The pain paradox

Pain, whether short, sharp and temporary, or a constant misery, affects all of us. Around 20% of the adult population of Europe and the US lives with chronic pain (defined as "localised or widespread pain lasting three months or longer"), most commonly  arising from low back problems, osteoarthritis or rheumatoid arthritis, and from nerve damage (neuropathic pain), a common consequence of diabetes and surgery.

Pain medication is a daily and essential  part of life for millions of individuals but we remain heavily reliant on a relatively small number of drug types, several of which were introduced into common use over a century ago. The origins of aspirin and purified opiates, both available commercially since the start of the 20^th century, go back thousands of years,  to the use of willow leaf or bark teas and extracts of poppy seeds and juices.

Paracetamol (acetaminophen), was introduced in the 1950s (some 50 years after its discovery) and “non steroidal anti-inflammatory drugs” (NSAIDS), a mainstay for arthritis sufferers, during the 1970s and 1980s. Synthetic opioids and opioid reformulations, such as  fentanyl and extended release oxycodone,  have acquired notoriety through their association with epidemic levels of abuse and dependence but these drugs remain invaluable in the relief of otherwise intractable pain (blame the system, not the product).

An analysis published by the Biotechnology Innovation Organization (BIO) highlights a surprising lack of innovation in pain drug development. While the BIO report focuses on the US, the picture is not radically different in Europe and Japan.

Almost all pain medications approved for sale in the  US during the past decade have been either reformulations of previously marketed drugs or have involved drugs previously approved for other indications. Only two novel pain medications have been approved since 2009, of which one, milnacipran, had previously received approval  as an antidepressant. Industry’s last great foray in pain drug development ended in the early 2000s,  as a class of anticipated blockbusters, the cyclooxegenase-2 (COX-2) inhibitors such as Celebrex® and Vioxx®,  turned out to be potentially unsafe in a significant subset of patients.

Pain drug development activity is not at a standstill, but is hardly thriving. The BIO analysis identified 220 clinical studies for pain indications, of which over half involve novel drugs. This seems respectable until you consider that, in total,  this clinical development activity is less than one-tenth of the activity devoted to cancer drug development, and that the majority of cancer studies involve novel agents.

Investment serves as a rough and ready barometer of relative commercial attractiveness. Novel pain drug development pulled in $576 million in venture funding during the period 2007 to 2016: in comparison, $10.3 billion was showered on novel cancer drug development during the same period. As an aside, despite the uncontested economic and societal impact of drug addiction, novel substance abuse treatments have attracted only $16 million in venture investment in a decade. 

Given the number of individuals in dire need of safer and more effective pain medication, why is industry and the investment community apparently disengaged from pain drug development? Perceived risk would appear to be a major factor, with the probability of FDA approval of a novel pain drug being around 2%, well below the 10% or better for drugs addressing other indications.

Reimbursement is another key issue. The pain drug market is largely generic and healthcare payers demand hard evidence of superiority or cost-effectiveness of new treatments over established medications, something that’s not easy to establish given  the difficulty in capturing and quantifying the subjective impact of pain in clinical studies.

Even when there is a clear basis for potential advantage over existing drugs, such as with the close to market calcitonin gene-related peptide (CGRP) inhibitors which have been shown to be highly effective in migraine prevention, the inability to predict which patients are likely to respond to treatment could make payers reluctant to meet the expected $8,500 per patient drug cost.  

Pain is biologically complex  and novel targets amenable to drug discovery are, to date, few and far between. As in oncology drug development, across the board innovation, combining AI analytics, population-based studies, biomarkers, predictive animal models and better means of patient data capture will be needed to find more prospective winners and to tempt industry and investors back to pain drug development.   

Photo credit: Trying2

The state of innovation in highly prevalent chronic diseases. Volume II: Pain and addiction therapeutics.   Thomas, D and Wesse, C. Bio Industry Analysis, February 2018. Biotechnology Innovation Organization.  Published online 12^th February 2018. http://tinyurl.com/y87l9cp5.