Pain management in reptile patients (Proceedings)

When one speaks of pain management in dogs they are discussing one species with research to back up their statements. Did you realize there are over 7000 species of reptiles? The three major orders are snakes, lizards and turtles. Commonly kept species of snakes range in size from a cornsnake (Elaphe guttata) at 2 feet to a Burmese Python (Python molurus) at 12 or more feet. Not only are they of different in size, but some reptiles are from the rain forest and some are from the desert, some are New World species (from South America for example) and others are Old World species (from Australia or Africa for example). In addition, it is known that different species of reptiles metabolize several drugs differently than other reptiles. For example, turtles die after administration of ivermectin, but most snakes (indigos are an exception) and most lizards (skinks are an exception) do not. It is hypothesized that turtles have GABA receptors in places other than the brain or that the blood:brain barrier in turtles allows ivermectin passage. Urocoan rattlesnakes, milk snakes, tricolor king snakes and indigo snakes all require a much lower dose of metronidazole than other species. There are many unknowns in regards to the metablolism or action of pain relieving drugs in the many species of reptiles. Therefore, when assessing a reptile patient for signs of pain, or deciding on which pain reliever to use, or what dose and how often to administer, it must be taken into account that there is NO GENERIC REPTILE, and one must be familiar with the very limited scientific research that has been conducted regarding pain management in reptiles. Also, each patient must be evaluated and re-evaluated individually and constantly.

Reptiles are poikilothermic, or "cold blooded" animals, therefore, their body temperature is roughly room temperature. Realize though that a reptile can maintain a body temperature for several hours, so if a reptiles is cold to the touch in the examination room that just left its home environment a hour ago, then that reptile should still be warm. Also, "pre-heating" of reptiles prior to surgery or heating as part of therapy is a common and an integral part of reptile medicine, because it is used to increase the metabolic rate. Ideally a reptile should be maintained within its "preferred optimum temperature zone" or POTZ for optimal metabolism of medications.

In general, turtles, with a suspected slower metabolic rate, are administered medications less frequently (for example an antibiotic is given every 3 days) than snakes (same antibiotic may be given every 2 days) than lizards (same antibiotic may be given every day).

What research has been done in reptiles and what is known?

Few studies have evaluated pain perception in reptiles. A 1969 study of indigo snakes (Drymarchon corais couperi), bull snakes (Pituophis catenfir sayi)] and one caiman (Caiman crocodilus) showed that relatively high doses of the opioids, etorphine (up to 5000 ug/kg), oxymorphone (1.5 mg/kg), and meperidine (200 mg/kg) produced no significant outward effects. So, for many years after the 1969 study veterinarians mistakenly assumed that those opioids had no analgesic effect either For comparison purposes, a typical canine dose of butorphanol (an opioid) is 0.2 mg/kg and causes sedation in the dog, whereas iguanas given 8.0 mg/kg IM showed no sedation at all.

Later studies showed more promise at evaluating pain perception in reptiles, or at least antinociception (avoidance of noxious stimuli). Curly-tailed lizards (Leiocephalus carinatus) given morphine (1-3 mg/kg) significantly increased their behaviorly selected body temperatures and this effect could be blocked and reversed with the opioid antagonist naloxone (1 and 10 mg/kg), suggesting opiate control of behavioral thermoregulation in lizards. Crocodiles (Crocodylus niloticus africana) exposed to a hot plate had significantly (P<0.001) increased response latency for "escape" or "lifting the foot" after intramuscular administration of morphine (0.5 and 0.05 mg/kg, respectively) or meperidine (2.0 and 1.0 mg/kg, respectively). Exposure to the hot plate as a stimulus provided a better pain model than did ocular instillation of capsaicin or intramuscular injection of formalin in these crocodiles, since it allowed for the measure of supertheshold "escape" responses, as well as threshold "lifting the foot" responses.

In a recent study, green iguanas (Iguana iguana) displayed no significant isoflurane sparing effect when butorphanol (1.0 mg/kg IM) was administered one to two hours prior to determination of the minimum alveolar concentration (MAC). In the latter study, electrostimulation of the tail was used to deliver the supramaximal stimulus needed to evaluate MAC changes under anesthesia.

My research on green iguanas showed a significantly (P≤0.05) lower response to near threshold electrostimulation after administration of the following drugs when compared to saline: morphine at 1.0 mg/kg IM, and butorphanol at 1.5 and 8.0 mg/kg IM. These findings indicated these drugs, at these dosages, provided some degree of analgesia. Further research on bearded dragons (18) evaluating a wide array of analgesics using the same pain model has been completed and will be published soon. Significantly (P≤0.05) lower tail movement responses were seen with the following drugs when compared to saline: butorphanol (at 1.5, 4.0 and 8.0 mg/kg IM), tramadol (at 11 mg/kg PO), morphine (at 1 mg/kg IM), carprofen (at 2 and 4 mg/kg IM), ketoprofen (at 2 mg/kg IM) and meloxicam (at 0.4 mg/kg IM).

Recently the analgesic efficacy and respiratory effects of butorphanol and morphine in red eared slider turtles (27 Trachemys scripta) was evaluated using an infra-red heat stimulus. Thermal withdrawal latencies were not statistically different between saline and butorphanol (at 2.8 or 28 mg/kg IM), but were statistically different for morphine (1.5 or 6.5 mg/kg IM) by 8 hours. Ventilation was depressed by butorphanol and even more so by morphine.

Further studies are needed to determine the pharmacokinetics of various medications in reptiles, including NSAIDs. Some research has been done evaluating opiate receptors in turtles, showing that they have proportionately more delta and kappa receptors, and less mu receptors, than rats. Interestingly, much more is known about amphibian pain and medication since an excellent, dose dependent, pain model is developed in them (the multi-dilution capsaicin swipe test).

Formulary doses and references (from Carpenter's formulary):

Based on my research tramadol (an opiate) (4 mg/kg PO) provided analgesia. I have used this dose clinically in one older iguana with wide spread osteomyelitis and concurrent renal disease and the owner seemed to think it helped the iguana move around easier.

How do you assess pain in reptiles and when do you give analgesics?

It is very difficult to assess pain in reptiles and there are no standard methods or assessments available to assess the level of pain in birds. Therefore, you are left with past experience, observation and anthropomorphism (if I had a fractured bone I would want an opiate). Reptiles seem very stoic and do not cry out in pain. I vividly remember many years ago amputating a rear leg in a chameleon and upon recovery he was making a squeaking-type noise and had tachypnea. Despite having been taught that "opioids don't work in reptiles" I gave him morphine. Fifteen minutes later when he stopped making the noise and breathed a more normal rate, I became a convert and gave reptiles analgesics and became dedicated to study the effects of analgesics in reptiles. In most cases I tend to give both an opiate (butorphanol) and an anti-inflammatory (meloxicam) the first 6 – 48 hours and then use only the anti-inflammatory for about 3 - 5 days. If renal disease is suspected, I will use tramadol instead of an NSAID.

Examples (this is what I currently due and will probably change as we all learn more):

Elective ovariectomy or ovari-ohysterectomy: A common presentation is an iguana with post-ovulatory follicular stasis in need of an ovario-hysterectomy or ovariectomy. A parmedian incision is commonly made with a radiosurgical unit and scissors to avoid the ventral abdominal vein. Ideally lidocaine should be infused into the muscle layers around the area to be cut just prior to cutting. The lidocaine should not be infused right at the incision site because extra liquid interferes with proper function of the radiosurgical unit. I would use butorphanol at 1.5 mg/kg IM about 15 minutes prior to cutting. We also administer IM meloxicam 0.4 mg/kg at this point. After intubation, any surgery in a reptile is ideally completed within an hour. Forced heated air blankets are superb for maintaining a POTZ in reptiles under anesthesia and since we have been using them, reptiles are recovering faster and with more strength. Generally butorphanol is given IM every 4-12 hours after the first injection, until the next morning (no PK or duration of analgesia studies have been performed in reptiles, so frequency of administration is a wild guess). We use appetite, body posture, gait and general activity of the iguana to assess whether not to give the 8 pm and 8 am doses. Generally, if painful, the iguana will exhibit kyphosis in an effort to keep the painful incision from touching the floor of the enclosure floor (unless she is totally debilitated for other reasons, say sepsis). Usually after administration of an effective analgesic, she will allow her coelomic incision to touch the floor. The morning after surgery we generally switch to oral meloxicam and give it once daily for 5 days.

Cat attack: There is usually much swelling associated with cat bites and infection/sepsis is a concern. Fractures can be present. GI absorption of any medication in a reptile is questionable, so if a medication is necessary I administer it IM or SC. Later, when the medication is not life-saving, I may switch to an oral form for the convenience of the owner. Besides fluids, warmth, and a broad spectrum, bacteriocidal antibiotic, I would administer butorphanol at 1.5 mg/kg IM every 4-12 hours and an anti-inflammatory such as meloxicam at 0.4 mg/kg IM every 24 hours.

References

Bennett RA. 1998. Reptile anesthesia. Sem Avian Exot Pet Med, 7(1):30-40.

Bennett RA. 1998. Pain and analgesia in reptiles and amphibians. Proc Assoc Rep Amph Vet, 1-5.

Paul-Murphy J, Ludders JW, Robertson SA, Gaynor JS, Hellyer PW, Wong PL. 2004. The need for a cross-species approach to the study of pain in animals. J Amer Vet Med Assoc, 224(5):692-697.

Mitchell MA. 2002. Diagnosis and Management of reptile orthopedic injuries. Vet Clin No Amer, Exot An Prac, 5(1):97-114.

Lawton MPC. 1999. Pain management after surgery. Proc No Amer Vet Conf, 782.

Machin KL. 2001. Fish, amphibian and reptile analgesia. Vet Clin No Amer Exot An Prac, 4(1):19-30.

Hinsch H, Gandal CP. 1969. The effects of etorphine (M-99), oxymorphone hydrochloride, and meperidine hydrochloride in reptiles. Copeia, 2:404-405.

Greenacre CB, Takle G, Schumacher JP, Klaphake EK, Harvey RC. 2007. Comparative antinociception of morphine, butorphanol, and buprenorphine versus saline in the green iguana (Iguana iguana) using electrostimulation, J Herpetol Med and Surg, 16(3):88-92.

Kavaliers M, Courtney S, Hirst M. 1984. Opiates influence behavioral thermoregulation in the curly-tailed lizard , Leiocephalus carinatus. Physiol Behav, 32(2):221-224.

Kanui TI, Hole K, Miaron JO. 1990. Nociception in crocadiles: capsaicin instillation, formalin and hot plate tests. Zoolog Sci, 7:537-540.

Kanui TI, Hole K. 1992. Morphine and pethidine antinociception in the crocodile. J Vet Pharmacol Therap, 15:101-103.

Mosley CAE, Dyson D, Smith DA. 2003. Minimum alveolar concentration of isoflurane in green iguanas and the effect of butorphanol on minimum alveolar concentration. J Am Vet Med Assoc, 222(11):1559-1564.

Sladky KK, Miletic V, Paul-Murphy J, Kinney ME, Dallwig RK, Johnson SM. Analgesic efficacy and respiratory effects of butorphanol and morphine in turtles. J Amer Vet Med Assoc, 2007, 230(9);1356-62.

Diethelm G. Reptiles. In: Carpenter JW (ed). Exotic Animal Formulary, 3rd ed., Elsevier, St. Louis, 2005, pp.55-134.