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Morphine Sulfate

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - The sulfate salt of a natural (derived from opium) occurring opiate analgesic, morphine sulfate occurs as white, odorless, crystals.  Solubility: 1 g in 16 ml of water (62.5 mg/ml), 570 ml (1.75 mg/ml) of alcohol. Insoluble in chloroform or ether. The pH of morphine sulfate injection ranges from 2.5-6.

 

Storage/Stability/Compatibility - Morphine gradually darkens in color when exposed to light; protect from prolonged exposure to bright light. Does not appear to adsorb to plastic or PVC syringes, tubing or bags. Morphine sulfate has been shown to be compatible at a concentration of 16.2 mg/l with the following intravenous fluids: Dextrose 2.5%, 5%, 10% in water; Ringer’s injection and Lactated Ringer’s injection; Sodium Chloride 0.45% and 0.9% for injection. The following drugs have been shown to incompatible when mixed with morphine sulfate: aminophylline, chlorothiazide sodium, heparin sodium, meperi­dine, pentobarbital sodium, phenobarbital sodium, phenytoin sodium, sodium bicarbonate, and thiopental sodium. Morphine sulfate has been demonstrated to be generally compati­ble when mixed with the following agents: Atropine sulfate, benzquinamide HCl, butor­phanol tartrate, chlorpromazine HCl, diphenhydramine HCl, dobutamine HCl, droperidol, fentanyl citrate, glycopyrrolate, hydroxyzine HCl, metoclopramide, pentazocine lactate, promazine HCl, scopolamine HBr, and succinylcholine chloride.

 

Pharmacology - Refer to the monograph: Narcotic (opiate) Analgesic Agonists, Pharmacology of, for more information. Morphine’s CNS effects are irregular and are species specific. Cats, horses, sheep, goats, cattle and swine may exhibit stimulatory ef­fects after morphine injection, while dogs, humans, and other primates exhibit CNS de­pression. Both dogs and cats are sensitive to the emetic effects of morphine, but signifi­cantly higher doses are required in cats before vomiting occurs. This effect is a result of a direct stimulation of the chemorecepetor trigger zone (CTZ). Other species (horses, rumi­nants and swine) do not respond to the emetic effects of morphine. Like meperidine, mor­phine can effect the release of histamine from mast cells.

 

Morphine is an effective centrally acting antitussive in dogs. Following morphine admin­istration, hypothermia may be seen in dogs and rabbits, while hyperthermia may be seen in cattle, goats, horses, and cats. Morphine can cause miosis (pinpoint pupils) in humans, rabbits and dogs.

 

While morphine is considered to be a respiratory depressant, initially in dogs respirations are stimulated. Panting may ensue which may be a result of increased body temperature. Often however, body temperature may be reduced due to a resetting of the “body’s ther­mostat”. As CNS depression increases and the hyperthermia resolves, respirations can be­come depressed. Morphine at moderate to high doses can also cause bronchoconstriction in dogs.

 

The cardiovascular effects of morphine in dogs are in direct contrast to its effects on hu­mans. In dogs, morphine causes coronary vasoconstriction with resultant increase in coro­nary vascular resistance, and a transient decrease in arterial pressure. Both bradycardias and tachycardias have also been reported in dogs. While morphine has been used for years as a sedative/analgesic in the treatment of myocardial infarction and congestive heart failure in people, its effects on dogs make it a less than optimal choice in canine patients with symptoms of cardiopulmonary failure. However, its use has been recommended by several clinicians in the initial treatment for cardiogenic edema in dogs.

 

The effects of morphine on the gastrointestinal (GI) tract consist primarily of a decrease in motility and secretions. The dog however, will immediately defecate following an injec­tion of morphine and then exhibit the signs of decreased intestinal motility and ultimately constipation can reesult. Both biliary and gastric secretions are reduced following adminis­tration of morphine, but gastric secretion of HCl will later be compensated by increased (above normal) acid secretion.

 

Initially, morphine can induce micturation, but with higher doses (>2.4 mg/kg IV) urine secretion can be substantially reduced by an increase in anti-diuretic hormone (ADH) re­lease. Morphine may also cause bladder hypertonia, which can lead to increased difficulty in urination.

 

Pharmacokinetics - Morphine is absorbed when given by IV, IM, SQ, and rectal routes. Although absorbed when given orally, bioavailability is reduced, probably as a result of a high first-pass effect. Morphine concentrates in the kidney, liver, and lungs; lower levels are found in the CNS. Although at lower levels then in the parenchymatous tissues, the majority of free morphine is found in skeletal muscle. Morphine crosses the placenta and narcotized newborns can result if mothers are given the drug before giving birth. These ef­fects can be rapidly reversed with naloxone. Small amounts of morphine will also be dis­tributed into the milk of nursing mothers.

 

The major route of elimination of morphine is by metabolism in the liver; primarily by glucuronidation. Because cats are deficient in this metabolic pathway, half-lives in cats are probably prolonged. The glucuronidated metabolite is excreted by the kidney.

 

In horses, the serum half-life of morphine has been reported to be 88 minutes after a dose of 0.1 mg/kg IV. At this dose the drug was detectable in the serum for 48 hours and in the urine for up to 6 days. The half-life in cats has been reported to be approximately 3 hours.

 

Uses/Indications - Morphine is used for the treatment of acute pain in dogs, cats, horses, swine, sheep, and goats. It may be also be used as a preanesthetic agent in dogs and swine. Additionally, it has been used as an antitussive, antidiarrheal, and as adjunctive therapy for some cardiac abnormalities (see doses) in dogs.

 

Contraindications/Precautions - All opiates should be used with caution in patients with hypothyroidism, severe renal insufficiency, adrenocortical insufficiency (Addison’s), and in geriatric or severely debilitated patients. Morphine is contraindicated in cases where the patient is hypersensitive to narcotic analgesics, and in patients taking monamine oxidase inhibitors (MAOIs). It is also contraindicated in patients with diarrhea caused by a toxic ingestion until the toxin is eliminated from the GI tract.

 

Morphine should be used with extreme caution in patients with head injuries, increased intracranial pressure and acute abdominal conditions (e.g., colic) as it may obscure the di­agnosis or clinical course of these conditions. Morphine may also increase intracranial pressure secondary to cerebral vasodilatation as a result of increased paCO2 stemming from respiratory depression. It should be used with extreme caution in patients suffering from respiratory disease or from acute respiratory dysfunction (e.g., pulmonary edema secondary to smoke inhalation).

Because of its effects on vasopressin (ADH), morphine must be used cautiously in pa­tients suffering from acute uremia. Urine flow has been reported to be decreased by as much as 90% in dogs given large doses of morphine.

 

Neonatal, debilitated or geriatric patients may be more susceptible to the effects of mor­phine and may require lower dosages. Patients with severe hepatic disease may have pro­longed durations of action of the drug.

 

Opiate analgesics are contraindicated in patients who have been stung by the scorpion species Centruroides sculpturatus Ewing and C. gertschi Stahnke as they can potentiate these venoms.

 

Adverse Effects/Warnings - At usual doses, the primary concern is the effect the opioids have on respiratory function. Decreased tidal volume, depressed cough reflex and the drying of respiratory secretions may all have a detrimental effect on a susceptible patient. Bronchoconstriction (secondary to histamine release?) following IV doses has been noted in dogs.

 

Gastrointestinal effects may include: nausea, vomiting and decreased intestinal persital­sis. Dogs will usually defecate after an initial dose of morphine. Horses exhibiting signs of mild colic may have their symptoms masked by the administration of narcotic analgesics.

 

The CNS effects of morphine are dose and species specific. Animals that are stimulated by morphine, may elucidate changes in behavior, appear restless, and at very high doses, have convulsions. The CNS depressant effects seen in dogs may encumber the abilities of working animals.

 

Body temperature changes may be seen. Cattle, goats, horses and cats may exhibit signs of hyperthermia. while rabbits and dogs may develop hypothermia.

 

Chronic administration may lead to physical dependence.

 

Overdosage - Overdosage may produce profound respiratory and/or CNS depression in most species. Newborns may be more susceptible to these effects than adult animals. Parenteral doses greater than 100 mg/kg are thought to be fatal in dogs. Other toxic effects can include cardiovascular collapse, hypothermia, and skeletal muscle hypotonia. Some species such as horses, cats, swine, and cattle may demonstrate CNS excitability (hyperreflexia, tremors) and seizures at high doses or if given intravenously (rapidly). Naloxone is the agent of choice in treating respiratory depression. In massive overdoses, naloxone doses may need to be repeated, animals should be closely observed as nalox­one’s effects may diminish before sub-toxic levels of morphine are attained. Mechanical respiratory support should also be considered in cases of severe respiratory depression.

 

Pentobarbital has been suggested as a treatment for CNS excitement and seizures in cats. Extreme caution should be used as barbiturates and narcotics can have additive effects on respiratory depression.

 

Drug Interactions - Other CNS depressants (e.g., anesthetic agents, antihistamines, phe­nothiazines, barbiturates, tranquilizers, alcohol, etc.) may cause increased CNS or respira­tory depression when used with morphine. Morphine is contraindicated in patients receiving monamine oxidase (MOA) inhibitors (rarely used in veterinary medicine) for at least 14 days after receiving MOA inhibitors in humans. Some human patients have exhibited signs of opiate overdose after receiving therapeutic doses of morphine while on these agents.

 

Laboratory Interactions - Plasma amylase and lipase values may be increased for up to 24 hours following administration of opiate analgesics as they may increase biliary tract pressure.

 

Doses -

Horses:

For analgesia:

a)   0.22 mg/kg IM or slow IV (Booth 1988a)

b)   0.2 - 0.6 mg/kg IV (slowly); premedicate with xylazine (1 mg/kg IV) to reduce excitement (Jenkins 1987)

c)   0.02 - 0.04 mg/kg IV (Muir 1987)

d)   0.05 - 0.12 mg/kg IV (Thurmon and Benson 1987)

 

Note: Narcotics may cause CNS excitement in the horse. Some clinicians recommend pretreatment with acepromazine (0.02 - 0.04 mg/kg IV), or xylazine (0.3 - 0.5 mg/kg IV) to reduce the behavioral changes these drugs can cause.

 

Warning: Narcotic analgesics can mask the behavioral and cardiovascular symptoms

associated with mild colic.

 

Elephants:

a) For analgesia: 3-6 mg/100 kg qid; for analgesia and sedation: 6-20 mg/100 kg qid (Schmidt, 1986).

 

Elephant References:

a) Schmidt, M: Elephants (Proboscidea). In: Fowler, M.E. (ed): Zoo and Wild Animal Medicine. 1986. Saunders, Philadelphia. p.892

 

Monitoring Parameters -

1) Respiratory rate/depth

2) CNS level of depression/excitation

3) Blood pressure if possible and indicated (especially with IV use)

4) Analgesic activity

 

Client Information - When given parenterally, this agent should be used in an inpatient setting or with direct professional supervision.

 

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

 

Veterinary-Approved Products: None

 

Human-Approved Products:

Morphine Sulfate for Injection: 0.5 mg/ml in 2, & 10 ml amps and 10 ml vials; 1 mg/ml in 2, 10, 30 & 60 ml amps and 10 ml vials; 2 mg/ml in 50 ml vials and 1 & 2 ml sy­ringes; 3 mg/ml in 50 ml vials; 4 mg/ml in 1& 2 ml syringes; 5 mg/ml in 1 & 30 ml vials; 8 mg/ml in 1 ml vials, amps & syringes; 10 mg/ml in 1 ml amps, vials, 10 ml vials and 20 ml amps; 15 mg/ml in 1 & 20  ml amps, & vials; 25 mg/ml in 4, 10 , 20, & 40 ml syringes and 20 ml ampuls; 50 mg/ml in 10, 20 and 40 ml syringes

 

Morphine Sulfate for Injection (preservative-free): 0.5 mg/ml, 10 ml amps & vials; 1 mg/ml, 10 ml amps & vials;Infumorph®   (Elkins-Sinn); Astramorph PF®   (Astra)

 

Morphine Sulfate Soluble Tablets: 10 mg, 15 mg, 30 mg

 

Morphine Sulfate Tablets: 15 mg, 30 mg

 

Morphine Sulfate Capsules:  15 mg, 30 mg

 

Morphine Sulfate Oral Solution; 10 mg/5ml in 100, 120 & 500 ml btls & unit dose (2.5, 5, 10 ml); 20 mg/5ml in 100, 120 & 500 ml btls & unit dose 5 ml; 20 mg/ml in 30 & 120 ml, in UD 1 ml and 1.5 ml vials; 100 mg/5 ml in 120 & 240 ml

 

Morphine Sulfate Controlled-release Tablets  15 mg, 30 mg, 60 mg, 100 mg, 200 mg

 

Morphine Sulfate Rectal Suppositories 5 mg, 10 mg & 20 mg, 30 mg in UD 12's and 50's

 

Note: All morphine products are Rx and a Class-II controlled substance. Very accurate record keeping is required as to use and disposition of stock. See the appendix for more in­formation.

 

 

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