anesthesia and analgesia Coelenterates Flatworms Jellyfish Corals Tricaine methane sulfonate (MS-222) and ethanol has been used for both anesthesia and analgesia. Crustaceans can and do respond to noxious stimuli by dropping appendages. Dose Comment 0.025-0.1 mg/kg Anesthesia within 15-45 seconds 90g/g IM Duration 1 hour Lidocaine 30 g/g IM injected intrathoracically; duration 25 minutes Procaine 25 mg/kg anesthesia within 20-30 sec, duration 2-3 h Xylazine HCl 70 mg/kg anesthesia within 5-6 min, duration 45 min 16-22 mg/kg anesthesia within 2-3 min Gastropods analgesia has not been addressed in the literature. Anesthetic agents have been used. Agent Ketamine

Insects As of this time, the ways to alleviate pain in insects are: a. to kill the animal humanely b. to apply supportive care. Nematodes roundworms - respond to neuroactive drugs Agent Dose Comment Gramine 0.01 mg/ml serotonin antagonist inhibits pumping Imipramine 20g/ml stimulates pumping; high concentration act as anesthetic Ivermectin 0.05 ng/ml inhibits pumping Muscimol 2g/ml This GABA agonist inhibits pumping Serotonin 1 mg/ml stimulates pumping Oligochaetes Leech only 5% ethanol is mentioned for anesthesia Polychaetes only MgCl2 for anesthesia is mentioned Sponges although surgery has been performed for decades, no anesthetics or analgesics are reported Tubellarians flatworms-flukes-tapeworms respond with characteristic behaviors to dopaminergic agonists and antagonists. Low levels of cocaine cause them to become motionless. References Flecknell, PA Analgesia and Post-Operative Care in Laboratory Animal Anaesthesia 3rd Edition, Elsevier/Academic Press, London, UK 160-174, 2009 Carpenter, JW. Exotic Animal Formulary, Elsevier/Saunders, St. Louis, MO, 2005 Fish RE, Brown MJ, Danneman PJ and Karas AZ. Anesthesia and Analgesia in Laboratory Animals, Academic Press, London, UK, 2008 Longley L., Anaesthesia of Exotic Pets, Saunders/Elsevier, London, UK, 2008 Johnson-Delany, C. Exotic Companion Medicine Handbook Wingers Publishing, INC, Lake Worth, FL 1996 Lewbart, GA. Invertebrate Medicine Blackwell Publishing, Ames, Iowa 2006 In conclusion, no matter if the veterinary practice is companion animal, large animal, exotic-zoo-wildlife or laboratory animal, no animal deserves to hurt, suffer or be in pain. In 1965, the UK government commissioned an investigation - led by Professor Roger Brambell - into the welfare of intensively farmed animals. On the basis of Professor Brambell's report, the UK government set up the Farm Animal Welfare Advisory Committee in 1967, which became the Farm Animal Welfare Council in 1979. The committee's first guidelines recommended that animals require the freedoms to "stand up, lie down, turn around, groom themselves and stretch their limbs". The guidelines have since been elaborated to become known as the Five Freedoms14: Freedom from thirst and hunger - by ready access to fresh water and a diet to maintain full health and vigor. Freedom from discomfort - by providing an appropriate environment including shelter and a comfortable resting area. Freedom from pain, injury, and disease - by prevention or rapid diagnosis and treatment. Freedom to express normal behavior - by providing sufficient space, proper facilities and company of the animal's own kind. Freedom from fear and distress - by ensuring conditions and treatment which avoid mental suffering.

It is our ethical duty to see that each patient receives adequate veterinary care in accordance with recommendations of the National Research Council published in the "Guide for the Care and Use of Laboratory Animals" 8th Edition 2010. Remember that physical medicine therapies such as rehabilitation, acupuncture, herbal, chiropractic and massage may be incorporated into an analgesic plan often with no detriment to a research protocol. Each and every person in the veterinary practice has a vital role to play in pain management. This includes the research setting where the veterinary staff is dependent on the observations of the animal care staff and the principle investigators and their laboratory staff as well as the veterinary practice. In the veterinary practice the veterinarian, practice

manager, veterinary technicians/nurses, receptionist, kennel staff and groomers all play a unique role that aids in keeping animals pain free. Remember to look at each of your patients, whether tiny or big, for the Fourth Vital Sign and do not allow them to suffer once you have identified it. I would like to personally thank Dr. Tamara Grubb and Dr. Robin Downing for their assistance with this manuscript. Their wisdom and experience are invaluable. Footnotes 1. International Association for the Study of Pain Retrieved 6 October 2009. This often quoted definition was first formulated by an IASP Subcommittee on Taxonomy Bonica, JJ (1979). "The need of a taxonomy". Pain 6 (3): 247 252. 2. Lynn, B (1984) "Cutaneous nociceptors" in Holden, AV & Winlow, W The neurobiology of pain. Manchester, UK: Manchester University Press. p. 106. 3. Woolf, CJ & Mannion, RJ (1999) "Neuropathic pain: aetiology, symptoms, mechanisms and management". The Lancet 353 (9168): 19591064. 4. Raj, PP (2007) "Taxonomy and classification of pain" in Kreitler, S; Beltrutti, D; Lamberto, A et al. The handbook of chronic pain. New York: Nova Science Publishers Inc. 5. McGraw-Hill Concise Dictionary of Modern Medicine. 2002 by The McGraw-Hill Companies, Inc. 6. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain Suppl 1986; 3:S1-S226. 7. Bogduk, Nikolai; Merskey, Harold (1994). Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms (2nd ed.). Seattle: IASP Press. pp. 212. 8. Morton, D. B. and Griffiths, P. H. M. (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Veterinary Record 116: 431-436. 9. Karas, AZ; Danneman, PJ; Cadillac JM (2008) Strategies for Assessing and Minimizing Pain in Anesthesia and Analgesia in Laboratory Animals (2nd Ed). London: Elsevier Inc. p211. 10. Flecknell, P (1999) Pain-assessment, alleviation and avoidance in laboratory animals ANZCCART News 12 (4) December pp 1-10 pg 4. 11. Woolf CJ. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Annals of Internal Medicine 140:441-451, 2004. 12. Woolf CJ. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Annals of Internal Medicine 140:441-451, 2004. 13. Karas, AZ; Danneman, PJ; Cadillac JM (2008) Strategies for Assessing and Minimizing Pain in Anesthesia and Analgesia in Laboratory Animals (2nd Ed). London: Elsevier Inc. p205. 14. Five Freedoms: Farm Animal Welfare Council: http://www.fawc.org.uk/freedoms.htm References 1. Animal Welfare Act (7 U.S.C. __ 2131 et. seq.) Code of Federal Regulations Title 9, Volume 1, Part 2, _ 2.31 [Revised as of January 1, 2000]

2. Health Research Extension Act, P.L 99-158, November 20, 1985 "Animals in Research" Interagency Research Animal Committee (IRAC). Federal Register; May 20, 1985. Public Health Service Policy on Humane Care and Use of Laboratory Animals (Revised September, 1986, Reprinted March, 1996) 3. Code of Federal Regulations Title 9, Volume 1, Part 2, _ 2.36 [Revised as of January 1, 2000] US Department of Agriculture, APHIS, Animal Care Division. Policy #11 --- Painful/Distressful Procedures --- April 14, 1997. 4. .Dennis SG and R Melzack. 1983. Perspectives on phylogenetic evolution of pain expression. In Animal Pain: Perception and Alleviation, RL Kitchell and HH Erickson, eds. American Physiological Society. Bethesda, MD, pages 151-160. 5. Hughes HC and CM Lang. 1983. Control of pain in dogs and cats. In Animal Pain: Perception and Alleviation, RL Kitchell and HH Erickson, eds. American Physiological Society. Bethesda, MD, pages 207-216. Morton DB and HM Griffiths. 1985. 6. Guidelines on the recognition of pain, distress and discomfort in experimental animals and a hypothesis for assessment. Vet Record 116(16):431-436. 7. Morton DB. 1986. Assessment of pain (Letter). Vet Record 119(17):435. 8. Spinelli JS and H Markowitz. 1987. Clinical recognition and anticipation of situations likely to induce suffering in animals. JAVMA 191(10):1216-1218. 9. National Research Council. 1992. Recognition and Alleviation of Pain and Distress in Laboratory Animals. Committee on pain and distress in laboratory animals, ILAR. National Academy Press. Washington, D.C., 10. Chapter 4, pages 32-52. FELASA Working Group on Pain and Distress. 1994. 11. Pain and distress in laboratory rodents and lagomorphs. Laboratory Animals 28:97-112. 12. American College of Veterinary Anesthesiologists. 1998. 13. Position paper on the treatment of pain in animals. JAVMA 213(5):55-57. 14. Wolfle TL. 1987. Control of stress using non-drug approaches. JAVMA 191(10):1219-1221. 15. Flecknell PA. 1996. Laboratory Animal Anesthesia: A Practical Introduction for Research Workers and Technicians. Academic Press; ISBN: 0122603613. 16. Loew FM. 1987. The challenge of balancing experimental variables: pain, distress, analgesia and anesthesia. JAVMA 191(10):1193-1194. 17. Benson GJ and JC Thurmon. 1987. Species differences as a consideration in alleviation of animal pain and distress. JAVMA 191(10):1227-1230. 18. The Humane Society of the United States. 2000. U.S. Humane Society challenges scientists to end research animal pain and distress by 2020. Press release 27 April. 19. Morton DB. 1985. Pain and laboratory animals (Letter). Nature 317:106, 12 Sept. 20. Code of Federal Regulations Title 9, Volume 1, Part 2, _ 2.31 d. [Revised as of January 1, 2000] National Research Council. Guide for the Care and Use of Laboratory Animals (Guide), 21. ILAR. National Academy Press. Washington, D.C. 1996; Chapter 3, pages 64-65.

22. Redgate ES; M Deutsch; SS Boggs. 1991. Time of death of CNS tumor-bearing rats can be reliably predicted by body weight-loss patterns. Lab Anim Sci, 41(3):269-273. 23. Wong JP; Saravolac EG; Clement JG; Nagata LP. 1997. Development of a murine hypothermia model for study of respiratory tract influenza virus infection. Lab Anim Sci, 47(2):143-147 April. 24. Ullman-Cullere MH; CJ Foltz. 1999. Body condition scoring: a rapid and accurate method for assessing health status in mice. Lab Anim Sci, 49(3):319-323. 25. Krarup A, P Chattopadhyay, AK Bhattacharjee, JR Burge and GR Ruble. 1999. Evaluation of surrogate markers of impending death in the galactosamine-sensitized murine model of bacterial endotoxemia. Lab Anim Science 49(5):545-550. 26. Vlach KD, JW Boles and BG Stiles. 2000. Telemetric evaluation of body temperature and physical activity as predictors of mortality in a murine model of staphylococcal enterotoxic shock. Comparative Medicine 50(2):160166. 27. Bradley, T. 2001. Recognizing Pain in Exotic Animals. Exotic DVM Vol 3.3 ICE Proceedings 21-26