Given the apparent efficacy of nabiximols in treating MSS and MS-related pain, nabiximols has also been studied to determine its effects on other etiologies of chronic pain, such as cancer-related chronic pain, which occurs in up to 90% of those with advanced disease [
22]. Opioids are a mainstay of treatment for pain in these patients, and alternative therapies are widely sought after to avoid drug-related adverse effects associated with long-term opioid use or pain refractory to opioid therapy. Animal models have shown that cannabinoid receptor agonists can act synergistically with opioids in chronic pain models, leading to THC becoming a subject of interest in the management of these patients [
23]. A double-blind, randomized, placebo-controlled study of nabiximols by Lichtman et al. sought to determine whether nabiximols could serve as effective add-on therapy for the management of chronic pain in cancer patients, with their primary endpoint being improvement in daily pain. These investigators found a nonsignificant improvement in daily pain NRS scores in patients receiving nabiximols compared to those on placebo [
24]. Despite this, the study did find improvement in some of their secondary endpoints, including improvement in sleep disruption and higher scores on the Patient Satisfaction, Subject Global Impression of Change and Physician Global Impression of Change questionnaires. Interestingly, the study also found that its US participants demonstrated greater improvement on nabiximols than did participants from outside the USA. It was postulated that this difference may have been due to the US participants being on an average of a > 25% lower opioid dose than non-US participants, resulting in a reduced downregulation of opioid receptors in the US participants and, subsequently, in a greater synergism between opioid and cannabinoid receptors [
25]. Other studies of nabiximols for the treatment of cancer-related pain have also failed to find significant improvement in baseline pain scores [
25,
26]. However, in the study by Portenoy et al., the secondary endpoint (comparing proportion of responders in the active drug arm vs. placebo arm) did demonstrate that nabiximols had an improved analgesic effect in patients on low- and medium-dose therapy (defined as 1–4 sprays per day and 6–10 sprays per day, respectively). The low-dose nabiximols group in this study demonstrated the greatest analgesic effect, with a 26% improvement in pain compared to baseline, while the high-dose group (defined as 11–16 sprays per day) did not demonstrate significant analgesic effects and was found to have poor tolerability [
26]. A common finding in these aforementioned studies is that nabiximols therapy tends to improve sleep in patients with chronic cancer-related pain, suggesting that even if nabiximols does not greatly improve pain scores, it may still provide benefit to patients with chronic pain who experience sleep disturbances [
24,
26,
27]. The authors of a recent review concluded that there is modest evidence for the benefit of nabiximols in the treatment of chronic pain and suggested that the decision to add this therapy be a discussion between patient and provider when first- and second-line therapy has failed [
28]. Overall, nabiximols appears to have some benefit for patients experiencing chronic cancer-related pain, including mild pain improvement and improved sleep. Sample sizes in the studies currently available tend to be small, so further investigation is required to determine whether the relatively small improvements on the pain scale ratings are significant on a wider scale.