In the late 1960s, while the American physician James Goddard looked for ways the FDA could better regulate the approval and marketing of medications, a public debate played out in the United Kingdom about whether terminally ill cancer patients should have a say about their end-of-life care. Should they have a right to doctor-assisted suicide? Euthanasia was illegal in all European countries (the Netherlands was the first to legalize it in 2000). A national reassessment would not get under way in the U.S. until the 1969 publication of Dr. Elisabeth Kübler-Ross’s seminal book On Death and Dying.
The policy debate in Britain, however, would change the way the Western world approached care for the dying. Cicely Saunders, an Oxford-educated nurse turned physician, spearheaded the drive for humane treatment of patients with end-stage cancer. She chanced upon a British drug company that had recently been acquired by the Sackler brothers. The ensuing debate sparked a partial reassessment about the use of opioids in controlling pain and the rights of the terminally ill to insist on treatment. What emerged was a concept of “death with dignity,” leading to the birth of the modern hospice movement.
Saunders is justifiably credited as almost single-handedly introducing the rights of the dying. As a London nurse during the 1940s she became convinced there had to be a better way than the “wretched habits of big, busy hospitals where everyone tiptoes past the bed and the dying soon learn to pretend to be asleep.”
There she witnessed the prevailing medical ethos that focused only on healing patients. Those who were terminally ill and could not be cured were considered a sign of failure. Saunders was stunned when doctors repeatedly lied to terminally ill patients, withholding any information about their grim prognoses. Few questioned their physicians.
In 1948, when she was 30, Saunders had qualified as a medical social worker. Shortly after that she met a 40-year-old Polish-Jewish refugee who had escaped from the Warsaw Ghetto. He was dying of cancer. In the terrible final weeks of his life in Whittington Hospital’s cancer ward, the two formed a bond, something she described to friends as a deep, spiritual love. His death sent her spiraling into a “pathological grief.” She found solace in a newfound belief that God had called her to care for the dying.
Over the next few years, Saunders tended to the dying at a north London hospital. One night she told a surgeon about her dream to open a home for the terminally ill, a place where medical knowledge would combine with compassion and love. He told her that neither patients nor doctors would listen to her. As a mere nurse she had no status in the rigid, hierarchical British medical community.
“Very well then,” she told him, “I will become a doctor.”
Saunders worked her way through medical school over five years and earned her degree in 1957. She accepted a scholarship to study pain management in the pharmacology department at London’s St. Mary’s Medical School. She also volunteered as an almoner at St. Joseph’s, a Catholic-run clinic where 45 beds were set aside for cancer patients whose prognoses were less than three months to live.Some physicians feared that Saunders’ heavy narcotic regimen would turn her terminally ill patients into sedated zombies.
Saunders kept a journal of her observations. All the patients were in severe pain and she thought they were unnecessarily suffering. In conversations with them she discovered that the vicious cycle of such agony was debilitating fear, anxiety, and hopelessness. Untreated pain, she concluded, was the cause of all chronic end-of-life symptoms, including deep depression.
Fears about opioid addiction meant that her colleagues sparingly dispensed painkillers. They provided at the most only four hours of relief. Instead of giving an additional dose when a patient complained about returning pain, doctors invariably wrote “p.r.n.” on the charts, for the Latin pro re nata, “as required.” Second doses the same day were rare.
She told the nurses in her ward that “constant pain calls for constant control and the regular giving of drugs.” According to Saunders, if a patient cried out from discomfort because the last painkiller had worn off, the nurses had failed in their treatment.
She met stiff resistance from doctors at St. Mary’s, leading her to conclude there was no intractable pain, only intractable physicians.
She did, however, make headway at St. Joseph’s by emphasizing how her concept of aggressively treating patients’ pain might be complementary with steadfast Catholic opposition to euthanasia. Saunders contended that “requests to end life are nearly always requests to end pain” and by relieving their physical discomfort and mental stress, patients would stop thinking about ending their own lives. Another side benefit, she said, was that if patients no longer had to ask constantly for more medication, they were less dependent on the staff and that freed the nurses to attend to other care.
The St. Joseph’s administration quietly approved her approach to see whether it worked as she expected. The narcotic most effective at alleviating severe pain was Heroin (diamorphine). She discovered that accidentally. Among the first 500 patients she treated with her protocols at St. Joseph’s, 42 reacted badly to morphine. They received heroin instead.
“No other drug makes these patients look and feel so comfortable,” she wrote. “In the doses we use, it does not cause changes in personality, frank euphoria or a ‘could not care less’ attitude, but it helps greatly towards our aim of keeping the patients feeling as well as possible for as
Saunders concluded that opioids were not nearly as addictive as doctors feared. “Patients may indeed be physically dependent on the drugs but tolerance and addiction are not problems to us, even with those who stay longest.” And she startled many physicians with the finding: “We have not found that diamorphine [heroin] has a greater tendency to cause addiction than any other similar drug. We have
Saunders reported that for some patients the quality of life improved immeasurably. Several at St. Joseph’s had demonstrated such “startling improvements,” she wrote to the Royal Society, that they were “able to return for further palliative treatment or go home for a while.”
Heroin’s major “drawback,” in her view, was that “it may be rather short in action.” She tried correcting that by increasing the doses. Instead of providing longer pain relief the higher doses only created more side effects. By trial and error, she learned it was better to add sedatives and tranquilizers. She also sometimes used a so-called Brompton cocktail, a mix of cocaine, gin, and Thorazine.
Some physicians feared that her heavy narcotic regimen would turn her terminally ill patients into sedated zombies. Instead, it allowed
By 1959 she had completed a ten-page proposal for a sixty-bed hospice. It was a cloistral institution that she initially considered restricting to only Anglican patients. Although her concept was different from anything else that existed, it also adhered to the traditional British medical view that even end-of-life patients required treatments proven best by scientific researchers.
Saunders registered a charity in 1961 and began raising money the following year. She proved to be an indefatigable fundraiser, flying to America to lobby humanist organizations and the Ford Foundation, as well as crisscrossing England in search of contributions. At times she seemed a one-person movement for the incipient hospice crusade.
She had by then written half a dozen articles on pain management in Nursing Times. It made her the national face for compassionate end-of-life care. By 1965, she had raised a remarkable £380,000 ($868,000 in 1965). It was enough to break ground on a South London location. That was the same year Queen Elizabeth awarded her the honor of an OBE (Officer of the Most Excellent Order of the British Empire).
St. Christopher’s, the world’s first modern hospice, opened with 54 beds in 1967. It did not look like a last stop for terminally ill patients. Its airy and open design instead resembled a quiet home in the countryside. It featured a large gathering room for families, a communal dining hall, and even a nursery for the children of staff members.
As its medical director, Cicely Saunders had total control over her palliative care research with patients. The hospice presented her an opportunity to test her observation about heroin’s superiority as a pain reliever. She invited another physician and researcher, Robert Twycross, to conduct a clinical study. Half the St. Christopher’s patients got heroin while the others received morphine.
Because of the high turnover rate in the hospice, in just over two years the study included 700 patients. The results demonstrated no significant difference between the painkillers. The findings put Saunders on a mission to find a better painkiller than heroin or morphine. She wanted an analgesic that alleviated pain for a long period on a single dose with few side effects.
The year before St. Christopher’s had opened, Arthur, Mortimer, and Raymond Sackler bought Cambridge-based H. R. Napp Pharmaceuticals. Napp, founded in 1923 by a Swiss chemist and pharmacist, had suffered several years of heavy losses from a slowing British economy and its own lackluster product line. Napp’s poor finances allowed the Sacklers to gain control at what Mortimer later bragged was a bargain.
The Sacklers had created Mundipharma in London 11 years earlier but had operated it only as a drug distributor with a sister Mundipharma in Switzerland. With the purchase of Napp, the brothers hoped to develop their foreign business in earnest. Mortimer soon bought a grand apartment in one of London’s most fashionable neighborhoods in order to spend more time overseeing the turnaround they planned.
They renamed the company Napp Pharmaceutical Group Limited. A couple of months later the brothers bought Scottish-based Bard Pharmaceuticals Co. (the same name as the drug company they had created in New York in 1955). They reconfigured Bard to serve as Napp’s “Production and Supply Chain and Quality Division.” Considering how little Napp had to sell, it was a sign of the ambitious plans the Sacklers had for their United Kingdom operations.
A small British drug company, Smith & Nephew Pharmaceuticals, had provided the morphine and heroin for the St. Christopher’s trials. Original correspondence located in the archives of King’s College, London, sets forth the efforts of Saunders and Smith & Nephew to find a better narcotic analgesic. They collaborated with Saunders on developing questionnaires to distribute to hospice patients to judge the effect of different pain meds. Smith & Nephew also prepared a more extensive survey for physicians. It sought their input about how they diagnosed and treated pain.
Saunders pressed for questions that went beyond asking whether specific medications relieved a patient’s physical pain. She wanted to know if the treatments affected the “mental stress and emotional problems of patients and relatives.” In the final questionnaire sent to 26,000 U.K. doctors, the survey included some rudimentary questions about the “morale” of both patients and their relatives.
One of the major obstacles any company then faced in developing a more effective narcotic analgesic was the ignorance about how opioids relieved pain. It would be another six years (1973) before researchers discovered that opioids attached to several brain receptors. It took until 1975 before scientists learned that some brain receptors produced natural opioids (endorphin and enkephalin) that blocked pain, slowed breathing, and had a calming effect. Their production was so limited, however, they were incapable of providing relief for moderate to severe chronic pain.
Synthetic opiates are initially effective because they fool the brain to recognize them as natural neurotransmitters. They attach to nerve cells and flood the brain with dopamine, producing the euphoria some patients describe. There is often nearly complete pain relief. At least until the pain receptors get accustomed to opioid and dopamine saturation.
Continued exposure to opiates causes the receptors to start misfiring; the only way to make up for that is increasing the dose. When the drug therapy stops, the receptors are incapable of producing natural painkillers. Pain becomes intense. And patients crave that pleasurable zone opioids create. That was why, researchers speculated, it was addictive (the same sensations and cycle of abuse as with nicotine, alcohol, and cocaine).
How and why opioids worked inside the body, however, were of less concern to Smith & Nephew than what the effect was on terminally ill patients in severe pain. Their focus was on providing enough narcotic in a single dose to alleviate the intensity of pain without causing sleepiness, motor coordination problems, and memory lapses. As important as getting the strength right, they hoped to be able to make each dose last longer.
Correspondence shows the company tried but failed to develop an analgesic that accomplished what Saunders wanted for her hospice patients. Instead of admitting outright failure, they dusted off a drug they had developed in 1960, Narphen. Smith & Nephew claimed it was
When they had originally marketed it, the sales pitch was not only that it was powerful, but that it “has fewer and less serious side-effects than morphine . . . quicker acting and longer lasting . . . [and] less physical dependence.” Narphen’s active ingredient was phenazocine, a synthetic opioid licensed from Sterling Drugs in the U.S. (the FDA did not approve it for sale in America until 1967).
The year that Cicely Saunders opened St. Christopher’s, the reports of a double-blind hospital study of Narphen showed it did provide fast and adequate mild to moderate pain relief with no reports of nausea or vomiting (one of the most persistent problems with morphine). It did, unfortunately, equal or surpass morphine’s dangerous suppression of a patient’s respiratory system. There were also soon reports rebutting Narphen’s claim it was not addictive.
Smith & Nephew might have failed to develop a better end-of-life painkiller but that did not stop them from using the information they gleaned from their postal surveys to create a clever marketing campaign for Narphen. The company ran full-page ads with the trademarked tagline “Powerful Analgesic Without Sedative Effect” in The British Medical Journal, the Lancet, and other premier U.K. medical publications. The ads were tweaked to reach different markets of prescribing doctors by addressing the top concerns the physicians had listed in the pain surveys.
Saunders thought Narphen was a decent enough painkiller, but it was certainly not the end-of-life pain treatment breakthrough for which she had hoped. That became ever more evident as Smith & Nephew promoted their drug for use “in emergencies, after accidents, and in orthopaedic and cardiac emergencies”; “as an adjunct to anaesthetics”; for “post-operative pain and restlessness”; and even for “obstetrics . . . reduces pain and apprehension during labor without interfering with uterine contraction.”
Inside the small world of independent British pharmaceutical companies, news spread that Saunders wanted a new medication that revolutionized pain control. It was the only way her patients might have a decent chance of spending their final days at home. When Mortimer Sackler learned about her quest, he assured Saunders that Napp had the scientific capability and know-how to develop the narcotic analgesic she wanted. Mortimer and Napp’s top executives did not know whether they could deliver on that bold promise. Still, they wanted to at least have a chance to do so; Smith & Nephew’s stumble handed the Sacklers an opportunity they did not want to pass up.
It was not long before Saunders and scientists at the newly configured Napp were exchanging ideas by mail and over the phone. The breakthrough at Napp, and its subsidiary Bard, was several years away. When it happened, however, it not only fulfilled the Sacklers’ promise to revolutionize pain care for the terminally ill, but unwittingly provided the technology that would later fuel America’s opioid crisis.
From Pharma by Gerald Posner. Reprinted by permission of Avid Reader Press, an imprint of Simon & Schuster, Inc.