Cannabinoids and cancer pain: A new hope or a false dawn?

The endocannabinoid system is involved in many areas of physiological function and homeostasis. Cannabinoid receptors are expressed in the peripheral and central nervous system and on immune cells, all areas ideally suited to modulation of pain processing. There are a wealth of preclinical data in a number of acute, chronic, neuropathic and cancer pain models that have demonstrated a potent analgesic potential for cannabinoids, especially in patients with cancer. However, although there are some positive results in pain of cancer patients, the clinical evidence for cannabinoids as analgesics has not been convincing and their use can only be weakly recommended. The efficacy of cannabinoids seems to have been 'lost in translation' which may in part be related to using extracts of herbal cannabis rather than targeted selective full agonists at the cannabinoid CB1 and CB2 receptors.

Do cannabinoids have a role in cancer pain management?

PURPOSE OF REVIEW: Historically cannabinoids have been used for both therapy and recreation, yet the elucidation of the endocannabinoid system and their chemistry has been relatively recent. Prohibition of cannabis has meant few clinical trials, especially in cancer pain. This review will consider previous animal and clinical data and assess more recent investigations of clinical effectiveness of cannabinoids in pain and specifically cancer pain. RECENT FINDINGS: Meta-analyses based on historical studies question the utility of cannabinoids in pain due to modest analgesia and problematic central side effects. However, there has been a resurgence in clinical trials of cannabis extracts and analogues. New data have contributed to the understanding of how cannabinoids work and proposed how to obtain analgesia unfettered by adverse effects. Moreover, recent clinical trials have demonstrated the current role of cannabinoids may be to attain small but significant benefit in refractory chronic and cancer pain. SUMMARY: Cannabinoids may be a useful addition to current analgesic treatments. The evidence supports a possible role for cannabinoids in refractory cancer pain. However, to realize the full potential of cannabinoids suggested by preclinical data, it is likely that peripheral CB1 or CB2 receptors or modulation of endocannabinoids will have to be targeted to achieve analgesia without dose limiting side effects.

A novel neuroimmune mechanism in cannabinoid-mediated attenuation of nerve growth factor-induced hyperalgesia.

BACKGROUND: Nerve growth factor (NGF) is central to processes involved in an inflammatory hyperalgesia. Administration of exogenous NGF induces a hyperalgesia that is dependent on local neutrophil influx. The effects of administration of the cannabinoid anandamide and the cannabimimetic palmitoylethanolamide on an NGF-induced hyperalgesia and neutrophil accumulation were examined in this study. METHODS: Baseline hind limb withdrawal latencies to a noxious heat stimulus were recorded before intraplantar administration of NGF (1 microg in 0.05 ml) to the hind paw of 75 male Wistar rats. Anandamide or palmitoylethanolamide (a substance that has cannabinoid-like actions but little affinity for cannabinoid receptors) at doses of 10 and 25 mg/kg were given (intraperitoneally) immediately after NGF. CB1 (SR141716A) and CB2 (SR144528) receptor antagonists were coadministered with the higher dose of cannabinoids. Withdrawal latencies were expressed as difference from baseline. Seventy rats received intraplantar NGF and intraperitoneal treatments. Neutrophil accumulation in the injected paw was assessed using a myeloperoxidase assay. RESULTS: Administration of NGF reduced latencies consistent with hyperalgesia. Anandamide and palmitoylethanolamide significantly reduced this hyperalgesia. The action of anandamide was CB1 receptor-mediated. SR144528 abrogated the action of palmitoylethanolamide. NGF also provoked neutrophil accumulation in the injected paw, denoted by an increase in myeloperoxidase. Palmitoylethanolamide significantly reduced neutrophil accumulation by an SR144528-sensitive action, whereas anandamide was without effect. CONCLUSIONS: NGF induced a thermal hyperalgesia that was attenuated by anandamide and palmitoylethanolamide. Only palmitoylethanolamide reduced neutrophil influx. Thus, cannabinoids show a neuronal CB1 receptor-mediated antihyperalgesic action and a separate inhibition of a proinflammatory neuroimmune process. Such a mechanism suggests a therapeutic site of analgesic action separable from central side effects.

Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors.

Cannabinoids have previously been shown to possess analgesic properties in a model of visceral hyperalgesia in which the neurotrophin, nerve growth factor (NGF), plays a pivotal role. The purpose of this study was to investigate the antihyperalgesic effects of two cannabinoids in NGF-evoked visceral hyperalgesia in order to test the hypothesis that endocannabinoids may modulate the NGF-driven elements of inflammatory hyperalgesia. Intra-vesical installation of NGF replicates many features of visceral hyperalgesia, including a bladder hyper-reflexia and increased expression of the immediate early gene c fos in the spinal cord. We investigated the action of anandamide and palmitoylethanolamide (PEA) on these parameters. Both anandamide (at a dose of 25 mg/kg) and PEA (at a dose of 2.5 mg/kg) attenuated the bladder hyper-reflexia induced by intra-vesical NGF. The use of cannabinoid CB1 receptor (SR141617A) and CB2 receptor (SR144528) antagonists suggested that the effect of anandamide was mediated by both CB1 and CB2 cannabinoid receptors whilst the action of PEA was via CB2 (or CB2-like) receptors only. Furthermore, anandamide (25 mg/kg) and PEA (2.5 mg/kg) reduced intra-vesical NGF-evoked spinal cord Fos expression at the appropriate level (L6) by 35 and 43%, respectively. However, neither CB1 nor CB2 receptor antagonists altered the action of anandamide. PEA-induced reduction in Fos expression was abrogated by SR144528. These data add to the growing evidence of a therapeutic potential for cannabinoids, and support the hypothesis that the endogenous cannabinoid system modulates the NGF-mediated components of inflammatory processes.