Since the dawn of man, one experience has constantly plagued his mortality: pain from the ravages of disease and injury has made him a prisoner of his body. It’s an experience that has been alleviated—at least in part— by opium, stumbled upon as a potent pain reliever by the Babylonians more than 3,000 years ago and refined into
morphine in the 19th century. Morphine, while very effective at temporarily blocking pain and having, in medicalese, “good analgesic capabilities,” nonetheless has serious drawbacks: prolonged use induces addiction and side effects such as hallucination and disorientation. Intensive research in North America and Europe since the Second World War had until recently failed to discover a “magic drug” combining the pain-killing properties without the deleterious effects. Now a McGill University chemistry professor, Dr. Bernard Belleau, has finally succeeded.
The chemical, called Butorphanol, has been developed under Dr. Belleau’s guidance over eight years at Bristol Laboratories’ Montreal facility and has passed five years of clinical trials on some 2,500 patients in the U.S. and Canada. It is to be used for the first time on patients at large this month under its brand name, Stadol, to relieve severe pain, such as that caused by cancer. The chemical, a synthetic with similar properties to morphine, works by tricking the brain into reacting in the same way as it does to the narcotic, explains Dr. Belleau, a spry 53-year-old who has pursued his search for a new pain-killer since soon after his graduation from McGill with a PhD in 1950. “The brain doesn’t object if something [synthetic] is introduced from the outside—so long as it is recognized by certain areas in the brain.”
The drug, whose only known side effect is mild sedation, is the culmination of years of research by hundreds of experts in both Canada and the U.S. Its perfection was the work of a group of
experts Dr. Belleau gathered under him when he was appointed consultant research director of Bristol’s new Montreal lab in 1962. It was tested, mostly in the U.S., through the parent company’s plant in Syracuse, New York, beginning with a small hand-picked group of hospital volunteers in 1973. The drug was recently approved for public use—in injection form only—by the U.S. Food and Drug Administration and the Canadian food and drug directorate. It is expected to take another year before an oral form is approved.
Dr. Belleau says his research began in the early 1950s when he became interested in the morphine alkaloids—their chemistry and the structural activity which formed the drug. “I wanted to develop synthetic analogues [similar in function] of these molecules. But that was really quite a chemical challenge. In order to understand a molecule, you have to find out which piece of the molecule is responsible for the activity. Then you modify your structure by synthetic methods to what happens to the activity.” In other words, not all hands fit the same glove.
Dr. Belleau says useful drugs “more often than not were discovered to have come from a natural product. As a medical chemist, I look at these molecules as prototypes. You have an interesting type of activity there but it’s not very specific. It interacts with too many systems, producing all kinds of other effects. So, the basic motivation is to say—okay, here is a molecule that could be useful. How can we clean it up? This is where the chemistry comes in.”
Butorphanol works in very specific areas. Once injected, it is carried in the flow of blood to the pain-perception areas of the brain. There it binds on specific receptor sites, inducing subtle changes that effectively jam the pain signals. The architecture of the molecule can be likened to a miniature Japanese garden, flat with three interconnected ponds and a small bridge in the middle. The molecule triggers the brain by its “clean” arrangement of functional groups to give a high analgesic activity, which blocks effects of narcotics such as hallucination and disorientation.
Addiction, as explained by Dr. Belleau, works this way: “A narcotic blocks pain perception but at the same time it inhibits some key biochemical pathways. The cell, in order to compensate for the blockage, starts synthesizing these compounds to overcome the block. So when you withdraw the narcotic, this results in a large excess of regulators, which is certainly enough to upset the biochemistry of these cells. This is the withdrawal symptom, a memory effect, the mind’s recall of the addiction. Whatever psychological or physiological reactions that were experienced cause most addicts to go back.”
Dr. Belleau sees his discovery as just the beginning of intensified research aimed at chemically treating specific diseases in the brain. “If you can develop chemistry to modify the structure of the molecules in such a way as to produce only the desired effect, without the side effects,” he says with considerable understatement, “then you’ve done something interesting.”
The story you want is part of the Maclean’s Archives. To access it, log in here or sign up for your free 30-day trial.
Experience anything and everything Maclean's has ever published — over 3,500 issues and 150,000 articles, images and advertisements — since 1905. Browse on your own, or explore our curated collections and timely recommendations.WATCH THIS VIDEO for highlights of everything the Maclean's Archives has to offer.