Cannabis – It’s all about the whole thing! [Cannabis – Es geht ums Ganze!]

In this context, the term “evidence” is misused in that it is understood to mean exclusively findings from data-based medicine (randomized controlled trials, RCT; meta-analyses) and the empirical values of the practitioners and patients are not taken into account, which is what evidence-based medicine (EBM) is composed of in the first place. This is all the more true when dealing with such a highly subjective phenomenon as pain, which is known to be inextricably linked to the affected person and cannot be proven with an objective measure. For example, while meta-analyses conclude that it seems unlikely that cannabinoids are highly effective drugs for chronic non-tumor pain [2], patients’ experiences point in the opposite direction [3]. In addition to the extraordinarily high heterogeneity of RCTs, the selection of outcome parameters in particular seems to influence study results. This is exemplified by a prospective cohort study with chronic pain patients, in which more than 1000 patients were included [4]. After 12 months of treatment with a CBM, pain intensity decreased by 20%, but the affective pain component and sleep disturbance each decreased by 33%, and the expression of depression and anxiety by 32% and 40%, respectively [4]. There was a saving effect of morphine equivalents by 42% [4]. It is clear here that the focus is not exclusively on reducing pain intensity, but on improving a variety of relevant areas of life associated with chronic pain.

It is well known that chronic pain develops on the basis of dysfunction in the corticomesolimbic system [5]. More recently, in patients with chronic nerve pain, Weizman et al [6] demonstrated that the more pronounced the dysfunctional connectome in the corticomesolimbic system, the greater the effect of Δ9-tetrahydrocannabinol (THC) on pain reduction [6]. These observations suggest that influencing the endocannabinoid system (ECS) in the brain, particularly the activation of the cannabinoid receptor CB1, is highly relevant to the treatment of chronic pain.

As long as drug and regulatory authorities insist on a hierarchy of target parameters in “pain trials”, with recording of pain intensity using a simple scale as the primary endpoint, CBM will have a hard time showing their clinical relevance in RCT. Capturing the affective dimension of pain and using composite scores that comprehensively describe the pain experience and quality of life are more appropriate in such a situation.

With the involvement of the European Medicines Agency (EMA), ways to conduct benefit-risk analyses in clinical pharmaceutical research have been identified (reviewed in Nutt et al [3]). An international group of pain practitioners with and without experience in the use of CBM, psychiatrists, neurologists, and scientists with expertise in the pharmacology of cannabinoids, and representatives of a patient group (United Patient Alliance) developed such a decision analysis [3]. Using 17 criteria weighted by clinical relevance, 12 drugs commonly used for chronic neuropathic pain were evaluated, including CBMs, antidepressants, gabapentinoids, and opioids. According to these, CBMs appear to be more important in terms of improving quality of life than in terms of reducing pain intensity alone [3]. This is especially true when compared to duloxetine, gabapentinoids, and amitriptyline [3]. With additional consideration of the side effect profile, all 3 CBM (1:1 combination of THC and cannabidiol [CBD], THC, CBD) showed an advantage over all other substances [3].

The phytocannabinoids present in whole extracts and cannabis flowers seem to have a great importance in terms of efficacy and side effect profile. Patients with chronic pain who were able to choose among different cannabis strains did not primarily orient themselves on the extent of pain reduction elicited, but on pain-associated factors (e.g., improvement of night sleep, [12]). Furthermore, the rate of side effects was found to be highly dependent on the profile of phytocannabinoids [12]. Consequently, it is recommended to develop cannabis varieties characterized by an effective cannabinoid and terpene profile with low side effects. Combined with effective and safe galenics, CBM can be expected to expand the armamentarium in pharmacological therapy for chronic pain.