The high cost of dying (shades of Questcor)

Although physician-assisted dying (PAD) remains a highly contentious and controversial topic, it is going on. It is now legal in six states in the United States. In these states, the law allows physicians to offer terminally ill adults the option of a lethal dose of an oral prescription medication, provided the patient meets strict criteria.

But what are these medicines, and how are they used? An investigation by Medscape finds a that a huge price jump in one of the oral drugs that is used for this purpose, as well as an acute shortage of another, have led to the development of a new drug cocktail.

The price hike began only a month after California proposed legislation, in 2015, that would make it the fifth state to allow PAD. The company manufacturing the drug most commonly used in this process, secobarbital, dramatically raised the cost of the drug, and the price has since jumped several more times.

The result was that the price tag of ending one's life jumped from around $200 to $3000 or higher…

In 2009, a lethal dose of secobarbital (100 capsules) cost less than $200 (less than $2 per capsule), a fraction of what it is now. During the next 6 years, the price gradually crept up to $1500 until its purchase by Valeant Pharmaceuticals, which promptly doubled the cost. Whether or not the timing with California's law was deliberate, some have called the move "exploitive," in that secobarbital is a generic drug that has been on the market for about 80 years.

More importantly, by 2015, secobarbital had become the only viable option for patients seeking to end their lives, and doubling the price suddenly put a heavy financial burden on the price of
dying. This leads to the question of choice ― why is there virtually none? Can it be that there is only one drug available in the United States for patients who choose this option?

Currently, six states can authorize physicians to offer terminally ill adults the option of a lethal dose of an oral prescription medication…

Several other countries permit this practice, but notably, Canada, Belgium, Luxembourg, and the Netherlands also allow euthanasia, whereby a physician can administer a lethal drug dose by injection. This allows more leeway and options as to the selection of drugs, cost, and mode of delivery.

For example, in Ontario, Canada ― a country where patients have a choice ― there have been very few cases of self-administration, less than 1%, according to James Downar, MD, CM, MHSc, a critical care and palliative care physician at the University Health Network in Toronto.

As far as he is aware, all self-administrated cases have involved oral phenobarbital, generally with chloral hydrate and morphine added. "There is a strong desire to avoid the oral route here, given the failure rate," Dr Downar told Medscape Medical News…

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.

"Cost can be an issue for the oral route ― that amount of phenobarbital is several hundred dollars as of the last check," Dr Downar noted. "I think some people get coverage for it, but it is not a reimbursed drug in Ontario. The intravenous meds are free, on the other hand, even when used outside of a facility."

In a lethal injection, the following drugs are administered in the following sequence: midazolam, to induce sedation; lidocaine, to reduce injection discomfort; propofol, to induce coma, myocardial depression, respiratory depression and vasoplegia; and rocuronium, to induce respiratory muscle paralysis. These details were outlined by Madeline Li, MD, PhD, FRCP(C), a psychiatrist in the Department of Supportive Care at the University Health Network–Princess Margaret Cancer Center, Toronto.

With oral drugs, the choice is not only contingent on drugs that are well tolerated and fast acting, but they also must be relatively easy for the patient to self-administer at a high dose…

Fast-acting barbiturates quickly became the drugs of choice, in particular, secobarbital and pentobarbital. In the first 19 years of Oregon's law, secobarbital was used for 59.3% of patients, pentobarbital for 34.3%, and other drugs for the remaining 6.5%...

The lethal dose is much higher. Typically, 9 g of secobarbital in capsules or 10 g of pentobarbital liquid or powder needs to be consumed at one time. The contents of the secobarbital capsules or pentobarbital powder are generally mixed with juice or another sweet substance to mask the bitter taste.

The choice of drug was largely made on the basis of factors such as availability, price, and preference of prescriber and patient…

"When the cost of secobarbital reached $1000, pentobarbital then became more popular between 2011 to 2014," he explained in an interview…

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….

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.

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. 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…

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 practice of buying inexpensive drugs from other companies and aggressively pushing up the price tag…

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…

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."…

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.

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…

"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….

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.

For now.

https://www.medscape.com/viewarticle/888271