Opioids and cannabinoids are commonly employed in the
palliative therapy of cancer. Opioids are used since many years in the
treatment of cancer-related pain [1], while the cannabinoid agents have been
clinically introduced only more recently [2,3]. However, there is a great
difference in their effects, since while the opioids are substantially used for
the only therapy of pain, cannabinoids may be effective not only in the
treatment of pain, but also of various other cancer-related symptoms, including
cachexia, anorexia, anxiety, vomiting and muscle contractions. Moreover, while
morphine and other mu-opioids are used for the only palliative therapy because
of their immunosuppressive action [4], cannabinoids may exert potentially
antitumor effects [5]. Therefore, cannabinoid therapy of cancer could
constitute the point of connection between palliative and curative therapies of
human neoplastic diseases. Then, the major difference between opioids and
cannabinoids in the treatment of cancer regards their effects on tumor growth
itself. In fact, while opioids, particularly the mu-opioid agonists, may
promote tumor growth by either exerting an immunosuppressive action on
antitumor immunity by counteracting T cell proliferation and differentiation
[4], or directly stimulating cancer cell proliferation [6], cannabinoids may
act as potential natural anticancer agents [5]. Then, the clinical use of
cannabinoid instead of opioids in the palliative therapy of cancer is justified
by their efficacy in the therapy not only of pain, but also of other symptoms,
mainly cachexia and vomiting, as well as because of their potential anticancer
activity and complete lack of immunosuppressive effects on the anticancer
immunity. In fact, even though at present they have been clinically used substantially
for the only palliative therapy of cancer, cannabinoids may also play an
anticancer activity through several mechanisms, including direct cytotoxic
action, inhibition of angiogenesis, and block of the secretion of pro-tumor
inflammatory cytokines [5], including IL-6, TNF-alpha, and mainly IL-17 [7],
which may directly stimulate cancer cell proliferation, by representing one of
the main pro-tumoral cytokines. In addition, the lack of efficacy of some
antitumor therapies, including cancer immunotherapy with monoclonal antibodies,
has appeared to be due to an enhanced IL-17 secretion [9]. Then, the inhibition
of IL-17 secretion could improve the efficacy of host anticancer immunity. In
any case, it has to be remarked that mu-opioid drug-induced immunosuppression
may change in relation to the type of agent, and in particularly it has been
shown that the greatest immunosuppressive effect is played by fentanyl, while
hydromorphone and oxycodone would not exert suppressive effects on the
antitumor immunity [10]. By synthetizing, opioid and cannabinoid agents may be
either synergic, or opposite in their therapeutic effects. In more detail,
opioid and cannabinoid drugs are synergic in the treatment of pain [11],
whereas they are opposite in the therapy of vomiting and anorexia, but they are
primarily opposite in their influence on tumor growth, promoted by opioids and
counteracted by cannabinoids. Delta and kappa opioids may exert both
stimulatory and inhibitory effects on the anticancer immunity, depending on
those and schedule of administration [12]. In addition. Oxytocin may also exert
antalgic effects [13], and it would play a fundamental role in the regulation
of connections between brain opioid and cannabinoid systems. Moreover, even
though the mechanism has to be better explained, from an empiric point of view
it has been demonstrated that the antalgic action of opioids and the duration
of their effects across the time without the need to increase their dosage
because of the occurrence of tolerance may be amplified by a rotation
administration of the different mu-opioid agonists [14], by changing the type
of the opiate drug across the time. On the contrary, at present it is not known
whether a same conclusion may be proposed for an eventual cannabinoid rotatory
treatment, not only to prolong their antalgic activity, since the mechanism of
tolerance is not relevant for cannabinoids, but also to enhance their potential
anticancer action by opposing the occurrence of tumor resistance to each
potential antitumor molecule through a rotatory administration of the different
cannabinoid agents. At this proposal, from a pharmacological point of view the
cannabinoid agents may be subdivided into two major classes [2,3], consisting
of cannabinoid receptor (CB) 1 and 2 agonists, and inhibitory of fatty acid
amide hydrolase (FAAH), the enzyme involved in cannabinoid catabolism, with a
consequent increase in the endogenous content of cannabinoids (4). In any case,
both classes of cannabinoids have appeared to exert a direct anticancer
activity [4]. Within the Cannabis plant, the only CB1-CB2 receptor agonist,
then provided by psychotropic effect, is tetrahydrocannabinol (THC),
cannabidiol (CBD) and cannabigerol (CBG) are the main FAAH inhibitors, while
cannabinol (CBN) may act as partial CB1 receptor agonist. The affinity for CB
receptor of CBG is greater than that of CBD, then the less anxiogenic factor of
Cannabis is CBD. On the other hand, the CB1-CB2 receptor agonists of the human
endocannabinoid system consist of arachidonyl-ethanol-amide (AEA), also termed
anandamide, and 2-arachidonyl-glycerol (2-AG), while the most investigated
endogenous FAAH inhibitor is represented by palmitoyl-ethanol-amide (PEA) [4].
In addition, previous preliminary clinical studies have shown that the
administration of cannabinoid agents from Cannabis in association with
potential endogenous anticancer hormones, such as the pineal indoles melatonin
(MLT) [15] and 6-methoxytryptamine (5-MTT) [16], and the enzymatic product of
ACE2, the angiotensin 1-7 (Ang 1-7) [17], may control tumor growth also in
advanced cancer patients, who failed to respond to the common standard
anticancer treatments [18,19]. On these bases, a study was planned to evaluate
the clinical effects of a rotatory therapy with three different cannabinoids,
consisting of CBD, PEA, and CBG in association with the pineal hormones MLT and
5-MTT, plus Ang 1-7 in advanced cancer patients, who failed to respond to the
standard anticancer treatment, then suitable for the only palliative therapy,
according to previous preliminary clinical studies [18,19].