Key messages

• It is unclear whether cannabinoids reduce pain or improve the quality of life of patients with refractory cancer pain, because the certainty of the available evidence is very low.
• Cannabinoids probably lead to a substantial increase on adverse events in patients with active cancer and refractory pain.

What is the evidence.
See evidence matrix  in Epistemonikos later

We identified nine systematic reviews [1],[2],[3],[4],[5], [6],[7],[8],[9], including seven primary studies [10],[11], [12],[13],[14],[15],[16] of which six are randomized controlled trials [10],[11],[12],[13],[14],[15]. This table and the summary in general are based on the latter. 

What types of patients were included

All of the trials included adults with active cancer and pain of diverse etiology (cancer, bone or neuropathic) [10],[11],[12],[13],[14],[15].

Four trials included inpatients [10],[11],[12],[13], and two outpatients [14],[15].

Only two trials [14],[15] included patients that were refractory to treatment, defined as moderate or intense pain despite treatment with 80 mg or more morphine equivalents.

What types of interventions were included

Three trials evaluated delta-9-tetrahydrocannabinol extracts [10],[11],[14], two trials [14],[15] addressed nabiximol, a preparation of tetrahydrocannabinol and cannabidiol, one trial tested a nitrogen analogue of Cannabis (NIB) [12] and one trial evaluated benzopyranoperidine [13].

All of the studies compared against placebo or treatment with codeine (in less than standard dose). One trial had several arms, including comparison against other cannabinoids [14].

What types of outcomes
were measured

To whom this evidence does and does not apply

• This evidence applies to adult patients presenting with pain of difficult management in the context of active cancer.
• None of the included studies evaluated the effects of smoked or vaporized Cannabis. There are more than 60 cannabinoids in the Cannabis plant, and route of administration might modify the effects, so any extrapolation to other therapeutic forms or route of administration not evaluated in the studies might be premature.

• The outcomes selected in this summary are those critical for decision-making according to the opinion of the authors of this summary. They coincide with the outcomes presented in most systematic reviews and guidelines.

• It is not possible to make a proper benefit/risk assessment because the certainty of the evidence on the effectiveness is very low. However, considering any effect is probably small, and side effects are common, the risk/benefit balance probably does not favor this intervention.

• Given the nature of this evidence most patients and physicians should be inclined against the use of this intervention. However, the social connotation of natural medicines and Cannabis particularly, might make some people favor its use despite the information provided in this summary.

• These drugs are generally of high cost. In the case of oral drugs, the direct cost is usually high. In the case of Cannabis, there are high costs associated with its production, regulation and distribution.

• It is important to note the difficulties on access to these medicines in countries where the formulations derived from Cannabis are prohibited by law.
• The drug that was used in the studies selected for this summary is not commercially available yet.

Differences between this summary and other sources

• The conclusions of this summary are consistent with the systematic reviews identified, although some reviews [6],[7] analyzing a broader spectrum of types of pain provide a more positive conclusion in favor of cannabinoids.
• The National Comprehensive Cancer Network guideline, European Society for Clinical Oncology guideline and the NICE guideline for clinical care at the end of life [17],[18],[19] do not mention cannabinoids as a therapeutic alternative. On the contrary, they recommend other analgesic agents, such as ketamine or new generation opioids like tapentadol. The American Society of Clinical Oncology guideline [20], which deals with surviving patients, recommends the use of cannabinoids for the treatment of chronic pain (regardless of type or origin) after making an appropriate cost/benefit consideration, an according to local laws.

• The likelihood of future evidence changing the conclusions of this summary about the benefits of cannabinoids in patients with cancer pain is very high, given the existing uncertainty.
• We identified at least two ongoing trials [21],[22] in the WHO International Clinical Trials Registry Platform addressing this topic, which could provide relevant information.
• New high quality systematic reviews might provide relevant information, considering most reviews identified have important limitations.