Abstract
AMITRIPTYLINE and other tricyclic antidepressants are used often orally for management of various types of chronic pain. 1 Amitriptyline is known to exert a variety of effects, among them blockade of multiple ion channels and receptors and inhibition of norepinephrine and serotonin reuptake 2–8; however, the underlying mechanism by which it relieves pain remains unclear. 9 Recently, amitriptyline was found to have potent local anesthetic (LA) properties in a rat sciatic nerve block model. 10 Many types of pain, including postoperative and neuropathic pain, are thought to be caused by a spontaneous high-frequency discharge of neurons. 11 LAs are known to show the phenomenon of use-dependent blockade, i.e. , at high-frequency stimulation, additional blockade is achieved at the same drug concentration. Amitriptyline was shown to have LA properties, to exert a high degree of use-dependent block of various Na+channel isoforms in vitro , 2 and to be a much more potent LA than bupivacaine 10 (clinically the most commonly used LA for long-lasting nerve blockade) in a rat model of sciatic nerve blockade. We decided to create a phenylethyl derivative of amitriptyline for several reasons: (1) A phenylethyl group has been added to many other drug classes, e.g. , fentanyl, 12,13 to increase drug potency. (2) In former experiments, when phenylethyl was added to lidocaine, the intrinsic affinity in blocking Na+channels as well as the LA potency greatly increased. 14 (3) Adding a short alkyl group has been unsuccessful. For example, QX-314 was associated with minimal permeability of membranes and therefore had a very limited clinical effect. 15 On the other hand, the addition of penylethyl to amitriptyline creates a quaternary ammonium (QA) in which the charge is more likely shielded by hydrophobic arms and that should at least partially retain the ability to traverse membranes. (4) Amitriptyline is severely limited by its cardiotoxicity. 16,17 Modifying it into a permanently charged drug, and therefore significantly increasing the time to traverse lipid membranes, should greatly decrease the time to and the peak of the plasma concentration, thereby reducing the adverse effect profile. (5) A high degree of use-dependent block, if retained after the addition of this phenylethyl group (as it was the case with lidocaine), should be capable of reducing high-frequency neuronal discharge at low plasma concentrations, and thus further reducing the adverse effect profile. We hypothesized that derivatizing amitriptyline to the permanently charged QA derivative N -phenylethyl amitriptyline (fig. 1) will create an LA drug with higher potency than amitriptyline and an even greater use-dependent blockade in vitro . Therefore, we compared the potency and use-dependent block of N -phenylethyl amitriptyline with that of amitriptyline. To determine the LA effect and the therapeutic range in vivo , we evaluated N -phenylethyl amitriptyline at various concentrations (1, 2.5, and 5 mm) for sciatic nerve blockade in rats and compared it with lidocaine, the LA most frequently used clinically. In addition, we performed histopathologic studies of sciatic nerve preparations to evaluate neurotoxicity.