caffiene, elavil (amitriptyline) and neuropathic pain

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Eur J Pharmacol. 2001 Nov 2;430(2-3):211-8.

Chronic administration of amitriptyline and caffeine in a rat model

of neuropathic pain: multiple interactions.

Esser MJ, Chase T, GV, Sawynok J.

Departments of Pharmacology and Anatomy and Neurobiology, Dalhousie

University, Nova Scotia, B3H 4H7, Halifax, Canada.

This study was designed to determine (1) whether chronic

amitriptyline administration was effective in alleviating symptoms of

neuropathic pain in a rat model of spinal nerve injury, and (2)

whether the effect of amitriptyline involved manipulation of

endogenous adenosine, by determining the effect of caffeine, a non-

selective adenosine A(1) and A(2) receptor antagonist, on its

actions. Nerve injury was produced by unilateral spinal nerve

ligation of the fifth and sixth lumbar nerves distal to the dorsal

root ganglion, and this resulted in stimulus-evoked thermal

hyperalgesia and static tactile mechanical allodynia. Animals

received pre- and post-surgical intraperitoneal doses of

amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in

combination, and following surgery, were administered amitriptyline

(15-18 mg/kg/day) and caffeine (6-8 mg/kg/day), alone or in

combination, in the drinking water. Rats were tested for thermal

reaction latencies and static tactile thresholds at 7, 14 and 21 days

following surgery. In the paw ipsilateral to the nerve ligation,

chronic amitriptyline administration consistently decreased the

thermal hyperalgesia produced by spinal nerve ligation over a 3-week

period, and this effect was blocked by concomitant caffeine

administration at all time intervals. In the contralateral paw,

thermal withdrawal latencies were more variable, with the most

reproducible finding being a reduction in thermal thresholds in the

amitriptyline-caffeine combination group. There was no effect by

either drug or the drug combination on the static tactile allodynia

produced by spinal nerve ligation in the ipsilateral paw. However,

chronic amitriptyline administration induced a tactile hyperaesthesia

in the contralateral paw at all time intervals, and this effect was

exacerbated by concomitant chronic caffeine administration. The

results of this study indicate that chronic administration of

amitriptyline is effective in alleviating thermal hyperalgesia, but

not static tactile allodynia, in the hindpaw ipsilateral to nerve

injury, and the block of this effect by caffeine suggests that this

effect is partially achieved through manipulation of endogenous

adenosine systems. Additionally, chronic amitriptyline administration

induces contralateral hyperaesthetic responses that are augmented by

caffeine. Both the symptom-specific effect, and adenosine involvement

in amitriptyline action may be important considerations governing its

use in neuropathic pain.