Introduction

Effective management of pain in non-mammalian vertebrates continues to be a challenge for veterinarians. In addition to enhanced recovery from surgery and disease, strategic use of analgesics will significantly improve the quality of anesthetic episodes in these species (from intubation to maintenance of a stable anesthetic plane). Pathways of nociception similar to those in observed mammals have been identified in amphibians and reptiles and faster resumption of normal behavior demonstrated with the use of appropriate analgesic protocols. Current publications have significantly advanced our understanding of nociception and effects of various analgesics in these species, providing opportunities for improved quality of care. Ongoing discussion of pain versus nociception in these species should not deter the clinician to use mammalian guidelines for identifying sources of pain and providing analgesia.^1,5,8-11 For the continuation of this document, we will refer to pain and analgesia/pain management.

As in mammals, pain left untreated causes significant morbidity in these patients and may lead to failure to thrive, delayed healing and possibly death. Understanding clinical manifestation of pain in these species is challenging, as is the application of the studies in various species.

The objectives of this presentation are 1) to review current knowledge on pain perception and clinical models used for studying analgesics; 2) to describe clinical signs of pain; and 3) to understand options for analgesia in amphibian and reptilian patients. Case presentations will be used to illustrate simple or multimodal approaches to common problems in these species with the purpose to improve patient welfare and case outcome.

Nociception, Pain Perception, and Experimental Models

Presence and conservation of opioid ligand and receptors and nociception pathways, combined with appropriate evasive behaviors following the application of noxious stimuli, have been demonstrated in amphibians and reptiles. Establishing reliable analgesimetry models (updated noxious stimulus: acetic acid test with swiping response in amphibians and limb withdrawal or evasive behavior following thermal or electrical stimulation in reptiles) has significantly enhanced our understanding of drug efficacy in different species, especially for opioids.^1,10,11

Recognizing Pain in Amphibian and Reptile Patients

Understanding normal behavior of amphibians and reptiles is essential to recognize signs of pain. Sources of acute pain, such as in cases of burns, fracture of bone or shell, invasive and painful procedures, surgery, etc., are perhaps more easily identified. Conditions causing chronic pain including gout, renal disease, and neoplastic processes, must be recognized and analgesia should be incorporated in the therapeutic regimens. It is also well recognized that hypothermia lowers pain threshold (in addition to severely compromising the condition of the animal), and should never be used for analgesia, restraint, or anesthesia in reptiles and amphibian species.²

Signs of pain in amphibians are vague and must be differentiated from clinical signs caused by ongoing disease processes. They can include: decreased activity, increased hiding, hypophagia (which can be difficult to discern from ongoing medical or surgical condition. Amphibians are known to produce endorphins called dermorphins, in response to pain however this should not preclude the use of opioids for analgesia.^7,11

Clinical manifestations of pain in reptiles exclude vocalization. They can also be vague and include the following: increased aggression, restlessness, decreased activity and increase hiding behavior, increased respiratory rate, self-mutilation, hypophagia, abnormal posture (hunched-up or crouched position, keeping limb at an abnormal angle, abnormal angle in water column for aquatic species), reluctance to lie down, and abnormal gait.

Therapeutic Options

There is limited, but growing, knowledge on the distribution, efficacy, and secondary effects of analgesic drugs. Species-specific variations have also been reported, complicating the interpretation and application of published information.^8-10

Accurate body weight must be obtained prior to the calculation of drug doses. In addition, each patient must be kept at the preferred optimal temperature zone (POTZ) to assure maximal absorption, metabolism and excretion of the drugs in addition to maintaining normal body functions. Finally, adequate fluid therapy to maintain hydration must be continued throughout the course of treatment, as indicated by the condition of the animal. Potentially nephrotoxic drugs should be used judiciously if a non-steroid anti-inflammatory drug (NSAID) is selected.⁷

Prevention of pain is still the most effective method and a multimodal approach is recommended. Pre-anesthetic protocols should include analgesics if surgery or pain is anticipated and can be followed with post-operative treatment as long as clinically indicated.²

Amphibians

Reports in the literature include the successful use of flunixin meglumine butorphanol (25 mg/kg intracoelomic), xylazine (10 mg/kg intracoelomic) and morphine (10 mg/kg IM) as effective analgesic options.¹¹ The author has also used short courses of SC or IM meloxicam at 0.2 mg/kg with apparent clinical effects.^7,11

Tricaine methanesulfonate (a sodium channel blocker, trade names including MS-222, Finquel) continues to be the most effective and popular anesthetic agent in these species. It has both analgesic and at higher doses, anesthetic properties. Sodium bicarbonate must be added to the water at the time of the dilution since the drug is highly acidic (testing is recommended but a good rule of thumb is to add the same weight of bicarbonate 1:1). Recommended doses for inducing maintaining anesthesia vary with species (0.25–3 g/L). Thus analgesic doses must be significantly reduced and are likely to cause some level of sedation.⁷

A total of 1.0 mg/kg of lidocaine or bupivacaine is recommended if topical or regional block are used.^7,11

Reptiles

In the great majority of reptilian species as in mammals, mu opioid receptors predominate and mu-agonists have been shown to be effective analgesics. Drugs that are mainly kappa agonist have minimal to no measurable effects.^8-10

Morphine (1.5–5.0 mg/kg SC, IM) and tramadol (oral or subcutaneously at 1–2 mg/kg every 24–48 hours or 5–10 mg/kg every 5–7 days) are now recommended.^1,8-10 In all cases, effective doses will cause significant and dose-dependent respiratory depression and respiratory function must be closely monitored. Using transdermal absorption, fentanyl patches may provide an alternate option for analgesia at 12.5 mcg/h and 25 mcg/h for 72 hours.^4,5 The use of hydromorphone at 0.5 mg/kg SC provides adequate analgesia (thermal stimulus).¹⁰

So far, in species tested, butorphanol and buprenorphine are ineffective analgesics in reptiles except in corn snakes where butorphanol seems to provide analgesia.^8-10

Selected non-steroidal anti-inflammatory drugs have been used in reptiles with significant clinical response. Meloxicam at 0.2 mg/kg once a day is used in several species, and ketoprofen 2 mg/kg seems to be effective in bearded dragons.^3,12

Pre-medication with medetomidine (0.1 mg/kg) and ketamine (5 mg/kg) prior to induction of anesthesia will provide pre-emptive analgesia and will help maintain a more stable level of anesthesia.⁶

Topical or regional blocks help in providing additional analgesia during surgical procedures. Lidocaine and bupivacaine can be used. Because of the very small weight of some of these patients, calculation of maximum doses and appropriate dilution of the solution is essential to avoid toxicity (reported guidelines recommend total doses not exceeding 1–2 mg/kg of bupivacaine and 1–4 mg/kg of lidocaine).⁶

References

1.  Baker, B. B., K. K. Sladky, and S. M. Johnson. 2011. Evaluation of the analgesic effects of oral and subcutaneous tramadol administration in red-eared slider turtles. J. Am. Vet. Med. Assoc. 238: 220–227.

2.  Bertelsen, M. F. Squamates (snakes and lizards). 2007. In: West, G., D. Heard, and N. Caulkett (eds.). Zoo Animal & Wildlife Immobilization and Anesthesia. Blackwell Publishing, Ames, Iowa. Pp. 223–232.

3.  Divers, S. J., M. Papich, M. McBride, N. L. Stedman, D. Perpinan, T. F. Koch, S. M. Hernandez, G. H. Baron, M. Pethel, and S. C. Budsberg. 2010. Pharmacokinetics of meloxicam following intravenous and oral administration in green iguanas (Iguana iguana). Am. J. Vet. Res. 71: 1277–1283.

4.  Gamble, K. 2008. Plasma fentanyl concentrations achieved after transdermal fentanyl patch application in prehensile tailed skinks, Corucia zebrata. J. Herpetol. Med. Surg. 34: 81–85.

5.  Gutwilling, A., and A. Abbott. 2012. Opioid dependent analgesia in ball pythons (Python regius) and corn snakes (Elaphe guttata). Proc. Assoc. Rept. Amphib. Vet. 2012: 66.

6.  Schumaker, J. 2007. Chelonians (turtles, tortoises, and terrapins). In: West, G., D. Heard, and N. Caulkett (eds.). Zoo Animal & Wildlife Immobilization and Anesthesia. Blackwell Publishing, Ames, Iowa. Pp. 259–268.

7.  Setter, M. 2007. Amphibians. In: West G., D. Heard, and N. Caulkett (eds.). Zoo Animal & Wildlife Immobilization & Anesthesia. Blackwell Publishing. Ames, Iowa. Pp. 205–210.

8.  Sladky, K. K., V. Miletic, J. Paul-Murphy, M. E. Kinney, R. K. Dallwig, and S. M. Johnson. 2007. Analgesic efficacy and respiratory effects of butorphanol and morphine in turtles. J. Am. Vet. Med. Assoc. 230: 1356–1362.

9.  Sladky, K. K., and M. E. Kinney. 2008. Analgesic efficacy of butorphanol and morphine in bearded dragons and corn snakes. J. Am. Vet. Med. Assoc. 233: 267–273.

10. Sladky, K. K. 2012. Clinical analgesia in reptiles. J. Exot. Pet Med. 21: 158–167.

11. Stevens, C. W. 2011. Analgesia in amphibians: preclinical studies and clinical applications. Vet. Clin. Exot. Anim. 14: 33–44.

12. Tutle, A. D., M. Papich, G. A. Lewbart, S. Christian, C. Gunkle, and C. A. Harms. 2006. Pharmacokinetics of ketoprofen in the green iguana (Iguana iguana) following single intravenous and intramuscular dose injections. J. Zoo Wildl. Med. 37: 567.