This drug has some mixed history. It appears on lists from neuropathy sites as a "cause" of axonal neuropathy.
Here is an example:
However, I couldn't quickly find the studies that support this yet.
I'll look later in more detail.
Recently there have been studies showing amitriptyline actually enhances peripheral nerve regeneration.
Here is the link to that article:
This might be dose dependent or a factor in those who do not metabolize this drug well. I do think this is very confusing.
Edit to add:
It appears that amitriptyline is being used as an injected anesthetic in some situations. So I found some neurotoxic in vitro (no in living subjects) on this subject. This would place the drug in high concentration near neurons:
Eur J Anaesthesiol. 2007 Aug;24(8):702-8. Epub 2007 Apr 17.
Differential neurotoxicity of tricyclic antidepressants and novel derivatives in vitro in a dorsal root ganglion cell culture model.
Haller I, Lirk P, Keller C, Wang GK, Gerner P, Klimaschewski L.
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria.
BACKGROUND AND OBJECTIVE: Tricyclic antidepressants are commonly employed orally to treat major depressive disorders and have been shown to be of substantial benefit in various chronic pain conditions. Among other properties they are potent Na+ channel blockers in vitro and show local anaesthetic properties in vivo. The present study aimed to determine their differential neurotoxicity, and that of novel derivatives as prerequisite for their potential use in regional anaesthesia. METHODS: To directly test neurotoxicity in adult peripheral neurons, the culture model of dissociated adult rat primary sensory neurons was employed. Neurons were incubated for 24 h with amitriptyline, N-methyl-amitriptyline, doxepin, N-methyl-doxepin, N-propyl-doxepin, desipramine, imipramine and trimipramine at 100 mumol, and at concentrations correlating to their respective potency in blocking sodium channels. RESULTS: All investigated substances showed considerable neurotoxic potency as represented in significantly decreased neuron numbers in cultures as compared to controls. Specifically, doxepin was more neurotoxic than amitriptyline, and both imipramine and trimipramine were more toxic than desipramine or amitriptyline. Novel derivatives of tricyclic antidepressants were, in general, more toxic than the parent compound. CONCLUSIONS: Tricyclic antidepressants and novel derivatives thereof show differential neurotoxic potential in vitro. The rank order of toxicity relative to sodium channel blocking potency was desipramine < amitriptyline < N-methyl amitriptyline < doxepin < trimipramine < imipramine < N-methyl doxepin < N-propyl doxepin.
PMID: 17437653 [PubMed - indexed for MEDLINE]
and this one :
Toxicol Appl Pharmacol. 2006 Nov 15;217(1):100-6. Epub 2006 Aug 15.
A proposed mechanism for amitriptyline neurotoxicity based on its detergent nature.
Kitagawa N, Oda M, Nobutaka I, Satoh H, Totoki T, Morimoto M.
Department of Anesthesiology, Tsuruta Orthopedic Clinic, Ushizu, Saga 849-0306, Japan.
Although amitriptyline has gained attention as a potent local anesthetic, recent animal studies showed that it can cause irreversible neural impairment. We hypothesized that nerve membrane disruption caused by solubilization, a common detergent property, accounted for amitriptyline neurotoxicity. We used a two-phase approach to test our hypothesis. Firstly, we determined (1) the molecular aggregation concentration of amitriptyline, (2) the concentration of amitriptyline that disrupts artificial lipid membranes and (3) the concentration of amitriptyline that causes hemolysis. Secondly, we compared these levels with neurotoxic concentrations determined from assessment in a rat model of spinal anesthesia using changes in cutaneous stimulus threshold (CST). Amitriptyline concentrations that caused molecular aggregation, model membrane disruption and hemolysis were 0.46%, 0.35% and 0.3%, respectively. Animal study showed a significant increase in CST at >or=0.3% of amitriptyline, indicating neurological impairment. Since amitriptyline caused model membrane disruption and hemolysis at the molecular aggregation concentration, solubilization plays a role in the destruction of artificial membranes and erythrocytes. Furthermore, these concentrations are also in good agreement with the minimum concentration causing neurological injury. Therefore, while additional studies, including histopathology, are necessary to clarify this observation, amitriptyline neurotoxicity appears to be associated with its detergent nature.
PMID: 16978678 [PubMed - indexed for MEDLINE]
and this one:
All involving injection as an anesthetic.
I am still looking for oral studies...
There are studies about SSRIs causing neuronal cell death...these have been around for few years. This paper includes amitriptyline with prozac (which has been most studied so far):