Researchers use DNA origami to generate tiny mechanical devices that deliver a drug that cuts off the blood supply to tumors in mice.
A fraught market for the barbiturates prescribed to terminally ill patients who choose to end their lives has physicians turning to options outside big pharma.
August 17, 2017|
©ISTOCK.COM/KATARZYNABIALASIEWICZIn early 2015, the price of the insomnia drug Seconal doubled overnight to around $30 per 100 mg capsule. The drug’s active ingredient, a barbiturate called secobarbital, was widely prescribed in the mid-20th century as a sleeping pill, before falling out of favor due to abuse, accidental overdoses, and the emergence of benzodiazepines as a safer alternative. Despite declining numbers of prescriptions, Seconal’s price has soared in recent years; costing just $2 per capsule in 2009, the drug retailed around $15 by the time its previous owner, Marathon Pharmaceuticals, sold the rights to Seconal in February 2015 to its current supplier, Canada-based Valeant Pharmaceuticals, which quickly raised the price to $30.
So why the rise? Just one month prior to Seconal’s price hike, California had proposed legislation that would make it the fifth state to allow medical-aid-in-dying, in which terminally ill patients given less than six months to live could choose to end their own lives with a physician’s prescription for a lethal quantity of a drug—Seconal being the drug of choice. Valeant denied ulterior motives for the decision. But some health-care practitioners called the move exploitative, whether or not the timing was deliberate. With Seconal’s climbing cost, the standard lethal-dose protocol—emptying 100 capsules into a beverage—has a price tag of $3,000 or more. “‘Shocked’ is one word you could use,” says David Grube, a family doctor in Oregon and national medical director of the nonprofit group Compassion and Choices, which advocates for better end-of-life medical care. “I had other feelings as well—all of them negative. . . . It’s pharmaceutical-company greed.”
“People are thinking about it less and less as suicide and rather as just a medical option for people who have terminal suffering.”—Charles Blanke,
Oregon Health and Science University
The move drew much unwanted attention to Valeant, already embroiled in federal probes after steep price hikes to two heart drugs—one by more than 500 percent. But the furor surrounding Seconal’s price increase raised another issue, too. Despite the growing number of states that allow medical-aid-in-dying—also known as death with dignity, or physician-assisted suicide—terminally ill patients don’t always have options when it comes to acquiring affordable means to end their lives peacefully and by choice.
When California’s law went into effect in June 2016, the populous state followed Oregon, Washington, Montana, Vermont, and the District of Columbia in legalizing prescriptions for a lethal dose of a drug to patients deemed mentally capable and able to self-administer, and Colorado legalized medical aid-in-dying just six months later. (SEE INTERACTIVE INFOGRAPHIC.) Although a lethal dose of Seconal can be covered by Medicaid in California or by one of multiple private insurance companies in Oregon and California, patients in other states are less fortunate. “It’s prohibitively expensive,” says George Eighmey, president of the nonprofit organization Death with Dignity and a state representative who helped pass Oregon’s legislation. As a result, he adds, doctors began to look for alternatives.
DEVELOPED BY KARL PAWLOWICZ
Medical aid-in-dying has been legalized in several countries on either side of the Atlantic, where the practice is generally considered distinct from euthanasia—when a physician ends a patient’s life by administering a lethal drug, usually by injection—or the practice of removing life-support from unresponsive but still-living patients. (SEE INTERACTIVE INFOGRAPHIC.) In the U.S., medical aid-in-dying was legalized in Oregon in 1997 following years of campaigning by advocacy organizations. Since then, more than 1,500 Oregonians have obtained lethal prescriptions and around 1,000 have taken the dose, almost always in the comfort of their own homes.
But legalization didn’t solve everything. “The law itself didn’t give any guidance whatsoever to [the type of] medication,” says Charles Blanke, an oncologist and a professor of medicine at Oregon Health and Science University, adding that the drugs being used for medical aid-in-dying have normally only been clinically tested in a therapeutic context. “It’s been a problem all along. . . . What happens in a case of toxicity when you’re trying to get a therapeutic effect and when you’re trying to help a patient end his or her own life might be very different.”
Early on, doctors relied on fast-acting barbiturates, Eighmey says, in part because they had been used effectively in Europe—and secobarbital wasn’t always the only option. Doctors could also prescribe a 10-gram liquid or powdered dose of pentobarbital, a similar barbiturate that was developed more than 80 years ago as a sleeping aid and marketed under the brand name Nembutal by Danish pharmaceutical company Lundbeck. After drinking the dose mixed in water or juice, “the person would fall asleep in a few minutes,” says Grube. “The sleep would get deeper and deeper until at a certain point they would stop breathing. It was a comfortable, peaceful death.”
Access to pentobarbital has become nearly impossible in the U.S., however, due to the drug’s association with execution by lethal injection. Since 2010, pentobarbital has been used in executions in many states as part of a three-drug cocktail—the other ingredients being pancuronium bromide to induce muscle paralysis and potassium chloride to stop the heart; recently, states including Ohio and Idaho have used pentobarbital in a one-drug procedure. A handful of botched executions in the last decade, in which patients appeared in pain after supposedly being anaesthetized with the drug, plus public opposition to capital punishment, have put heavy pressure on pentobarbital manufacturers to stymie the supply. In 2011, Lundbeck and its US partner, Akorn Pharmaceuticals, placed stringent restrictions on access to the drug for nontherapeutic uses, prompting similar moves by companies keen to distance themselves from execution deaths. (See “Prisons Attempt to Circumvent Lethal Drug Shortages.”)
Medical aid-in-dying is generally considered distinct from euthanasia—when a physician ends a patient’s life by administering a lethal drug, usually by injection—or the practice of removing life-support from unresponsive but still-living patients.
As a result, secobarbital—exclusively available as Valeant’s Seconal in the U.S.—became almost the only option for doctors writing lethal prescriptions for patients who qualified for medical aid-in-dying. But as 2015’s price hike by Valeant underlined, affordable access is far from guaranteed. Although secobarbital is, in theory, easy to produce, and patents covering its manufacture expired in the 1990s, there are currently no generic alternatives—due in large part to lack of demand, says Blanke. “Death-with-dignity patients make up a teeny fraction of overall patients,” he says. From a pharma perspective, “I can’t believe it’s that cost-effective or worth the fuss to make a generic,” he adds.
Strict federal regulation of barbiturates presents further obstacles, Grube suggests. A series of legislative moves in the 20th century, starting with the Food, Drug, and Cosmetic Act of 1938, brought the manufacture and distribution of barbiturates under tighter regulatory control, making it illegal to buy, possess, or sell the drugs without a prescription, and placing quotas on the pharmaceutical companies approved to make them. “It’s not like a diabetes pill, where, if you have quality assurance and good hygiene, anybody can distribute it,” he says. “These are narcotics, so they’re highly regulated because of potential for misuse. It’s a hassle.”
In search of practical alternatives, physicians have recently begun to invent drug combos that can be manufactured by compounding pharmacies, which mix drugs into products on a prescription-by-prescription basis. Compounded products are not subject to regulation by the US Food and Drug Administration, and have been associated with some high-profile controversies, from a 2012 outbreak of meningitis traced back to fungal contamination of products from the New England Compounding Center, to reports of compounded products containing anything from 0 percent to more than 500 percent of the labeled potency.
Nevertheless, evidence suggests that there’s a place for compounded alternatives to Seconal. Following the price hike, doctors in Washington State proposed a combination of powdered phenobarbital, chloral hydrate, and morphine sulfate that could be purchased from a compounding pharmacy for around $500. The chloral hydrate burned the throat, but the mixture was still chosen by more than a third of patients offered the option at the End of Life center in the state in 2015. Last year, the same physicians suggested another combination that excluded chloral hydrate: morphine, diazepam, and digoxin. But this mixture was slow-acting in some patients; at least two people died more than a day after taking the medication. Recently, the group proposed increasing the dosage of those three drugs and adding propranolol, a beta blocker, moves which would not inordinately increase the price of the combination. Organizations are reluctant to release other recipes under discussion due to likely pressure on manufacturers from opponents to medical aid-in-dying, Eighmey says.
It’s a subject that clearly needs more research, Blanke notes—though the obstacles are obvious. “It’s not as though we’re going to randomize patients between two different cocktails,” he says. “But we need to help patients and derive new formulations. There hasn’t really been certified scientific methodology applied, and I think that needs to change.”
While only a small section of the country currently allows medical aid-in-dying, signs of change are on the horizon. As of July 2017, 30 states are considering legislation, according to Death with Dignity, and Eighmey notes that while many of these states are not in a good position politically to pass such legislation, the move reflects a growing awareness and acceptance of end-of-life options. Multiple nationwide surveys have shown substantial public support for legalizing the practice, and a 2017 Gallup poll showed that 57 percent of Americans deemed doctor-assisted suicide to be morally acceptable.
In states that already allow the practice, more patients are turning to medical aid-in-dying, too. In 2016, Blanke and colleagues analyzed 18 years of data in Oregon and found that the number of lethal prescriptions had risen from 24 in 1998, just after legalization, to 218 in 2015, mostly for patients with cancer. “People are thinking about it less and less as suicide and rather as just a medical option for people who have terminal suffering,” he says. “More physicians are willing to do it, and even though access is still a huge problem, most patients eventually find a doctor who will help them.”
For now, however, pharmaceutical companies themselves show little interest in getting involved. Akorn, the U.S.’s only supplier of pentobarbital, “established a procedure that they will not ship it to any pharmacies who plan to use [the drug for] death with dignity,” says Eighmey. And Valeant has long refused to discuss such uses of Seconal. As medical aid-in-dying constitutes “an off-label use of the product, we are unable to participate or provide any comment,” writes the company’s vice president of corporate communications, Lainie Keller, in an email to The Scientist.
Still, there are grounds for thinking that medical aid-in-dying, and the drugs the process requires, might become more available in the future to patients facing terminal prognoses. “Ten years ago, only the state of Oregon was using it,” says Eighmey. “Now we’re up to six states and the District of Columbia.” For many physicians working with patients weighing their end-of-life options, the goal is clear. “The medication should be affordable, and it should be covered by all insurances,” says Grube. “There should be protections, of course, so that the laws are not abused. But there shouldn’t be barriers.”
DEVELOPED BY KARL PAWLOWICZ
Patients seeking medical aid in dying aren’t the only ones faced with difficulty obtaining lethal drugs. Until recently, Pfizer was the sole US supplier of several chemicals used for lethal injection in prison executions, after the Illinois-based pharmaceutical company Hospira, since acquired by Pfizer, halted manufacture of the fast-acting barbiturate sodium thiopental in 2011, and EU suppliers such as Danish firm Lundbeck introduced sweeping bans on US imports of pentobarbital due to the drug’s use in prisons. In 2016, following substantial pressure from activist groups and investors, Pfizer followed suit, announcing restrictions that effectively shut down the domestic supply of execution drugs.
The resulting shortages have prompted drastic action from states determined to maintain their capability to carry out death sentences. Both Texas and Arizona were caught in 2015 attempting to import sodium thiopental illegally from overseas, and several states, including Georgia, Missouri, and Oklahoma, have passed secrecy laws meaning they are not obliged to reveal how drugs used in lethal injections are obtained. Last February, Arizona proposed a bizarre solution to its dilemma by inviting death row inmates to supply their own pentobarbital in order to guarantee a peaceful execution—a move that was widely scorned by criminal defense lawyers.
In the meantime, prison officials in states with a backlog of executions are working to catch up. Earlier this year, Arkansas pushed ahead with an extremely controversial plan to execute eight people over the course of 10 days. The reason for the rush? The state’s supply of midazolam—a sedative manufactured by Pfizer that has been associated with several botched executions—was about to hit its expiration date, and prison officials were not confident they’d be able to source more. Other states have hastily legalized different modes of killing their inmates should the drugs remain unavailable. In 2014, Tennessee preemptively reinstated use of the electric chair; the following year, Utah brought back execution by firing squad, and Oklahoma authorized use of nitrogen gas chambers, a method that Mississippi also authorized this year. (To date, none of these states have carried out these types of executions.)
While some opponents of capital punishment hope that drug shortages will prompt further discussion about the constitutionality of state executions, others point out that restricted access to lethal drugs has made executions even less humane. And although 19 states have now abolished or overturned the death penalty, the Supreme Court’s ruling just two years ago (Glossip v. Gross) that lethal injection using midazolam did not amount to “cruel and unusual punishment”—the drug was used just last month in Ohio’s execution of Ronald Phillips—means that the debate is far from over.
Correction (August 29): The US map has been updated to correctly identify the light orange–shaded states as those considering legislation, while the medium orange states have no proposed legislation. The Scientist regrets the error.