Elephant specific information, if available, is in blue.

Chemistry – A synthetic opiate antagonist, naltrexone HCl occurs as white crystals having a bitter taste. 100 mg are soluble in one ml of water.

 

Storage/Stability/Compatibility – Naltrexone tablets should be stored at room tempera­ture in well-closed containers.

 

Pharmacology – Naltrexone is an orally available narcotic antagonist. It competitively binds to opiate receptors in the CNS, thereby preventing both endogenous opiates (e.g., endorphins) and exogenously administered opiate agonists or agonist/antagonists from oc­cupying the site. Naltrexone may be more effective in blocking the euphoric aspects of the opiates and less effective at blocking the respiratory depressive or miotic effects.

 

Naltrexone may also increase plasma concentrations of luteinizing hormone (LH), corti­sol and ACTH. In dogs with experimentally-induced hypovolemic shock, naltrexone (like naloxone) given IV in high dosages increased mean arterial pressure, cardiac output, stroke volume, and left ventricular contractility.

 

Uses/Indications – Naltrexone may be useful in the treatment of self-mutilating or tail-chasing behaviors in dogs or cats.

 

Pharmacokinetics – In humans, naltrexone is rapidly and nearly completed absorbed, but undergoes a significant first-pass effect as only 5-12% of a dose reaches the systemic cir­culation. Naltrexone circulates throughout the body and CSF levels are approximately 30% of those found in the plasma. Only about 20-30% is bound to plasma proteins. It is unknown whether naltrexone crosses the placenta or enters milk. Naltrexone is metabo­lized in the liver primarily to 6-beta-naltrexol, which has some opiate blocking activity. In humans, serum half life of naltrexone is about 4 hours; 6-beta-naltrexol, about 13 hours. Naltrexone, as metabolites are then eliminated primarily via the kidney.

 

Contraindications/Precautions/Reproductive Safety – Naltrexone is generally consid­ered to be contraindicated in patients physically dependent on opiate drugs, in hepatic fail­ure or with acute hepatitis. The benefits of the drug versus its risks should be weighed in patients with hepatic dysfunction or who have had a history of allergic reaction to naltrex­one or naloxone.

 

Very high doses have caused increased embryotoxicity in some laboratory animals. It should be used during pregnancy only when the benefits outweigh any potential risks. It is unknown whether naltrexone enters maternal milk.

 

Adverse Effects/Warnings – At usual doses, naltrexone is relatively free of adverse ef­fects in non-opioid dependent patients. Some human patients have developed abdominal cramping, nausea and vomiting, nervousness, insomnia, joint or muscle pain, skin rashes. Dose-dependent hepatotoxicity has been described in humans on occasion.

 

Naltrexone will block the analgesic, antidiarrheal and antitussive effects of opiate agonist or agonist/antagonist agents. Withdrawal symptoms may be precipitated in physically de­pendent patients.

 

Overdosage/Acute Toxicity – Naltrexone appears to be relatively safe even after very large doses. The LD50 in dogs after subcutaneous injection has been reported to be 200 mg/kg. Oral LD50’s in species tested range from 1.1 g/kg in mice to 3 g/kg in monkeys (dogs or cats not tested). Death at these doses were a result of respiratory depression and/or tonic-clonic seizures. Massive overdoses should be treated using gut emptying pro­tocols when warranted and giving supportive treatment.

 

Drug Interactions – In addition to blocking the effects of pure opiate agonists (e.g., morphine, meperidine, codeine, oxymorphone, etc.) naltrexone also reverses the effects of opioid agonist/antagonists such asbutorphanol, pentazocine or nalbuphine.

 

Laboratory Considerations – Naltrexone reportedly does not interfere with TLC, GLC, or HPLC methods of determining urinary morphine, methadone or quinine. Naltrexone may cause increases in hepatic function tests(e.g., AST, ALT) (see adverse effects above).

 

Doses –

 

Elephants:

a) Five adult wild African elephants weighing 3000-3500 kg were immobilized with 10 or 12 mg etorphine (28-40 µg/kg).  Naltrexone was administered at 100 times the etorphine dose (1000 or 1200 mg).  Recovery time was 2-4  minutes (Horne et.al. 2001).

 

b,c) A 2817 kg female Asian elephant was induced with 1.75 mg etorphine IM, followed by 0.75 mg etorphine at 40 minutes. The elephant was  intubated with a 30 mm endotracheal tube and maintained with 1.5-2.0% isoflurane. Additional etorphine (total additional 1.4 mg) was supplemented IV during the procedure to surgically remove P-3.  Thirty minutes prior to the completion of the procedure isoflurane was discontinued, but oxygen continued to flow.  Additional etorphine was given intermittently IV (0.4 mg total) during the remaining 45 minutes of recumbency.  Naltrexone was given IV and the elephant was standing within 3 minutes. (Fowler et.al. 1999 and 2000).  (Author’s (Mikota) note: the dose of Naltrexone reported in the 1999 publication of this case was 250 mg and the dose reported in the 2000 publication was 60 mg).

 

d) Thirty-seven wild African elephants were immobilized as follows:  Calves (4-6 years; n=4) were immobilized with 1 mg carfentanil and adults with 3 mg carfentanil mixed with 1500 IU of hyaluronidase.  All animals were reversed with naltrexone at a rate of 100 mg for every mg of carfentanil used.  For 15 elephants, mean minutes elapsed for initial effect of standing still, recumbency, and recovery following reversal were 5.0 ±1.6, 10.7±3.9, and 5.9±3.9 respectively (Karesh et.al. 1997).

 

e) Naltrexone dose (mg) = 50 times the carfentanil dose (Kock et.al. 1993).

 

f) To reverse carfentanil in wild African elephants naltrexone is used at 40 times the carfentanil dose (Raath, 1993).

 

g) For reversal of carfentanil, 100 mg naltrexone per mg of carfentanil (Lance, 1991).

 

Elephant References:

a) Horne,W.A., Tchamba,M.N., and Loomis,M.R. 2001. A simple method of providing intermittent positive-pressure ventilation to etorphine-immobilized elephants (Loxodonta africana) in the field. Journal of Zoo and Wildlife Medicine 32:(4):519-522  Abstract: Five African elephants (Loxodonta africana) were immobilized with etorphine in Waza National Park, Cameroon, for the purpose of deploying radio/satellite tracking collars.  A portable ventilator constructed from two high-flow demand valves and the Y-piece of a large animal anesthesia circuit was used to provide intermittent positive-pressure ventilation with 100% oxygen.  Oxygenation status improved dramatically in all five elephants.  In one hypoxemic elephant, arterial PaO2 increased from 40 to 366 mm Hg.  The results of this study demonstrate that both oxygenation and ventilation can be readily controlled etorphine-immobilized elephants even under remote field conditions.

b) Fowler,M.E., Steffey,E.P., Galuppo,L., and Pascoe,J.R. 2000. Facilitation of Asian elephant (Elephas maximus) standing immobilization and anesthesia with a sling. Journal of Zoo and Wildlife Medicine 31:(1):118-123  Abstract: An Asian elephant (Elephas maximus) required general anesthesia for orthopedic foot surgery. The elephant was unable to lie down, so it was placed in a custom-made sling, administered i.m. etorphine hydrochloride in the standing position, and lowered to lateral recumbency. General anesthesia was maintained with isoflurane administered through an endotracheal tube. After surgery, the isoflurane anesthesia was terminated, with immobilization maintained with additional i.v. etorphine. The elephant was lifted to the vertical position, and the immobilizing effects of etorphine were reversed with naltrexone. The suspension system and hoist for the sling were designed specifically for the elephant house.

c) Fowler,M.E., Steffey,E.P., Galuppo,L., and Pascoe,J.R.  1999. Standing immobilization and anesthesia in an Asian elephant (Elephas maximus). Proc. Am. Assoc. Zoo Vet. Pages: 107-110

d) Karesh,W.B., Smith,K.H., Smith,F., Atalia,M., Morkel,P., Torres,A., House,C., Braselton,W.E., and Dierenfeld,E.S.  1997. Elephants, buffalo, kob, and rhinoceros:  immobilization, telemetry, and health evaluations.  Proceedings American Association of Zoo Veterinarians. Pages: 296-230

e) Kock,R.A., Morkel,P., and Kock,M.D., 1993. Current immobilization procedures used in elephants. In: Fowler,M.E. (Editor), Zoo and Wild Animal Medicine Current Therapy 3. W.B. Saunders Company, Philadelphia, PA, USA pp. 436-441

f) Raath,J.P. 1993. Chemical capture of the African elephant. In: The Capture and care manual : capture, care, accommodation and transportation of wild African animals. Pretoria : Wildlife Decision Support Services : South African Veterinary  Foundation, Pretoria pp. 484-511

g) Lance,W.R. 1991. New pharmaceutical tools for the 1990’s. Proceedings of the American Association of Zoo Veterinarians 354-359

Monitoring Parameters – 1) Efficacy; 2) Liver enzymes if using very high dose pro­longed therapy

 

Client Information – Stress the importance of compliance with prescribed dosing regi­men. Additional behavior modification techniques may be required to alleviate symptoms.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products: Trexonil (Wildlife Pharmaceuticals)

 

Human-Approved Products:

Naltrexone HCl Oral Tablets 50 mg; ReVia®(DuPont); (Rx)