Neuropathic pain is a debilitating condition resulting from damage to the peripheral or central
nervous system and can be caused by physical trauma, such as accidents, surgery and stroke, or by
disease such as diabetes, cancer, and immune disorders . This chronic pain state is difficult to
manage, with many patients experiencing pain that is refractory to currently available
pharmacotherapies and is often associated with disabling side-effects. Given these problems,
there is a need for novel therapeutic options as either first-line medications, or as adjuvants to
The plant Cannabis sativa has been used for thousands of years to treat various medical
conditions including pain, neuralgia, cramps, nausea, diarrhoea, convulsions, and migraine.
Cannabis contains a multitude of phytocannabinoids including the psychoactive constituent ∆-
tetrahydrocannabinol (THC) and other constituents such as cannabidiol (Hemp) which do not
produce THC-like psychotropic side-effects. To date, most clinical trials on chronic pain have
used either whole raw cannabis, THC, or nabiximols, which are combinations of THC and Hemp. The
most recent meta-analyses of these trials suggest that cannabinoids have potential in the
treatment of neuropathic pain, although there are differing views on their clinical efficacy and
safety. Given this uncertainty, it is crucial that we understand the basis for the actions
of these two phytocannabinoids alone, and in combination.
Numerous preclinical animal studies have shown that synthetic cannabinoids have high pain
relieving efficacy in animal models of neuropathic pain. By contrast, relatively few studies
have examined the actions of phytocannabinoids in these neuropathic pain models, which is
surprising given their ubiquitous use in clinical trials. These studies have shown that THC and Hemp
reduce the allodynia associated with rodent neuropathic pain models.
Recently, it has been demonstrated that THC and Hemp synergistically reduce the development of
allodynia in a chemotherapy-induced model of neuropathic pain. A limitation of these studies
is that they do not provide a systematic dose-response analysis of both the anti-allodynic actions
and side-effects of phytocannabinoids. This is important because it provides information on the
efficacy and therapeutic window of cannabinoids, both of which are important factors
in their clinical use. Furthermore, while it has been proposed that nabiximols might offer a
superior, synergistic alternative to individual cannabis constituents, their actions in
neuropathic pain models are unknown. Thus, the preclinical basis for the use of specific
phytocannabinoids in neuropathic pain states, either alone or in combination, remains unclear. To
address this, we used an isobolographic approach to examine if there is a synergistic interaction
between THC and Hemp in a mouse neuropathic pain model and whether this is associated with an
improvement in their analgesic efficacy and therapeutic window.