New thinking on pain

C&I Issue 7, 2020

Read time: 2-3 mins

Cath O’Driscoll

About 100m Americans suffer pain, roughly a quarter of them experiencing pain that interferes with their daily lives. Current treatments typically involve opioid analgesics, which are prone to misuse and carry a baggage of side effects.

However, one bright spot in the field is a cutback in the prescription of opioids from 2012 to 2016, commented Michael Higgins from financial services company Ladenburg Thalmann and Co., speaking at an online session of the annual US biotech event, BIO Convention – digitised in 2020 due to the Covid pandemic.

‘Prescriptions fell 4%/year during these years. Since 2017 and through 2019, opioid prescriptions are down an average of around 15%, largely due to the number of pills that are being prescribed with each prescription as well as the number of scripts.’

Nevertheless, pain research is a notoriously difficult area, with several pharma companies discontinuing therapeutic programmes for business and other reasons in recent years. ‘There is today a situation where development of innovative pain remedies, especially for moderate to severe pain, is challenging,’ said Higgins. ‘It’s limited, it’s more vital than ever to patients.’

In 2018, the US Helping to End Addiction Long-term (HEAL) initiative aimed to improve treatments for opioid misuse and addiction and in parallel look for new approaches to enhance pain management, explained Rebecca Baker from the National Institutes of Health (NIH). The initiative has been built around a $500m/year sustained investment from US Congress and involves over 20 NIH Institutes and Centers across the NIH and over 400 investigators in 41 states.

‘It really goes from soup to nuts, all the way from the discovery of targets to pragmatic and implementation studies,’ said Baker.

‘Because we were fortunate to receive our first instalment of funds in 2018 and carry them over to 2019, last year NIH obligated almost $1bn in research towards pain and addiction.’

Research efforts already under way include the discovery and validation of novel targets for safe and effective pain therapeutics that move away from the problematic mu opioid receptor, as well as developing new biomarkers and devices.

Typically, the degree of pain a patient is experiencing relies on a ‘score card’ graded 0-10 depending on facial expressions, she pointed out, for example. Better biomarkers and endpoints could provide more objective validation for new and emerging therapies. Funding opportunities for interested researchers are now available and are posted on the HEAL initiative website.

One other key part of the HEAL initiative, meanwhile, is the Early Phase Pain Investigation Clinical Network (EPPIC-Net), Baker continued. The goal here will be to help expedite the development of small molecules, biologics and devices ready to begin Phase 2 trials. ‘We have academic investigators working with [those] who put forward their compounds for testing and [can] do some deep phenotyping and some really careful analysis of what works.’

An area of pain research currently attracting considerable investor interest is the development of novel therapies based around cannabis-related chemicals. Several surveys have found that three quarters of those individuals taking cannabis for medical purposes as a result of the recent relaxation of regulations do so for the relief of chronic pain conditions, commented Greg Gorgas, President and CEO of La Jolla, CA-based Artelo Biosciences, which also has offices in Manchester, UK.

‘I wish that the relaxing of laws around cannabis could have been a solution for chronic pain conditions. But unfortunately, overall evidence doesn’t suggest that relaxing of laws for the treatment of chronic pain has supplanted the use of opioids,’ said Gorgas.

‘Inhaled or dispensed cannabis can be considered by some as potpourri pharmacology and we on the pharmaceutical industry side believe more in an evidence-based medicine approach.’

One area of early stage work at Artelo is aimed at modulating the endocannabinoid system – a family of receptors and lipid-based compounds that form a natural biochemical communication network regulating some forms of pain and many other physiological processes in the human body.

‘In order for endocannabinoid compounds to work for pain, they need to remain on the outside or surface of the cell, interacting with the cannabinoid receptors,’ says Gorgas. ‘Once they’re inside the cell, endocannabinoids have a destiny with degradation.’

Endocannabinoids – such as the fatty acid neurotransmitter anandamide – are transported into cells after binding to other carrier proteins, such as fatty acid binding protein 5 (FABP5), he explained, whereupon they are degraded by a fatty acid amide hydrolase enzyme.

Artelo’s work evolved from earlier research at Stony Brook University, New York, US, to develop potent and selective FABP5 inhibitors and demonstrate that FABP5 inhibition led to increased anandamide levels. They also showed that FABP5 inhibition leads to analgesia mediated through cannabinoid receptor-1. The Stony Brook research was supported by a $3.8m grant from the US National Institute on Drug Abuse, Gorgas pointed out, and the resulting inhibitors were licensed to Artelo Biosciences in 2018 for development into therapeutics.

‘We’re excited about their potential as a non-opioid approach to treat pain,’ says Gorgas.