Opioid misuse is a public health crisis that has resulted in debilitation, deaths, and significant social and economic impact. The epidemic has been fueled by widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids such as heroin. In this article, we examine some steps to overcoming this issue and improving the way we treat pain.
This article was authored by Rishabh Chawla from V-Bio Ventures.
The magnitude of the opioid epidemic is startling: in the US, about 4% of the population misuses licit or illicit opioids. In 2018, a full 70% of the 67,000 fatal drug overdoses in the US involved a prescription or illicit opioid. And this is far from just a US problem: according to the World Health Organization, in 2016 an estimated 27 million people around the globe suffered from opioid use disorders.
The origin of the opioid crisis can be traced back to 1995, prior to which many physicians felt concerns regarding the undermanagement of pain symptoms. To properly evaluate and manage pain, the American Pain Society elevated pain from merely a symptom to the fifth vital sign of the human body (in addition to body temperature, pulse, respiratory rate and blood pressure). This decision resulted in clinicians conducting routine pain assessments and prompted increased prescriptions for pain medication.
Studies have found that as many as 80% percent of people who use heroin first misused prescription opioids.
Around the same time, a sustained release formulation of Oxycodone was approved: OxyContinR, developed by Purdue Pharma. The addictive nature of the drug, combined with aggressive marketing by Purdue Pharma, caused the annual sales of OxyContin to soar from $48 million in 1996 (the first year after approval) to $1.1 billion by 2000, and a peak at $3.1 billion in 2010. Sales have since dropped and, with the company plagued by lawsuits related to the opioid crisis, Purdue Pharma filed for bankruptcy in 2019. It was by no means the only company profiting from prescription opioids, however, with others continuing to this day.
The high prescription rates of legal painkillers are important, as studies have found that as many as 80% percent of people who use heroin first misused prescription opioids. Many international drug cartels have taken advantage of the fraught situation by distributing illicit opioids across the world, adding further fuel to the fire.
Alternatives to opioids
Considering the widespread prescription of opioids, it may be surprising to hear that the medication is not actually very efficacious. The Number Need to Treat (NNT) is a metric that indicates the average number of patients who need to be treated to prevent one bad outcome (in this case, to prevent pain in just one individual). The NNT for current pain drugs ranges from approximately 3.5 (for opioids) to 15, reflecting the poor efficacy of most pain killers and, particularly, of non-opioid pain drugs. Millions of patients worldwide are suffering from either acute or chronic pain. To truly fight this epidemic, it’s therefore not enough to just improve our control over prescriptions; we also need to develop safe and effective alternatives to opioids.
Millions of patients worldwide are suffering from either acute or chronic pain. To truly fight this epidemic, it’s therefore not enough to just improve our control over prescriptions; we also need to develop safe and effective alternatives to opioids.
This is no simple task. Pain, like cancer, is not a unitary phenomenon and cannot be treated with a single universally effective drug class. To move forward, we need to recognize the complexity of pain. There are several distinct types of pain driven by different mechanisms, such as physical tissue damage, somatosensory nerve damage, or inflammation, and each of these require appropriate therapeutic interventions.
While pain remains a complex challenge, many novel therapeutic targets have been identified in the last two decades. Methods like genomics, proteomics, epigenetics, lipidomics and single-cell RNA sequencing have been used to identify biochemical pathways involved in pain signal generation, transmission and perception.
Using these strategies, several targets have been identified, including: Angiotensin Type 2 Receptor (AT2R); Neurotensin Receptor1(NTSR1); Matrix metalloproteinases 9/2 (MMPs 9/2); fms like tyrosine kinase 3 (FLT-3); Metabotropic Glutamate Receptor 7 (mGluR7); and ion channels such as Nav1.7 and transient receptor potential (TRP) channels. Unfortunately, many drugs directed against these recently identified targets have failed in clinical trials, often due to inadequate preclinical models, inadequate biomarkers, or toxicity.
Better models for pain
Innovation in preclinical models and biomarkers will be essential to improving the success rate of pain drug development. There has been little progress in preclinical mouse pain models in the past decades, with most still based on reflex responses as they are relatively easy to measure. These assays offer poor translation to clinical success and don’t represent pain within the complete physiological context. Better models and alternatives to spontaneous pain responses are being explored in different labs worldwide, to better address the range of pain phenotypes in need of treatment.
Another critical factor in evaluating novel pain drugs is the need for more objective pain assessments during clinical trials. Pain is subjective and depends on individual differences in a person’s physiological, emotional and cognitive state. Currently, most clinical trials for pain use a subjective 10-point scale that does not provide an objective readout, which is potentially contributing to trial failures.
In light of the progress so far, we at V-Bio remain hopeful that new and improved pain drugs will successfully advance through clinical development in the near future.
One possible solution is the use of imaging biomarkers, such as functional and pharmacological MRI, in pain assessment. This could be of great value in studying drug-effects and dosing based on pharmacokinetic/pharmacodynamic data. It could facilitate more reliable and objective pain readouts than the 10-point pain scale and thereby enhance the quality and accuracy of information obtained in clinical trials.
Digital biomarkers also hold promise for migraine prevention, acute migraine treatment, osteoarthritis pain and chronic back pain. This was exemplified by a recent study in chronic lower-back pain, where step counting was used to measure movement after treatment. Movement increased by five-fold in the treated patient group compared to the control group, despite the patients being unaware of the improvements. This implies that digital biomarkers could be another important objective tool in assessing the effectiveness of new pain treatments.
Read this previous BioVox article for more on how digital biomarkers can lower the cost of clinical trials.
Combating the crisis
A rise in awareness of the global opioid crisis has led to an increase in pain treatment innovation. These efforts have been supported by increased governmental funding, particularly in the past decade. In light of the progress so far, we at V-Bio remain hopeful that new and improved pain drugs will successfully advance through clinical development in the near future. Such safe and efficacious alternatives to opioids would provide a welcome relief to the millions of people in pain world-wide.
