Chronic Pain: The Need and Hope for Opioid Alternatives

On January 11, 2016, a Phase 1 trial in France of the investigational drug BIA 10-2474was abruptly haltedwhen one of the six dosed subjects fell into a coma after experiencing symptoms resembling a stroke. The subject died several days later and four otherswere leftwithwhat doctors suspect may be lasting neurological damage. What precipitated this tragedy is still unclear. As an inhibitor of fatty acid amide hydrolase, a critical enzyme in the biosynthesis of endocannabinoids, it was thought that BIA 10-2474 could target aberrant neurotransmission in disorders ranging from anxiety and Parkinson's disease to chronic pain. While the failure of the BIA 10-2474 trial should not be downplayed, it does at least herald the critical need for further investigation into new ways of treating nervous system disorders— including chronic pain, whose current therapies include those that may themselves be perilous. Chronic pain is generally defined as that which lasts between three and six months after the acute symptoms should have subsided. It can arise from myriad conditions including arthritis, diabetic neuropathy, cancer, traumatic injury, certain viral infections, and many other diseases that lead to persistent inflammation or nerve dysfunction. Roughly 25% of people worldwide will at some point suffer from chronic pain. Consequently, theWHO estimates chronic pain to be one of the leading causes of Years Lost to Disability globally. In the US alone, where up to 12 million people have chronic pain, this equates to an economic burden of nearly $635 billion per year. Opioids are widely used as first line drugs for both acute and chronic moderate to severe pain.While opioids often produce unmatched analgesic effects, at sufficient doses or with prolonged use they can trigger psychoactive effects, tolerance, and addiction. Prescription opioid abuse has exploded in developed nations over the last decade. In the US, the epidemic has grown to such proportions that the Centers forDisease Control estimates over 19,000 people died from overdose of prescription opioids in 2014, a cause of death whose rate now exceeds that of motor vehicle accidents. These troubling statistics led the US Food and Drug Administration in February, 2016 to largely amend its stance on opioids. Among other policy statements was a call to action to develop novel therapies with reduced potential for misuse. Given that opioids are the only currently-available means of relief from chronic pain for many patients, one branch of research focusses on ways to limit their use at the high doses necessary to elicit harmful effects. These efforts include drug formulations that confer delayed release and technologies such as implantable devices that dispense precise doses to provide only analgesia. Other research is aimed at developing opioids with fewer adverse effects. Of the mu, delta, and kappa subtypes of opioid receptors, most analgesia is thought to derive from mu activation. Recent studies in pre-clinical pain models suggest that a synthetic opioid derivative, UMB 425, which both agonizes mu and antagonizes delta receptors, provides analgesia without the development of tolerance. Another compound, MMG22, both agonizes mu receptors for analgesia and antagonizes metabotropic glutamate