Opioid America: Two Heroes and Two Culprits (2016)

Because of their ability to induce analgesia, euphoria, or other mood changes, the use of various pharmacologically active botanicals, and later of certain non-prescribed pharmaceuticals, has been a feature of virtually every known culture. In the 19th century, America saw a vast array of patented medications, tonics, and elixirs, many of which had neuroactive components, cultural analogs of the opium dens of China and the absinthe cafés of Paris. One suspects that in all these cases, the users were a mix of true addicts and recreationalists. But we may have something different on our hands. The Centers for Disease Control and Prevention report that opioid overdose deaths in the United States have quadrupled since 2000. One dimension is the over-prescription of pain relievers, and another is a substance that has adulterated street heroin in many parts of the country. Media reports of these deaths come pounding in on an almost daily basis in most all American cities and to a considerable degree (often even more so on a per capita basis) in rural areas. We are all duly alarmed about this, even those of us who are not public health professionals. Let's take a moment to reflect on some good news from the past, two heroes, and also to call out a present villain. A transformative moment in the history of pharmacology occurred in 1972, when an opioid receptor was discovered by the first hero, Candace Pert (Fig. 1), working in a U.S. National Institutes of Health (NIH) laboratory headed by Solomon Snyder (1). This ushered in a golden age of opioid pharmacological insights. Candace Beebe Pert (1946-2013). She discovered the first opioid receptor in 1972 while working in the laboratory of Solomon Snyder at the NIH. Image is taken from the documentary, “What the Bleep Do We Know!?” directed by William Arntz, et al.; Captured Light/Roadside Attractions (2004) / Alamy. More understated than Pert, and thus less well known, is a second hero, Jack Fishman (Fig. 2), who synthesized naloxone, a highly bioactive competitive inhibitor of opioid receptors. For many years now, thousands of victims of heroin overdose have been saved by the administration of naloxone. Unlike methadone for sustained weaning, part of all rational treatments, naloxone has been extraordinarily effective in the acute life and death setting. Jack Fishman (born Jacob Fiszman) (1930-2013). A steroid chemist, he later turned to opioid pharmacology and invented naloxone. Image courtesy of The Rockefeller University. Pert and Fishman are heroes for these contributions and these alone, given that the designation does not require multiple achievements. Yet, both of their lives evoke admiration. Pert excelled at a time when women faced tremendous hurdles as scientists, and even though I believe that things have not changed that much, role models like her have made a difference. Fishman fled the Holocaust as a young boy via a series of trans-Asia trains from his native Poland all the way to Shanghai, and then sailed to America. It was my privilege to know him well, and I so wish I had known Candace Pert. Now for the culprits. The first is the often well-intended, but unfortunately sometimes indiscriminate, prescription of opioid-based drugs for pain management. Not all pain is equally responsive, and not all patients have the same pain thresholds. Pain management per se is not a medical specialty. How many of us know of a pain center in our community, i.e., devoted to all dimensions of treatment, including psychological (e.g., the increasingly deployed mindfulness approaches which are showing promise)? Such centers are rare and are not the same as addiction treatment or rehabilitation centers. The good news is that the opioid epidemic has triggered substantial congressional dialogue and state government action, and medical schools and professional societies have soberly recognized the need for a new training paradigm for pain management. It may even be anticipated that medical school accreditation renewals will be at risk in the near future if a given program is found to be deficient in a pain management curriculum and clinical training. The second culprit is a relatively new molecule on the scene. In recent years, first-responding EMT personnel and emergency department physicians started to see something different in patients of heroin overdose, including severe cardiac impairment. Fentanyl (Fig. 3) has been laced into much of the U.S. heroin pipeline and is a double culprit: first, the dealer skims more profit, because the more expensive heroin is diluted on a mass basis (and thus, with this profit, the dealer can expand the operation), and second, there is fentanyl's cardiotoxicity. As I mentioned at the beginning, we humans, from our shared evolution with plants, have such a love affair with all the substances they harbor and the variants that chemists have cooked up. This has all been mostly good for us over hundreds of millions of years, but now we need to take stock of a perfect storm.