Veterinary Drug Handbook (VDH) is the reference veterinarians turn to when they want an independent source of information on the drugs that are used in veterinary medicine today.


MORPHINE SULFATE

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), 570ml (1.75 mg/ml) of alcohol. Insoluble in chloroform or ether. The pH of morphine sulfate injectionranges 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. Thefollowing drugs have been shown to incompatible when mixed with morphine sulfate: aminophylline, chlorothiazide sodium, heparin sodium, meperidine, pentobarbital sodium, phenobarbitalsodium, phenytoin sodium, sodium bicarbonate, and thiopental sodium. Morphine sulfate has beendemonstrated 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, pentazocinelactate, promazine HCl, scopolamine HBr, and succinylcholine chloride.

Pharmacology - MORPHINE SULFATE

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 emeticeffects of morphine, but significantly higher doses are required in cats before vomiting occurs. Thiseffect 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 arestimulated. 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 CNSdepression increases and the hyperthermia resolves, respirations can become depressed. Morphineat 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. Indogs, morphine causes coronary vasoconstriction with resultant increase in coronary vascular resistance, and a transient decrease in arterial pressure. Both bradycardias and tachycardias have alsobeen reported in dogs. While morphine has been used for years as a sedative/analgesic in thetreatment of myocardial infarction and congestive heart failure in people, its effects on dogs make ita 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 indogs.
The effects of morphine on the gastrointestinal (GI) tract consist primarily of a decrease inmotility and secretions. The dog however, will immediately defecate following an injection ofmorphine and then exhibit the signs of decreased intestinal motility and ultimately constipation canreesult. Both biliary and gastric secretions are reduced following administration of morphine, butgastric 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 secretioncan be substantially reduced by an increase in anti-diuretic hormone (ADH) release. Morphine mayalso cause bladder hypertonia, which can lead to increased difficulty in urination.

Pharmacokinetics - MORPHINE SULFATE

Morphine is absorbed when given by IV, IM, SQ, and rectal routes. Althoughabsorbed when given orally, bioavailability is reduced, probably as a result of a high first-passeffect. 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 foundin skeletal muscle. Morphine crosses the placenta and narcotized newborns can result if mothers aregiven the drug before giving birth. These effects can be rapidly reversed with naloxone. Smallamounts 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 0.1mg/kg IV. At this dose the drug was detectable in the serum for 48 hours and in the urine for up to6 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, ithas 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 geriatricor severely debilitated patients. Morphine is contraindicated in cases where the patient ishypersensitive 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 iseliminated from the GI tract.
Morphine should be used with extreme caution in patients with head injuries, increased intracranialpressure and acute abdominal conditions (e.g., colic) as it may obscure the diagnosis or clinicalcourse of these conditions. Morphine may also increase intracranial pressure secondary to cerebralvasodilatation as a result of increased paCO2 stemming from respiratory depression. It should beused with extreme caution in patients suffering from respiratory disease or from acute respiratorydysfunction (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 dogsgiven large doses of morphine.
Neonatal, debilitated or geriatric patients may be more susceptible to the effects of morphine andmay require lower dosages. Patients with severe hepatic disease may have prolonged durations ofaction 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 onrespiratory function. Decreased tidal volume, depressed cough reflex and the drying of respiratorysecretions 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. Dogswill usually defecate after an initial dose of morphine. Horses exhibiting signs of mild colic mayhave their symptoms masked by the administration of narcotic analgesics.
The CNS effects of morphine are dose and species specific. Animals that are stimulated bymorphine, 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 mostspecies. Newborns may be more susceptible to these effects than adult animals. Parenteral dosesgreater 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 highdoses or if given intravenously (rapidly). Naloxone is the agent of choice in treating respiratorydepression. In massive overdoses, naloxone doses may need to be repeated, animals should beclosely 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. Extremecaution should be used as barbiturates and narcotics can have additive effects on respiratorydepression.

Drug Interactions

Other CNS depressants (e.g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc.) may cause increased CNS or respiratory depressionwhen used with morphine.
Morphine is contraindicated in patients receiving monamine oxidase (MOA) inhibitors (rarelyused in veterinary medicine) for at least 14 days after receiving MOA inhibitors in humans. Somehuman patients have exhibited signs of opiate overdose after receiving therapeutic doses ofmorphine while on these agents.
Laboratory Interactions - Plasma amylase and lipase values may be increased for up to 24hours following administration of opiate analgesics as they may increase biliary tract pressure.