Neurotoxicity of Intrathecally Administered Fentanyl in a Rat Spinal Model


  • Brief Summary for Table of Contents: Intrathecal fentanyl has dose-dependent side effects but does not induce histopathological changes or neurodysfunction even at excessively high dose.

Tamie Takenami, MD, Department of Anesthesiology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. Tel: +81-42-778-8111; Fax: +81-42-778-8441; E-mail:


Objective.  Intrathecally administered fentanyl rarely causes drug tolerance or formation of inflammatory masses and might therefore be a suitable treatment option for chronic pain. However, the neurotoxicity of intrathecally administered fentanyl remains to be clarified. We examined the histological changes, neurodysfunction, and side effects of intrathecal fentanyl in rats.

Design.  The rats received fentanyl at 0.12 µL/g body weight (0, 50, 1,000, 2,000, and 5,000 µg/mL in saline) via an intrathecal catheter. Seven days after the injection, the spinal cord with both roots were removed for histological examination. The neurological function was evaluated by monitoring walking behavior and latencies to radiant heat. Side effects were also recorded.

Results.  No histological abnormalities were observed in the spinal cord, anterior and posterior roots, cauda equina nerves, or arachnoid membrane. Formation of white neomembrane was noted around the catheter in some animals, but there was no significant difference in the incidence among the groups. The sensory threshold was significantly higher at 1 and 2 hours after injection in the 50 and 5,000 µg/mL groups, respectively. However, there was no significant difference in the sensory threshold among the five groups at 7 days postinjection. All of the rats walked normally within 4 hours even after injection of 5,000 µg/mL fentanyl. The incidence of apnea, muscular rigidity, and bradycardia increased significantly at ≥1,000 µg/mL dose.

Conclusions.  The side effects of intrathecally administered fentanyl were concentration-dependent, although no neuronal tissue damage, inflammation, or irreversible neurodysfunction were observed even at 5,000 µg/mL.