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My Achy Breaky Herp:Analgesia in the World of Reptiles

Louden Wright, DVM

Resident in Zoological Medicine

University of California, Davis

Overview

• Challenges of reptile analgesia

• How do reptiles feel pain?

• Studying pain relief in reptiles

• Routes of administration

• Drug options

• Summary

Challenges of Reptilian Analgesia

• Difficulty in assessing reptilian pain

• Lack of knowledge regarding pharmacokinetics

• Unknown side effects of many drugs

• Variation in analgesic efficacy across taxa

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Do reptiles feel pain?

• Pain vs. nociception• Nociception is the sensory system’s response to harmful stimuli• Pain implies an emotional response to stimulus

• Pain pathways in reptiles homologous to mammals• Limbic system and cerebral cortex are relatively reduced… but present• More developed in lizards and chelonians than snakes, crocodilians

• Clearly evident behavioral and physiological responses to painful stimuli

• Similar to providing analgesia to mammals or babies that cannot communicate

Pain Pathways

Recognizing Pain and Analgesia(or nociception)

• Behavioral changes• Development of behavioral ethogram

• Abnormal ambulation

• Anorexia

• Hunched posture

• Change in aggression

• Elevated/extended head

• Decreased coiling (snakes)

• Changes in color

• Changes in respiration

Assessment of physiologic parameters• Heart rate

• Blood pressure

• Changes in hormone levels• Catecholamines

• Cortisol

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Who Cares?

• Better case outcome• Less morbidity and mortality in cases of trauma or surgery

• Legal requirement• Animal Welfare Act of 1966• Other animal protection laws

• Scientific data supports analgesia• Nociception has been repeatedly demonstrated• Some analgesics have shown efficacy in reducing evident nociception

• Ethical reasons• Veterinary oath• If they might feel pain, they should be treated as if they do

Studying Analgesia in Reptiles

Case Reports Safety/

Toxicology PK Data Pain models

Chemical

Stimulation

Electro-stimulation

SurgicalThermal

threshold

Surgical Model

• Perform procedure to induce a pain stimulus

• Evaluate efficacy of analgesics in controlling pain• Ethograms• Measurement of heart rate, respiratory rate• Measurement of hormones (cortisol, catecholamines)

• Not all surgical pain is similar

• Ethical dilemma of control groups

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Thermal Threshold Model

• Applies a source of thermal pain to an appendage

• Infrared heat stimulus across acrylic surface

• Measures time elapsed until the limb iswithdrawn

• Not a common clinical source of pain

• Variable thermal nociception in reptiles

Journal of Exotic Pet Medicine 2012 21, 158-167DOI: (10.1053/j.jepm.2012.02.012)

Copyright © 2012 Elsevier Inc

Thermal Threshold Model

• Administered oral or subcutaneous tramadol to red-eared sliders

• Doses of 5 – 10 mg/kg increased thermal withdrawal latency• Analgesia from 6-96 hours• No significant respiratory depression

• Doses of 25 mg/kg caused decreased ventilation frequency• 4/11 turtles also had flaccid limbs and necks

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Electrostimulation Model

• Similar to thermal threshold test, but uses electrical stimulus

• A voltage is applied to the tail or other appendage• Ethogram developed in some species to quantify response

• Has been used in withdrawal latency and volatile anesthetic MAC-sparing studies in reptiles

Electrostimulation Model

• Evaluated published anecdotal doses of several opioids and NSAIDs

• Applied electrical current across the tail and evaluated head, body, and tail movement in response

• Saw evidence for analgesic efficacy with butorphanol(1.5-8 mg/kg), tramadol (11 mg/kg), morphine (1 mg/kg), carprofen (2-4 mg/kg), ketoprofen (2 mg/kg), and meloxicam (0.4 mg/kg)

Chemical Model

• Examined antinociceptive effects of morphine and pethidine

• Habituated tortoises to restraint

• Found decreased duration of painful behavior with both drugs• Naloxone ablated reduction when given concurrently to opioid

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Variation in Results

• A variety of peripheral nociceptors exist• Thermal

• Chemical

• Mechanical

• Not all receptors respond to the same stimuli• Different receptors likely react differently in various species

Route and location of administration

• Intravenous

• Intramuscular

• Subcutaneously

• Orally

• Transdermal

• Intrathecal

Intravenous

• Difficult to access in some species

• Easier than you wound think in others

• Ventral coccygeal vein, jugularvein, ventral abdominal vein

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Intramuscular/Subcutaneous

• Long thought that subcutaneous space was poorly vascularized in reptiles• Some studies have shown more stable PK

in SQ than IM

• Both are appropriate routes of injection

• Administer in cranial half of body• Renal portal system Journal of Exotic Pet Medicine 2012 21, 17-31DOI: (10.1053/j.jepm.2011.11.013)

Copyright © 2012 Elsevier Inc

Oral

• Often avoided due to concern about slow uptake or slow gastrointestinal transit time

• Oral administration of tramadol to turtles resulted in quicker onset and longer duration of action than subcutaneous administration. (Baker et al 2011)

• Analgesic effect seen in turtles within 4 hours of administration (Baker et al 2011)

Transdermal

• Very little data on this route of administration

• Keratinized skin may make absorption challenging

• Transdermal fentanyl patch examined in two species• Prehensile tailed skink – highly variable rate of absorption (Gamble 2008)

• Ball pythons achieved high plasma fentanyl concentrations (Kharbush et al 2017)

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Intrathecal

• Administration of local anesthetic to intrathecal space• Lidocaine 4 mg/kg• Bupivicaine 1 mg/kg• Morphine 0.1-0.2 mg/kg• Must use preservative-free formulations

• Indications include surgery of the phallus, tail,cloaca and pelvic limbs

• Turtles should be adequately sedated oranesthetized before performing this

Journal of Exotic Pet Medicine 2012 21, 17-31DOI: (10.1053/j.jepm.2011.11.013)Copyright © 2012 Elsevier Inc

Opioids

• Classified by receptor subtype (mu kappa, delta)• Full mu-receptor agonist

• Partial mu-receptor agonist

• Mixed receptor agonist

• All receptor classes are expressed in reptiles• Mu opioid receptors have been confirmed in the spinal cord and brain of ball

pythons and red-eared sliders (Kharbush et al 2017)

• Lack of understanding about effects of each receptor

• Monitor respiratory status with ANY opioid administration

Butorphanol• Mixed mu-receptor antagonist, kappa-receptor agonist• Massive variation is dosage reported

• 0.02-25 mg/kg (Read 2004)

• Doses >10 mg/kg associated with potentially fatal respiratory depression

• Questionable efficacy• No apparent analgesic efficacy in bearded dragons, red-eared sliders, and iguanas

(Fleming and Robertson 2007, Mosley et al 2003, Sladky et al. 2008, 2009)• Electrical stimulation model suggested some analgesic efficacy in iguanas (Greenacre et

al 2006, 2008)

• Respiratory effects• High dose (28 mg/kg) showed transient respiratory depression in red-eared sliders (Sladky

et al 2007)• Anecdotal reports of death in snakes administered high dose butorphanol (Sladky and Mans

2012)

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Buprenorphine

• Partial mu-opioid receptor agonist

• No evidence of analgesic efficacy• 0.075-0.1 mg/kg SC, IM

• Did NOT increase latency withdrawal time from thermal stimuli• In red-eared sliders dosed at 0.2 mg/kg (Mans et al 2011)

• Did NOT show analgesic effect from electrical stimuli• In green iguanas up to 0.1 mg/kg (Greenacre et al 2006)

Morphine

• Pure mu-opioid receptor agonist• Recommended doses are 0.5-4 mg/kg

• Effective analgesia in a variety of species with different pain models• Bearded dragons, crocodiles, red-eared sliders showed increased thermal tolerance

(Baker et al 2011, Kanui and Hole 1992, Sladky et al 2008)

• Decreased duration of nociceptive behavior in Speke’s hinged tortoise with formalin test (Wambugu et al 2010)

• Increased electrical stimulation tolerance in green iguanas and bearded dragons (Greenacre et al 2006, 2008)

• Can cause severe respiratory • Doses >5mg/kg are not recommended

Hydromorphone

• Pure mu-opioid receptor agonist

• Five times as potent as morphine

• Increases thermal tolerance in red-eared sliders (Mans et al 2012)

• Increased thermal withdrawal time for 24 hours (0.5mg/kg SQ)

• Recommended dosages are 0.5–1 mg/kg

West-ward.com

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Tramadol

• Causes anti-nociception through several routes• Mu opioid receptor agonist, although weaker than morphine• Inhibits reuptake of and increases concentrations of serotonin and norepinephrine

in CNS

• Analgesic efficacy has been shown in chelonians and lacertilians• 5-10 mg/kg provides analgesia for 24 hours in chelonians (Baker et al 2011, Giorgi et al 2015)

• Similar dose provided analgesia to bearded dragons (Greenacre et al 2008)

• No significant respiratory depression reported at these doses

• Respiratory depression still seen at higher doses• 25 mg/kg led to profound respiratory depression in red-eared sliders (Baker et al 2011)

Fentanyl

• Pure mu opioid receptor agonist• 75 to 100 times the potency of morphine• IV or transcutaneous administration

• Prehensile tailed skinks and ball pythons absorb and maintain high levels of fentanyl administered transcutaneously• Skinks showed no change in behavior (Gamble 2008)

• Ball pythons showed no analgesic effects (Kharbush et all 2017)

• Analgesic efficacy has not been determined• Further research is indicated, given positive results of other mu-receptor agonists

NSAIDs

• Block binding of arachidonic acid to cyclooxygenase (COX) enzymes• Prevents production thromboxane B2

• In turn prevents production of inflammatory prostaglandins

• Classified for specificity for COX-1 or COX-2

• Reptilian COX expression• Eastern box turtles produce high levels of COX-1 & 2 in the liver and kidneys

• Also produce higher levels of COX-1 than COX-2 in inflamed muscle (Royal et al. 2012)

• Ball pythons express higher COX-1 than COX-2 concentrations in inflamed skin (Sadler et al 2016)

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NSAIDs

• Ketoprofen (Equipotent between COX-1 and COX-2)• Short half life when administered IM in green iguanas at 2 mg/kg (Tuttle et al. 2006)

• No information on efficacy

• Meloxicam (COX-2 specific NSAID)• Doses from 0.1-0.5 mg/kg IV, IM, SQ, PO, q 24-48h have been recommended

• Provided measurable levels for 24 hours in iguanas (0.2 mg/kg) (Hernandez-Divers et al 2004)

• Did not alter post-operative behavior in ball pythons (0.3 mg/kg) (Olesen et al 2008)

• Suggestion of enterohepatic or renal recirculation in chelonians (Rojo-solis et al 2009)

• No studies on safety or toxicity in reptiles

Local Anesthetic Drugs(lidocaine, bupivacaine, mepivacaine)

• Na-channel blockers that prevent transduction of nerve impulses

• Single study examining efficacy (Wellehan et al 2006)

• Successful mandibular nerve block in crocodilian species with mepivacaine

• Intrathecal efficacy has been shown in chelonians

• Lidocaine 4 mg/kg

• Bupivicaine 1 mg/kg

• Morphine 0.1-0.2 mg/kg

• Drug formulations are acidic

• Consider dilution with bicarbonate or saline

Journal of Zoo and Wildlife Medicine 2006 37-3, 405-408 DOI: 10.1638/05-047.1 Copyright © 2006 American Association of Zoo Veterinarians

Other Parenteral Analgesics

• Ketamine• Used at a low dose for analgesia in mammals

• Increases sedation in reptile species

• Analgesic efficacy has not been evaluated

• α-2-adrenergic agonists• Medetomidine, dexmedetomidine frequently used for sedation

• Analgesic efficacy has not been evaluated

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Multi-modal analgesia

• Administration of medications that provide analgesia at various spots of the central and peripheral nervous system• Opioids – central nervous system• NSAIDs – peripheral inflammation• Local anesthetics – peripheral transmission of nociception

• May be the most appropriate approach to pain in reptiles• Minimizes risk of adverse side effects

• Most effective prior to painful stimulus

Summary

• Opioids• Butorphanol has shown minimal efficacy across a variety of taxa

• Mu-opioid receptor agonists have consistently shown the greatest effect

• Risk of respiratory depression

• NSAIDs• Evidence of COX-1 and COX-2 production in reptiles

• COX-1 may be more closely tied to inflammation in reptiles

• More research is needed into efficacy and safety across taxa

• Local anesthetics• Show promise in local and intrathecal administrations

Taxa Summary

• Chelonians• Mu-opioid receptor agonists appear efficacious, though high doses cause some respiratory

depression• Intrathecal administration of local anesthetics or morphine is effective for regional analgesia

• Lacertilians• Mu-opioid receptor agonists appear efficacious, though are associated with respiratory

depression

• Ophidians• No medications have shown consistent efficacy in reducing nociceptive behavior• Inflammatory response may be tied to COX-1

• Crocodilians• Mepivacaine works to block nerves locally• … that’s about it.

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Literature Cited

• Baker BB, Sladky KK, Johnson SM. Evaluation of the analgesic effects of oral and subcutaneous tramadol administration in red-eared slider turtles. Journal of the American Veterinary Medical Association. 2011 Jan 15;238(2):220-7.

• Darrow BG, Myers GE, Sladky KK, KuKanich B. Fentanyl transdermal therapeutic system pharmacokinetics in ball pythons (Python regius). InProc Annu Conf Am AssocZoo Vet 2010 (pp. 238-239).

• Fleming GJ, Robertson SA. Use of thermal threshold test response to evaluate the antinociceptive effects of butorphanol in juvenile green iguanas (Iguana iguana). In: Proceedings 2006 Sep 19 (pp. 279-280). Annu Meet Am Assoc Zoo Vet.

• Gamble KC. Plasma fentanyl concentrations achieved after transdermal fentanyl patch application in prehensile-tailed skinks, Corucia zebrata. J Herp Med Surg. 2008;18(3-4):81-5.

• Greenacre CB, Takle G, Schumacher J, Klaphake EK, Harvey RC. Comparative antinociception of morphine, butorphanol, and buprenorphine versus saline in the green iguana, Iguana iguana, using electrostimulation. J Herpetol Med Surg. 2006;16:88-92.

• Greenacre CB, Massi K, Schumacher JP. Comparative antinociception of various opioids and non-steroidal anti-inflammatory medications versus saline in the bearded dragon (Pagona vitticeps) using electrostimulation. Proceedings of the Association of Reptilian and Amphibian Veterinarians. Los Angeles (CA). 2008:87.

• Hernandez-Divers SJ, McBride M, Koch T, Perpinian D, Wilson GH, Stedman NL. Single-dose oral and intravenous pharmacokinetics of meloxicam in the green iguana (Iguana iguana). InProc. Assoc. Rept. Amphib. Vet 2004 (Vol. 2004, pp. 106-107).

• Kanui TI, Hole K. Morphine and pethidine antinociception in the crocodile. Journal of veterinary pharmacology and therapeutics. 1992 Mar 1;15(1):101-3.

• Kharbush RJ, Gutwillig A, Hartzler KE, Kimyon RS, Gardner AN, Abbott AD, Cox SK, Watters JJ, Sladky KK, Johnson SM. Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain μ-opioid receptor mRNA expression in ball pythons. American journal of veterinary research. 2017 Jul;78(7):785-95.

• Kinney ME, Johnson SM, Sladky KK. Behavioral evaluation of red-eared slider turtles (Trachemys scripta elegans) administered either morphine or butorphanol following unilateral gonadectomy. Journal of Herpetological Medicine and Surgery. 2011 Jun;21(2):54-62.

• Mans C. Clinical technique: Intrathecal drug administration in turtles and tortoises. Journal of Exotic Pet Medicine. 2014 Jan 1;23(1):67-70.

• Mans C, Lahner LL, Baker BB, Johnson SM, Sladky KK. Antinociceptive efficacy of buprenorphine and hydromorphone in red-eared slider turtles (Trachemys scriptaelegans). Journal of Zoo and Wildlife Medicine. 2012 Sep 20;43(3):662-5.

Literature Cited

• Mosley CA, Dyson D, Smith DA. Minimum alveolar concentration of isoflurane in green iguanas and the effect of butorphanol on minimum alveolar concentration. Journal of the American Veterinary Medical Association. 2003 Jun 1;222(11):1559-64.

• Olesen MG, Bertelsen MF, Perry SF, Wang T. Effects of preoperative administration of butorphanol or meloxicam on physiologic responses to surgery in ball pythons. Journal of the American Veterinary Medical Association. 2008 Dec 15;233(12):1883-8.

• Read MR. Evaluation of the use of anesthesia and analgesia in reptiles. Journal of the American Veterinary Medical Association. 2004 Feb 1;224(4):547-52.

• Royal LW, Lascelles BD, Lewbart GA, Correa MT, Jones SL. Evaluation of cyclooxygenase protein expression in traumatized versus normal tissues from eastern box turtles (Terrapene carolina carolina). Journal of Zoo and Wildlife Medicine. 2012 Jun;43(2):289-95.

• Sadler RA, Schumacher JP, Rathore K, Newkirk KM, Cole G, Seibert R, Cekanova M. Evaluation of the role of the cyclooxygenase signaling pathway during inflammation in skin and muscle tissues of ball pythons (Python regius). American journal of veterinary research. 2016 May;77(5):487-94.

• Sladky KK, Kinney ME, Johnson SM. Analgesic efficacy of butorphanol and morphine in bearded dragons and corn snakes. Journal of the American Veterinary Medical Association. 2008 Jul 15;233(2):267-73.

• Sladky KK, Kinney ME, Johnson SM. Effects of opioid receptor activation on thermal antinociception in red-eared slider turtles (Trachemys scripta). American journal of veterinary research. 2009 Sep;70(9):1072-8.

• Sladky KK, Mans C. Clinical anesthesia in reptiles. Journal of exotic pet medicine. 2012 Jan 1;21(1):17-31.

• Sladky KK, Miletic V, Paul-Murphy J, Kinney ME, Dallwig RK, Johnson SM. Analgesic efficacy and respiratory effects of butorphanol and morphine in turtles. Journal of the American Veterinary Medical Association. 2007 May 1;230(9):1356-62.

• Sladky KK, Miletic V, Paul-Murphy J, Kinney ME, Dallwig RK, Johnson SM. Analgesic efficacy and respiratory effects of butorphanol and morphine in turtles. Journal of the American Veterinary Medical Association. 2007 May 1;230(9):1356-62.

• Wambugu SN, Towett PK, Kiama SG, Abelson KS, Kanui TI. Effects of opioids in the formalin test in the Speke’s hinged tortoise (Kinixy’s spekii). Journal of veterinary pharmacology and therapeutics. 2010 Aug 1;33(4):347-51.

• Wellehan JF, Gunkel CI, Kledzik D, Robertson SA, Heard DJ. Use of a nerve locator to facilitate administration of mandibular nerve blocks in crocodilians. Journal of Zoo and Wildlife Medicine. 2006 Sep;37(3):405-8.

• Williams CJ, James LE, Bertelsen MF, Wang T. Tachycardia in response to remote capsaicin injection as a model for nociception in the ball python (Python regius). Veterinary anaesthesia and analgesia. 2016 Jul 1;43(4):429-34.