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Chapter 12 Opioids

DEFINITION/OVERVIEW

 Natural opioids are found in the seeds of the opium poppy (Papaver somniferum). Opium powder is about 10% morphine and 0.5% codeine. Oxymorphone, codeine, hydromorphone, and heroin are derived from morphine.

 There are numerous synthetic opioids on the market manufactured primarily for human and animal pain relief and tranquilization. Most are not FDA‐approved for horses.

 The exact mode of action varies slightly by drug due to different receptor activity and affinity.

 The primary effects are seen in the CNS; however, there are opioid receptors throughout the body.

 Most pain relief is via agonists binding to mu receptors in the CNS and periphery. Mu receptors vary in location and density for horses compared with other species.

 Opioids licensed for equine patients:Butorphanol (kappa agonist and mu antagonist) – schedule IV, pain management (good for equine GI pain).Pethidine (Meperidine) – schedule II, pain management, labeled for spasmodic colic.Buprenorphine (partial mu agonist) – pain management.

 Other opioids used in equine health care, but not licensed specifically for equine patients:Fentanyl (pure mu agonist).Tramadol.Morphine (pure mu agonist).Nalbuphine (partial agonist/antagonist similar to butorphanol) – not DEA.Remifentanil.Methadone (pure mu agonist).Hydromorphone.

 Opioids easily cross the blood–brain barrier allowing for receptors causing cough reflex suppression, respiratory depression, and a depressed CNS.

 Clinical findings include decreased in gut motility and increased water absorption, causing constipation and impaction. Clinically, this is usually observed at high doses.

 Existing toxicology research is in humans, dogs, and cats with variations in the lethal doses in each species.

 Use of opioids (particularly mu agonists), historically, has been limited in the horse due to adverse side effects. In horses, clinical signs of toxicosis include excitation, agitation, increased locomotor activity and decreased gut motility. Side effects are likely due to the receptors’ affinity for the medications and how densely the receptors are in their specific locations in the equine brain.

ETIOLOGY/PATHOPHYSIOLOGY

Mechanism of Action

 The major opioid receptors are mu (μ), delta (δ), and kappa (κ). Opioid receptors are found in many locations such as the CNS, autonomic nervous system, GI tract, heart, kidney, pancreas, adipocytes, and on the surface of lymphocytes.

 When the body senses pain or stress, opioid receptors are stimulated by endogenous endorphins and enkephalins.

 Similarly, opiates have various affinity and, when administered, they function as agonists, antagonists, or as both at their unique opioid‐binding site. When activated, the following specific actions occur:μ 1 – supraspinal analgesia.μ 2 – spinal analgesia, respiratory suppression, decreased gut motility.δ – higher affinity for enkephalins, spinal analgesia.κ – spinal and supraspinal analgesia, sedation, dysphoria.

 Each opiate has a unique half‐life and level of toxicity.

Toxicokinetics (based upon morphine – others may vary)

 Onset is 5–10 minutes after IV administration.

 Duration of action is 2–6 hours, which may be prolonged if in the extradural space.

 Poor lipid solubility.

 Hepatic metabolism.

 Renal excretion.

Toxicity

 Toxicity is dose‐dependent. Clinical signs, especially respiratory, are observed at therapeutic doses. Severe adverse effects and death can occur at high concentrations.

Systems Affected

 Neurological – decreased CNS activity, initial excitation leading to depression, hypothermia, seizures, coma, death.

 Respiratory – depression.

 Gastrointestinal – decreased motility, increased water absorption.

 Cardiovascular – bradycardia, possible vasodilation, hypotension.

SIGNALMENT/HISTORY

Risk Factors

 Neonates have undeveloped blood–brain barrier, making them more susceptible.

 Opioid toxicosis in the horse is usually iatrogenic.

Historical Findings

 Iatrogenic.

 Inadvertent exposure via ingestion of fentanyl patches.

CLINICAL FEATURES

 Because toxicity would likely result from iatrogenic administration in the horse, it is imperative that the clinician is cognizant of clinical signs associated with CNS excitation then depression, GI stasis causing episodes of colic, and decreased pulmonary/cardiovascular activity.

DIFFERENTIAL DIAGNOSIS

 Dermorphin administration.

 Electrolyte imbalance.

 CNS Stimulants (amphetamine, methamphetamine).

 CNS depressants (benzodiazepine).

 Colic of other etiology.

 Ethanol.

 Ethylene glycol.

 Ivermectin.

 Marijuana toxicosis.

DIAGNOSTICS

CBC/Serum Chemistry

 Hypoglycemia.

 Elevated BUN.

Other Diagnostic Tests

 Arterial blood gas.

 LC‐MS.

THERAPEUTICS

Detoxification

 Remove the source of the toxicosis.

 Provide supportive care as needed.

 If suspected, oral overdoses could be evacuated via nasogastric intubation. Once evacuated, administer activated charcoal at 1 g/kg with mineral oil and water to help decrease absorption of the medication, and assist with the potential GI stasis/impaction.

Appropriate Health Care

 Monitor cardiovascular and respiratory activity. Assisted ventilation may be essential if severely overdosed.

 Gastrointestinal activity may be greatly compromised and monitoring for possible GI stasis should be considered.

Antidotes

 Naloxone 0.01–0.02 mg/kg up to 0.05 mg/kg IV bolus. Note: the half life is 1–1.5 hours and may have to be repeated because its half‐life is shorter than morphine.

 Butorphanol (for pure mu agonist) – 0.01–0.1 mg/kg IV, IM.

Drugs of Choice

 IV fluids as needed for volume expansion and dehydration.

 Cardiovascular:Atropine (anticholinergic, but will decrease gut motility) – 0.02 mg/kg IV.Glycopyrrolate (anticholinergic, but will decrease gut motility) – 0.005 mg/kg IV.

 GI Protectants:Omeprazole 2–4 mg/kg PO q24h.N‐methylnaltrexone (research only) – does not cross blood–brain barrier and may reduce negative GI effects when a mu agonist such as morphine has been given.

 CNS signs:Detomidine 0.02‐0.04 mg/kg IV or IM.Xylazine 1.1 mg/kg IV; 2.2 mg/kg IM.

Precautions/Interactions

 Pethidine (Meperidine) is short‐acting. Can cause seizures if administered IV. Diazepam or pentobarbitone would help control these clinical signs.

 Avoid use in horses with renal insufficiency.

 Fentanyl has been noted to be a heavy respiratory depressant, and mechanical ventilation should be used with gas anesthesia.

 Caution should be used if administering other depressants with opioids as the negative side effects could increase. Benzodiazepines should be avoided.

 Ethanol is contraindicated.

 Respiratory depression in neonates has been described when morphine has been administered to mares prior to birth.

COMMENTS

Prevention/Avoidance

 Limit opioid use and monitor closely when used.

 Educate clients regarding adverse effects in horses.

Possible Complications

 Seizures.

 Hyperthermia.

Expected Course and Prognosis

 Prognosis for recovery is good if respiratory and cardiovascular functions are maintained.

Abbreviations

See Appendix 1 for a complete list.

Suggested Reading

1 Boscan P, Van Hoogmoed LM, Farver TB, et al. Evaluation of the effects of the opioid agonist morphine on gastrointestinal tract function in horses. Am J Vet Res 2006; 67:992–997

2 Boscan P, Van Hoogmoed LM, Pypendop BH, et al. Pharmacokinetics of the opioid antagonist N‐methylnaltrexone and its effects on gastrointestinal tract function in horses treated or not treated with morphine. Am J Vet Res. 2006; 67:998–1004

3 Combie JD, Nugent TE, Tobin T, Pharmacokinetics and protein binding of morphine in horses. Am J Vet Res 1983; 44(5): 870–874.

4 Gupta GC. Veterinary Toxicology, 2nd edn. San Diego: Elsevier, 2012.

5 Matthews NS, Carroll GL, Review of equine analgesics and pain management. AAEP Proc 2007; 53:240–244.

6 Reed SM, Bayly WM, Sellon DC, ed. Equine Internal Medicine, 4th edn. St Louis: Elsevier., 2018.

7 Roger T, Bardon T, Ruckebusch Y. Colonic motor responses in the pony: relevance of colonic stimulation by opiate antagonists. Am J Vet Res 1985; 46:31–35.

8 Van Hoogmoed LM, Boscan PL. In vitro evaluation of the effect of the opioid antagonist N‐methylnaltrexone on motility of the equine jejunum and pelvic flexure. Equine Vet J 2005; 37:325–328.

Author: Jay Deluhery, DVM, MBA, CJF

Consulting Editor: Dionne Benson, DVM, JD