The choice of drug was largely made on the basis of factors such as availability, price, and preference of prescriber and patient.
“In the Oregon experience, the first medication and the one most often used was secobarbital,” said Matt Whitaker, California state director of Compassion and Choices, a leading nonprofit organization that advocates for better care and expanding options at the end of life.
“When the cost of secobarbital reached $1000, pentobarbital then became more popular between 2011 to 2014,” he explained in an interview.
In the state of Washington, the opposite was true, according to Robert Wood, MD, the former director of the HIV/AIDS Program at Public Health–Seattle and King County and now a volunteer medical adviser with End of Life Washington.
“Pentobarbital powder, which was used as the main life-ending medicine until 2015, has disappeared from the US market but is still being used in Europe for physician-assisted dying,” he said. “Secobarbital was at that time a great alternative, although one had to dismantle 100 capsules to obtain powder to mix into a lethal brew, a process that takes about 1 person-hour of effort.”
The cost of a lethal dose of pentobarbital powder was about $350 and had remained constant during the period in which the price of secobarbital climbed upward.
When PAD began to be legalized in US states, beginning with Oregon in 1997, both secobarbital and pentobarbital were inexpensive and easily accessible. They were potent and effective, relatively tolerable for the patient, and seemed to be the ideal agents to fill this need. After 2015, those dynamics changed dramatically.
The cost of secobarbital skyrocketed, making pentobarbital the far more affordable option. But at the same time that the price of secobarbital doubled, the oral formulation of pentobarbital vanished from the shelves of US pharmacies.
Price Doubled Overnight
In 2015, the price of secobarbital doubled overnight, to about $30 per 100-mg capsule. This becomes very pricey when multiplied by 100 ― the number of capsules that must be taken for a lethal effect.
Secobarbital entered the US market in 1929 and currently has limited clinical uses aside from assisted dying. Secobarbital was manufactured and sold by Eli Lilly until the early 2000s, at which time marketing and manufacturing rights were sold to Ranbaxy Pharmaceuticals, which in turn sold them to Marathon Pharmaceuticals in 2009. During this period of fluctuating “ownership,” the price remained stable until the sale to Marathon. At that point, a lethal dose of secobarbital cost about $200 or less, but began to precipitously rise.
Veena Shankaran, MD, and colleagues from the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance, Washington, tracked the mean out-of-pocket cost for secobarbital between 2010 and 2016, as prescribed at their institutions. As reported in JAMA Oncology, in 2010, the cost was $387.52. It then progressively increased: $638.31 in 2011, $860.83 in 2012, $1131.39 in 2013, $1451.21 in 2014, $1757.29, until reaching an all-time high of $2878.79 in 2016, after the drug was acquired by Valeant in 2015.
“Valeant Pharmaceuticals, now under federal investigation, is a highly publicized example of ruthless drug price inflation practices,” write the authors.
Valeant is headquartered in Montreal, Canada, where, ironically, secobarbital is not available. The company has been accused of jacking up the price to coincide with the implementation of California’s law. Washington, Oregon, Vermont, and Montana (Colorado’s law was passed in 2016) are have relatively small populations. Vermont and Montana have a combined population of only about 1.6 million people. But even taken together, the population of all five states barely equals a third of the number of people that reside in California.
Overnight, California’s law dramatically changed the demographics from about 13 million people living in states where PAD is legal to more than 50 million. Being the most populous state in the United States, with a population larger than that of Canada, the number of patients seeking PAD is expected to significantly increase over time.
According to the Canadian press, Valeant stated that it does not promote the drug, that it only sold about 1000 prescriptions in 2015, and that itexpects to earn less than US$3 million in sales in 2016.
Secobarbital was not the only drug for which there was a substantial price hike after being acquired by Valeant. The company had made it a business practiceof buying inexpensive drugs from other companies and aggressively pushing up the price tag.
In 2015, the company increased the costs ― by about 66% ― of its brand name products, which were approximately fives times as much as comparable pharmaceutical manufacturers. For example, Glumetza (extended release metformin), used for diabetes, rose from $896 for ninety 1000-mg tablets to $10,020. Syrpine (trientine HCL), a treatment for Wilson’s disease, jumped from $1395 for 100 250-mg capsules to $21267. Cuprimine (penicillamine), also used for Wilson’s disease, rose nearly 3000% after Valeant purchased the rights to sell it, from $888 for 100 250-mg capsules to $26,189. The cost of Isuprel (isoproterenol), used primarily as a bronchodilator and heart stimulant, increased eightfold, from $4489 for 25 0.2-ml ampules to $36,811.
Valeant has since come under fire for various questionable business practices. Last year, the company’s CEO resigned amid accusations of price gouging and accounting irregularities, with an intense federal investigation hot on his tail. A Congressional committee was digging deep into their drug-pricing policies as well as ties to a mail-order pharmacy, Philidor, which was used by Valeant to bypass the efforts of pharmacies and insurance companies to substitute cheaper generics for some of their higher-priced drugs. In addition, the company came under investigation by the Securities and Exchange Commission and was struggling with more than $30 billion in debt that it had accumulated. Its stock price plummeted by 87% last year, with about $80 billion in shareholder value disappearing.
A new CEO has stepped up to the plate. In an interview with CNBC, he says that he is working hard to reduce the $30 billion debt, placing more focus on research and development, and, importantly, putting new pricing policies in place.
Joseph Papa, who took over as CEO in May 2016, has stated that he is following through on his promise “to stem the outcry surrounding Valeant’s alleged price gouging.”
“Within the first 2 weeks I joined the company, we started what I would refer to as a Patient Access and Pricing Committee,” he told CNBC. “That Patient Access and Pricing Committee looked at making sure, as a primary objective, that patients had access to Valeant products. We’ve done that. That’s well underway.”
Despite attempts at a company overhaul, drug prices to date have not decreased, at least not for secobarbital. The price tag for a lethal dose remains as high as it was two years ago.
Medscape Medical News queried Valeant as to whether there were any plans to make secobarbitol more accessible to patients in states that allow PAD, but the company declined to comment on that issue.
“Thanks for reaching out; however, the topic of your story is in regard to an off-label use of the product, so we are unable to provide comment and address questions regarding pricing of our medicines that are being used in an off-label manner,” commented Kristy Marks, director of corporate communications at Valeant.
For some patients, insurance will cover the cost of secobarbital, but coverage in the United States is not consistent for healthcare in general. Insurers will often not reimburse for a drug that is used off label, and location and insurance type determine coverage for PAD.
“A law passed in 1997 prohibits federal insurance from covering medical aid in dying,” said Whitaker. “So, this means that Medicare or Veterans Affairs do not pay for it, so patients on those plans will have to pay out of pocket.”
He also points out that California is in a “better” position than other states were when their laws were first passed. “Oregon and Washington were treading new territory,” said Whitaker. “California has the benefit of 30 years of collective experience from those two states. They were able to speak with their peers and get an idea of what worked and what didn’t.”
All of California’s Medi-Cal plans, the state’s Medicaid program, will cover the cost of medication. In addition, about 80% of private insurers provide coverage as well, including large payers, such as Blue Cross Blue Shield, Kaiser Permanente, and Sutter, along with many local health plans.
Nearly 500 healthcare facilities in the state, such as Kaiser Permanente, the University of California, San Francisco and Los Angeles, Stanford, Tenetm and Sutter, as well as 104 hospice locations have also adopted policies that are supportive of patients who choose this option and of physicians and other medical professionals who choose to participate.
However, Medicaid programs do not cover the cost in Washington state, Vermont, or Montana, and coverage remains unclear in Colorado.
A Drug Gone AWOL
Similar to secobarbital, the barbiturate pentobarbital is another “ancient” drug that has been prescribed in the United States for decades ― as both an injectable and oral agent. Although the injectable version continues to be available, the entire inventory of oral formulations, including capsules, liquid and powder, has been removed from the marketplace.
“Our pharmacists have scoured the country trying to find a source of pentobarbital,” said Carol Parrot, MD, a Washington-based retired anesthesiologist who now serves as an attending or consulting physician for Death With Dignity patients throughout the state. “But there are no FDA-regulated sources remaining in the US.”
In an interview, Dr Parrot explained that it might be possible for individual patients to order it from another country. “But the prescriptions written by doctors go to licensed pharmacists, and they can only get drugs from suppliers who are FDA licensed and regulated,” she said. “Pentobarbital is available for veterinary practice, but the FDA specifies that it cannot be used for people.”
The word on the street is that pentobarbital became virtually impossible to access because of its association with capital punishment. This premise has been repeated in media stories, journal articles, and among clinicians and advocates ― and has been largely accepted as the reason for pentobarbital’s abrupt departure from US pharmacies.
However, the evidence diverges somewhat from this theory, especially with regard to injectable pentobarbital. That formulation, which was once used in executions, remains very much available in the United States, albeit with some restrictions.
Pentobarbital was first compounded in 1930, and over the decades has been used for a number of therapeutic indications, including sedation, as a preanesthetic, and for controlling status epilepticus. It achieved a degree of notoriety when it became part of the drug combination used for executions.
There is a peculiar irony in that drugs used for both executions and PAD have become increasingly hard to come by, with markets drying up on both ends of this highly polarized spectrum. Powerful emotions rage for these two explosive issues on all sides, but at the end of the day, the same outcome is sought ― a drug or drug combination that will allow a rapid and painless death.
At the present time, capital punishment is legal in 31 states and is performed exclusively by lethal injection. Pentobarbital was used for the first time as an execution drug in December 2010 as the first ingredient in a three-drug cocktail that was administered to an inmate in Oklahoma as state penitentiaries scrambled to find a substitute for sodium thiopental, which had become unavailable.
In early 2010, a number of states were reporting shortages of sodium thiopental, which had been used as a solo drug but was primarily used as part of a three-drug combination for executions. The situation became so dire that executions were being canceled or postponed.
The shortage of sodium thiopental arose from two causes. One was that it was manufactured by a single pharmaceutical company, Hospira. The second was that the drug’s active pharmaceutical agent was supplied to the company by a third party and became unavailable in 2010.
In an interview with ABC News, a Hospira spokesperson stated that it the drug marketed “solely for use as indicated on the product labeling, and that it is not indicated for capital punishment, and Hospira does not support its use in this procedure.”
In early 2011, Hospira announced that it would stop production of the drug completely. after a bid to start making sodium thiopental in Italy stalled when the Italian government said it would only license manufacture if the drug was not used for executions.
In a statement, Hospira noted, “Italy’s intent is that we control the product all the way to the ultimate end user to prevent use in capital punishment.”
Further discussion with wholesalers and the primary distributors of the product led Hospira to believe that diversion of the drug to departments of corrections could not be prevented.
“Based on this understanding, we cannot take the risk that we will be held liable by the Italian authorities if the product is diverted for use in capital punishment. Exposing our employees or facilities to liability is not a risk we are prepared to take,” the company stated.
Facing dire shortages of the drug, some states were importing it illicitly. California and Arizona had acquired the drug from a UK wholesaler, for example, which in turn had obtained it from a British pharmaceutical company. After learning that the drug was being used in executions, the British government imposed export controls to prevent importation for use in capital punishment in the United States.
As the obstacles to obtaining sodium thiopental mounted, death penalty states began to increasingly rely on pentobarbital. It became the drug of choice, but access to the drug turned out to be short lived. In a scenario similar to what had transpired with sodium thiopental, Danish drugmaker Lundbeck, the sole manufacturer of injectable pentobarbital at that time, pulled the plug only 6 months after pentobarbital made its debut in the Oklahoma execution.
Lundbeck had been largely unaware that its drug was being used for executions; the international distribution networks of pharmaceutical agents can make it exceedingly difficult to keep track of where products are heading or what they are being used for. But after being alerted by the European rights group Reprieve that its drug was being used to execute prisoners in US prisons, Lundbeck took swift action.
However, unlike Hospira, the company did not stop manufacturing pentobarbital but instead overhauled their program to restrict its use and keep it out of the US penal system. All orders for pentobarbital were to be supplied exclusively through a specialty pharmacy program, which would allow them to control distribution and deny access to prisons that execute inmates.
Lundbeck has since divested a number of its products, including pentobarbital, to US-based Akorn Inc, but the restrictions remain. As part of their agreement, Akorn is committed to continue with the restricted distribution program.
Lost in the Rabbit Hole
The question then looms: did the restrictions implemented by Lundbeck have any bearing on the availability of oral pentobarbital?
One factor that raises doubt as to this is the fact that only injectable pentobarbital is used for executions. Oral formulations were never used for this purpose.
Injectable pentobarbital remains available in the United States, albeit with restrictions to keep it from being used in capital punishment. Lundbeck also initiated restrictions in 2011, and oral pentobarbital remained available until about 2015, so there was a 4-year gap.
Most important is that Lundbeck never manufactured any oral form of the drug.
“Lundbeck only owned the injectable formulation of the drug,” said Sally Young, vice president of public affairs at Lundbeck. “As you may be aware, because Lundbeck is in the business of saving lives, we worked diligently to prevent use of our injectable pentobarbital in lethal injections while enabling it to remain available for use in treating patients with an acute epilepsy syndrome.
“The company succeeded by implementing a restricted distribution program, which we announced on July 1, 2011,” she told Medscape Medical News. “The product was part of a portfolio of therapies that the company divested in December 2012 to focus on the newer, strategic assets in Lundbeck’s portfolio.
“I do not know who owns the rights to the oral formulation of the therapy, nor why it would have been unavailable in the US,” Young added.
The FDA lists several US-based pharmaceutical companies that at one time or another manufactured a variety of oral formulations of pentobarbital. All have been discontinued.
When questioned about this, the FDA told Medscape Medical News, “As the oral pentobarbital products were voluntarily withdrawn or discontinued by the manufacturers, the companies are the best source of information on why they are no longer available in the United States.”
Virtually all of the companies that once produced these products have merged with or been acquired by other drug manufacturers. Several were contacted by Medscape Medical News but either they did not respond to the inquiry or were unable to offer any insight into the discontinuation of oral pentobarbital. Product lines often change after mergers and acquisitions, and pentobarbital may have been dropped because of its extremely limited use in healthcare settings.
The injectable formulation can be used orally, but the cost for pentobarbital injectable solution (50 mg/mL) is about $1185 for a supply of 20 mL, and the price for a lethal dose would be prohibitive.
Matt Whitaker noted that the powdered form of pentobarbital was prepared in compounding pharmacies. “PCCA ― professional compounding centers of America, which was the wholesale supplier to compounding pharmacies in Oregon and Washington at that time ― never disclosed the source of the medication,” he said. “There was speculation that the source might have been in Europe, and the strong opposition to the use of capital punishment may have had something to do with it.”
Although the powder would never be used for executions, there still may have been that fear, Whitaker hypothesized, with all of concern at that time regarding drugs used in capital punishment. “But still, it’s all speculation, since they never divulged the source or what happened to it. It’s all really just a rabbit hole that we’ve gone down.”
Finding the Perfect Cocktail
The uncanny and uncomfortable parallel between executions and PAD takes on yet another twist, as prison officials and prescribing physicians struggle to find the ideal drug or combination of agents ― one that is humane, inexpensive, and fast acting. Both uses are highly controversial and ultimately lead to end of life ― but they are at polar ends of the spectrum.
It would seem, though, that at least with regard to PAD, a new and inexpensive drug cocktail has become available. Several physicians in Washington, including Dr Wood and Dr Parrot, being disturbed by the burgeoning price of secobarbital, decided to return to the drawing board and make use of inexpensive generic drugs that currently are widely available in the United States.
“When the price of secobarbital rose from the $500 range to $3000 or more for the same dose, our group decided to try some other options,” explained Dr Wood. “First, we tried a mixture of chloral hydrate and alcohol ― the ‘Mickey Finn’ of times past ― along with phenobarbital and morphine.”
However, patients complained of a burning sensation. It was assumed that the burning was caused by the alcohol, which was then made optional. “But over time, we discovered that the chloral hydrate itself was very ‘burning’ in the mouth, throat, esophagus, stomach for some folks, and our volunteers decided they wanted us to design something better.”
Last summer, Dr Wood and his colleagues convened a group of internists, anesthesiologists, a toxicologist, a cardiologist, and a pharmacologist to devise a better drug cocktail. They came up with DDMP (diazepam 0.5 g, digoxin 25 mg, morphine 10 gm, and propranolol 2 g) that uniformly worked.
“Given the circumstances of these patients, it was challenging to develop a protocol to take the place of barbiturates,” said Dr Parrot. “Most of the patients using Death With Dignity in Washington State have cancer, and many are using large doses of narcotics to manage pain.”
The initial protocol contained lethal doses of pain and anxiety drugs, as well as backup cardiac drugs. But data from the first 70 patients indicated that 80% died in 4 hours or less, but the remaining 20% took longer.
To refine the drug cocktail, Dr Parrot and her colleagues studied the “outliers” for whom death took longer.
“We needed to figure out what characteristics were common to the outlier group and what to do to speed up the process, while still providing a safe, peaceful, painless death,” she said. “What we found was that patients who took longer to die included those in intractable pain, those using IV narcotic drips, or patients tolerant to alcohol.”
She explained that other factors and patient characteristics also had to be considered. A new drug regimen (DDMP2), which contains higher doses of three of the four drugs, was developed and is now recommended. Times have iproved for all groups of patients using this regimen.
DDMP2 contains diazepam 1 g, digoxin 50 mg, morphine 15 g, and propranolol 2 gm.
With the new protocol, patients passed more quickly, and there were no adverse events other than the nausea and vomiting often seen in terminally ill patients.
DDMP2 is now being increasingly used in the United States, said Dr Parrot. “We have also received requests from Canada. We are using this this formula with everyone, and keeping the statistics on all patients. DDMP2 has a much tighter time frame, and the majority of patients will die within 2 hours, though we still have outliers.”
A compounding pharmacy is needed to prepare each mixture; about 60 patients have received DDMP2 to date. Once they have 10 more cases, the group intends to submit a brief article for publication, describing this work.
Numbers Are Small but Slated to Grow
Despite the controversy, PAD accounts for only a small fraction of annual deaths. As evidenced by a 2016 report on their Death With Dignity Act, Oregon reported that during the 19-year period that the law has been in effect, 1749 people have received prescriptions. Of this group, 1127 (65%) have died from ingesting the medications. The rate extrapolated to 37.2 per 10,000 total deaths.
The majority of patients (88.6%) died at home, and most (88.7%) were enrolled in hospice care. No referrals were made to the Oregon Medical Board for failure to comply with the requirements.
During the first 6 months of California’s law, 111 terminally ill individuals ended their lives using lethal prescriptions. More than 250 people began the process. Of the 191 patients who eventually received prescriptions, 21 died of natural causes, and 111 ended their own lives. There is no information on what happened to the remaining 59 individuals who received prescriptions.
Most of the California patients had cancer ― as has been the case in other states that allow PAD.
As of June 1, 2017, 1 year after passage of California’s law, at least 504 patients have received prescriptions for medical aid in dying, as determined on the basis of inquiries to Compassion and Choices’ Doc2Doc consultation program, but the actual rate is undoubtedly higher, because not every patient contacts that organization. Because California’s population is 10 times larger than that of Oregon, the number of individuals choosing this option will be significantly higher.
Similar bills have been introduced in 26 states, including Alaska, Arizona, Connecticut, Delaware, Hawaii, Indiana, Iowa, Kansas, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Nebraska, Nevada, New Jersey, New Mexico, New York, Oklahoma, Pennsylvania, Rhode Island, Tennessee, Utah, and Wisconsin. In addition, a ballot initiative has been proposed for Nov 2018 in South Dakota.
New York and Pennsylvania together would give about 32 million more people the option of PAD.
As more laws are passed across the United States, the need for an effective and affordable medication or drug combination becomes increasingly imperative. Even if covered by insurance, artificially inflated drug costs place a burden on the healthcare system and on society in general, so a safe and inexpensive option would benefit everyone.
Currently, unless the generic and widely available drugs used in DDMP2 fall victim to price gouging or some other unforeseen issue, it appears that a viable option has become available.