Amitriptyline Neurotoxicity: Dose-related Pathology after Topical Application to Rat Sciatic Nerve

Background: Amitriptyline is a tricyclic antidepressant drug used systemically for the management of neuropathic pain. Antidepressants, as a class of drugs with direct neurologic actions, are becoming widely used for the management of chronic pain, although their mechanisms are not entirely understood. Amitriptyline exerts potent effects on reuptake of norepinephrine and serotonin and blocks [alpha]2A adrenoreceptors and N-methyl-d-aspartate receptors. Because amitriptyline is also a particularly potent blocker of sodium channels and voltage-gated potassium and calcium channels, it has been recommended as a long-acting local anesthetic agent. Unfortunately, amitripty-line has significant toxic side effects in the central nervous system and cardiovascular system that are dose-related to its systemic administration. Therefore, before amitriptyline can be used clinically as a local anesthetic agent, it should be thoroughly explored with respect to its direct neurotoxic effect in the peripheral nervous system.

Methods: The left sciatic nerve of Sprague-Dawley rats (12/ group) received a single topical amitriptyline dose of 0.625, 1.25, 2.5, or 5 mg; a saline group (n = 2) was used as control. Neuropathologic evaluations were conducted in separate animals (n = 4) 1, 3, and 7 days later.

Results: Amitriptyline topically applied in vivo to rat sciatic nerve causes a dose-related neurotoxic effect. Drug doses of 0.625-5 mg all caused Wallerian degeneration of peripheral nerve fibers, with the number of affected fibers and the severity of the injury directly related to the dose.     

Amitriptyline poisoning in a 2-year old

We describe a case of a 2-year-old boy who ingested 35 mg.kg(-1) of amitriptyline. He developed central nervous system toxicity, as demonstrated by coma and seizures and cardiac toxicity (cardiac arrest) within 1 h of ingestion. The cardiac toxicity was refractory to standard therapy. His cardiac rhythm alternated between ventricular tachycardia and pulseless ventricular tachycardia/ventricular fibrillation for a period of 17 h. Following prolonged cardiopulmonary resuscitation and aggressive supportive management, the patient recovered both cardiovascularly and neurologically. An echocardiogram and MRI brain were subsequently performed and were normal. The patient was discharged 2 weeks later with normal cognitive, behavioral and motor function. We discuss the benefit of prolonged and effective cardiopulmonary resuscitation in the management of this potentially fatal poisoning.     

Neurotoxicity of intrathecal lidocaine

Lidocaine is a local anesthetic belonging to the amide group and has been administered intrathecally for over 40 years. Although no serious complications had been attributed to lidocaine before the 1990s, subarachnoid administration is now the subject of controversy following its implication in numerous cases of neurological complication. The clinical pictures described in the literature are cauda equina syndrome, which is mainly associated with continuous subarachnoid anesthesia through microcatheters, and transitory neurological symptoms, also termed radicular irritation syndrome and associated with single injections. The literature reveals a clearly higher incidence of transitory neurological symptoms with lidocaine than with other local anesthetics. Although the underlying mechanism remains unclear, the main hypotheses being the neurotoxicity of lidocaine itself or the malpositioning of the paravertebral musculature due to extreme relaxation. The various factors that can lead to neuropathy have been widely described in the many articles reporting complications. Arthroscopy and lithotomy positions are significantly related to the appearance of symptoms, as are early ambulation or the use of small-gauge needles or pencil-point needles. Further clinical studies should be undertaken. No consensus on subarachnoid administration of lidocaine has emerged, yet no alternative has been demonstrated to be safe and to offer similar pharmacological features (short latency, short duration of action and good muscle relaxation). Prilocaine, mepivacaine, articaine and bupivacaine at low doses have been suggested as alternatives.     

Amitriptyline stimulates weight gain in hemodialysis patients

Sixteen chronic hemodialysis patients were enrolled in a double blind 13 week study of amitriptyline vs. placebo in non-crossover design. Patients receiving active drug reached therapeutic serum concentrations at doses of 50 to 200 mg/day, but antidepressant effect was not demonstrable. Patients receiving active drug had slightly greater fluctuation in weight pre- vs. Post-dialysis and had slightly greater postural hypotension post-dialysis than control patients. The trend in post-dialysis weight indicated gain in the active drug group and loss in the placebo group; this difference was highly statistically significant. Weight gain in depression and anorexia nervosa patients treated with amitriptyline is reviewed and it is suggested that amitriptyline may be a useful agent in stimulating appetite in other diseases also.     

A Physiologic Assessment of Intrathecal Amitriptyline in Sheep

Background: Intrathecal injection of amitriptyline enhances antinociception from intravenous morphine and reduces neuropathic pain behavior in animals. This study represents part of a preclinical assessment of intrathecal amitriptyline to determine its safety for use in humans.

Methods: Low thoracic intrathecal, femoral, and pulmonary arterial catheters were inserted in 18 adult ewes, followed 96 h later by intrathecal injection of saline or 5 mg amitriptyline and by determination of spinal cord blood flow, hemodynamic variables, behavioral changes, cerebrospinal fluid concentrations of catecholamines and amitriptyline, and spinal tissue concentrations of amitriptyline. In six other ewes, low thoracic intrathecal and femoral arterial catheters were inserted and blood pressure and heart rate were measured after intrathecal injection of saline or 0.25, 1, or 5 mg amitriptyline. Four other ewes received cervical intrathecal injection of 5 and 10 mg amitriptyline, and antinociception was determined.

Results: Thoracic intrathecal injection of amitriptyline produced dose-dependent sedation but did not significantly affect spinal cord blood flow or hemodynamic variables. Spinal cord tissue concentrations of amitriptyline were 100 times greater in tissue near the tip of the thoracic intrathecal catheter compared with cervical cord tissue. Cerebrospinal fluid concentrations of catecholamines did not significantly change after amitriptyline was administered. Cervical intrathecal injection of 5 mg amitriptyline produced mild antinociception, whereas 10 mg produced intense sedation and, in one sheep, seizures and death.     

Amitriptyline for Prolonged Cutaneous Analgesia in the Rat

Background: Amitriptyline has been reported to be a more potent local anesthetic than bupivacaine. In keeping with the objective of identifying drugs for prolonged cutaneous analgesia, the authors compared the cutaneous analgesic effectiveness of amitriptyline and bupivacaine in rats.

Methods: Rats were subcutaneously injected on shaved dorsal skin. The skin wheal raised after injection of 0.6 ml of various concentrations of either amitriptyline or bupivacaine with and without epinephrine (1:200,000) was marked. Inhibition of the cutaneous trunci muscle reflex was evaluated quantitatively by the fraction of times a total of six pinpricks applied to the marked area failed to elicit a nocifensive motor response compared with control responses. No responses out of six pinpricks was defined as 100% maximum possible effect.

Results: Complete recovery from the cutaneous analgesia elicited by 0.05% and 0.5 amitriptyline versus 0.05 and 0.5% bupivacaine occurred in 9.9 +/- 0.2 and 19.3 +/- 0.4 h versus 2.2 +/- 0.1 and 16.1 +/- 0.2 h, respectively (mean +/- SE). Addition of epinephrine increased this duration to 14.1 +/- 0.1 and 21.4 +/- 0.2 h versus 3.2 +/- 0.1 and 17.0 +/- 0.3 h, respectively. Complete nociceptive blockade after coinjection of 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine lasted 24 +/- 0.5 h, and com-plete recovery from this block took 33 +/- 0.5 h. Areas under the percent maximum possible effect versus time curve were 1,770 +/- 24 and 1,471 +/- 50% h for 0.5% amitriptyline and bupivacaine with epinephrine, respectively, whereas this value was 2,836 +/- 62% h for the coinjected 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine admixture.     

Amitriptyline versus bupivacaine in rat sciatic nerve blockade

BACKGROUND: Amitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of amitriptyline in rats and in vitro. METHODS: Sciatic nerve blockade was performed with 0.2 ml amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated. RESULTS: Complete sciatic nerve blockade for nociception was obtained with amitriptyline for 217 +/- 19 min (5 mM, n = 8, mean +/- SEM) and for 454 +/- 38 min (10 mM, n = 7) versus bupivacaine for 90 +/- 13 min (15.4 mM, n = 6). The time to full recovery of nociception for amitriptyline was 353 +/- 12 min (5 mM) and 656 +/- 27 min (10 mM) versus 155 +/- 9 min for bupivacaine (15.4 mM). Amitriptyline was approximately 4.7-10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 +/- 2.7 vs. 189.6 +/- 22.3 microM) at - 150 mV, and to the inactivated Na+ channels (IC50 of 0.9 +/- 0.1 vs. 9.6 +/- 0.9 microM) at -60 mV. High-frequency stimulation at 3 microM caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for amitriptyline. CONCLUSION: Amitriptyline is a more potent blocker of neuronal Na+ channels than bupivacaine in vivo and in vitro. These findings suggest that amitriptyline could extend its clinical usefulness for peripheral nerve blockade.