New indications for old molecules

New indications for old molecules

  • Issue 70

One of the Sunday symposia at this year’s Euroanaesthesia was an intriguing session on new indications for old molecules.

The first talk was on the role of cannabinoids for pain control, given by Caterina Aurilio, Professor in Anaesthesia, Intensive Care and Pain Medicine, University of Campania “L. Vanvitelli”, Naples, Italy.

She said: “Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. Cannabinoids today have been studied in depth. They are a group of chemical compounds that activate cannabinoid receptors; they include the phytocannabinoids, endogenous cannabinoid and synthetic cannabinoids.”

Two subtypes of cannabinoid receptors, termed cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptor have been cloned. CB1 receptors are most abundantly expressed in the central nervous system, most densely in motor and limbic regions, and in areas that are involved in pain transmission and modulation, such as periaqueductal grey, rostral ventromedial medulla, spinal cord dorsal horn, and in the periphery. CB2 receptors, on the other hand, are found mainly outside the CNS, predominantly in peripheral tissues with immune functions.

Canada, the Netherlands, Israel, Spain, and certain states in the United States have legalised dried cannabis for medicinal purposes; however, cannabis remains illegal in most European countries and Australia. Three derivatives of cannabis (termed “cannabinoids”) exist: oral nabilone, oral dronabinol, and a 50:50 mixture of tetrahydrocannabinol (THC) and cannabidiol buccal spray, which is currently the only cannabinoid with an official indication for pain.

“Cannabinoid treatments for cancer pain have been studied in a few randomised trials, but the evidence has been less than convincing,” said Prof Aurilio. “For neuropathic pain, cannabinoids could probably play a role in the treatment of pain due to multiple sclerosis and pain related to spinal cord injury associated to spasticity.”

Furthermore, she added that no convincing, unbiased evidence suggests that nabilone is of value in treating people with fibromyalgia. Finally, in osteoarthritic pain there have been encouraging preclinical data on the use of cannabinoids, however results have been disappointing in multiple clinical trials due to the appearance of side-effects or lack of efficacy. She concluded: “More clinical trials should be promoted to determine the possible translation to humans of the very promising results already obtained in the preclinical studies.”

The second half of this session, “Does the use of ketamine for pain treatment make a difference?”, was presented by Professor Marco A.E. Marcus, Chairman of the Department of Anaesthesiology, ICU and Perioperative Medicine, Hamad Medical Corporation, Qatar;
Professor of Clinical Anaesthesiology, Weill-Cornell Medical College Qatar; and Professor Anaesthesiology, Qatar University, Doha, Qatar.

He said: “Many unresolved issues exist in acute and chronic pain therapy. It is possible ketamine can play a role in these unresolved issues. Ketamine is a compound that came on the market in the 1970s, and its renaissance is due to new insights into its central and peripheral working mechanisms.”

Prof Marcus highlighted that the immediate antidepressant effects of the compound might be beneficial, since pain and depression are associated. But he also focused on its peripheral actions when used in regional blocks.

Acute pain is difficult to treat, partly because of the fear of side effects of the compounds being used. By reviewing literature from 2016, Prof Marcus’ talk dealt with questions such as: can ketamine reduce the amount of such compounds, while at the same time reducing persistent postoperative pain? Is there a role for Ketamine in intractable cancer pain? And could ketamine be the new, ideal drug in the emergency room or intensive care?

A literature search revealed just four randomised controlled trials that studied the efficacy of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None of these showed a clinically relevant benefit of ketamine in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as analgesic in cancer pain.   A further 16 open-label studies and case series that were retrieved from the literature search showed efficacy of ketamine in treating pain in terminal cancer patients.   Prof Marcus said: “The discrepancy between the outcome of randomised controlled trials and open and case studies possibly reflect the complexities of pain treatment in terminal cancer patients, the lack of appropriate dosing regimens in randomised controlled trials, the differences in patient populations studied, and the complexities of ketamine with its complex effects on the central nervous system.”

He concluded: “Despite lack of conclusive clinical evidence to support its use, clinicians from various disciplines in many countries continue to use ketamine as adjuvant to opioids for acute and chronic pain management.”