Safety of chronic intrathecal morphine infusion in a sheep model

• Published in: Anesthesiology (Philadelphia) Vol. 99; no. 1; pp. 188 - 198
• Main Authors: GRADERT, Tamara Lee, BAZE, Wallace B, SATTERFIELD, William C, HILDEBRAND, Keith R, JOHANSEN, Mary J, HASSENBUSCH, Samuel J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01-07-2003
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - cerebrospinal fluid; Analgesics, Opioid - toxicity; Animals; Biological and medical sciences; Biotransformation; Cisterna Magna - metabolism; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Female; Hindlimb - physiology; Infusion Pumps, Implantable; Injections, Spinal; Lameness, Animal - chemically induced; Male; Medical sciences; Morphine - administration & dosage; Morphine - cerebrospinal fluid; Morphine - toxicity; Pharmacology. Drug treatments; Sheep; Spinal Cord - pathology; Subarachnoid Space; Toxicity: nervous system and muscle; Nervous system diseases; Continuous; Toxicity; Morphine; Opiates; Nervous system; Narcotic analgesic; Intrathecal administration; Vertebrata; Mammalia; Perfusion; Animal; Sheep; Artiodactyla; Ungulata
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-200307000-00029

The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep.
Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis.
Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components.
The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.