Most people experience less than satisfying sleep at least occasionally, but some sufferers go for years without relief. Not being able to fall asleep at the normal hour in a reasonable length of time is known as “sleep onset insomnia.” Older people especially may suffer from waking too soon or not getting enough deep sleep. Sleep is a complex neurochemical phenomenon, and a wide variety of different causes for poor sleep make it hard to diagnose and relieve.
What’s often called sleep hygiene is a collection of good practices and habits that tend to lead to better sleep. Harvard Medical School’s Division of Sleep Medicine has a good list.
If you’re getting exercise and avoiding caffeine or alcohol late in the evening, you might still have problems. Chemical sleep inducers in the form of drugs and supplements can help get you to sleep or keep you asleep, but prescription medications like Ambien and Lunesta can have side-effects, cost a lot, and can be addictive. Many people have been hooked on them (and the drugs of past eras like tranquilizers and sedatives) for years, unable to stop without going through far worse withdrawal symptoms.
If your problem is getting to sleep, your body and mind may be revved up and out of synch with your natural sleep hours. Not engaging in eating, drinking, or stimulating activities for a few hours before normal bedtime can help. Some natural supplements — chemicals already found in your body or food that promote sleep — work for many people. A list:
Melatonin, one of the body’s primary sleep signalling chemicals, is continuously produced by the pineal gland, but destroyed by light hitting the eyes, so it is a driver of the sleep-wake cycle that lags exposure to light; it’s partly because exposure to light synchronizes your sleep cycle that staying up late with bright lighting can disturb it. Taking natural melatonin a few hours before normal bedtime reinforces the natural cycle somewhat, although there’s little evidence of it crossing the blood-brain barrier after absorption by the digestive system. Try sprinkling a bit of melatonin in powdered form under your tongue, perhaps by opening a commercial capsule like these. Melatonin, like some other drugs and vitamins, can be absorbed somewhat by the blood-vessel-rich skin under the tongue — this is called sublingual administration. Melatonin successfully reduces time-to-sleep and insomnia for most people, though it is less effective at keeping you asleep. If you’re already getting up to go to the bathroom at 3 AM, though, you can do another sublingual dose of melatonin and sleep a few more hours successfully.
5-HTP or its precursor L-Tryptophan. Tryptophan is an amino acid component of the proteins in many meats, eggs, and dairy products, and is commonly believed to create the sleepiness after a big Thanksgiving turkey dinner — though turkey meat has no more L-Tryptophan than most other meats. It is also usually credited for the “glass of milk at bedtime” method for assisting sleep. After a Japanese manufacturer of L-Tryptophan produced contaminated batches in 1989, injuring thousands and killing as many as 37 people, L-Tryptophan was banned by the FDA in the US. These restrictions were loosened and finally lifted completely in 2005. As a result of that incident, though, more people still take 5-HTP, which is a metabolite of L-Tryptophan and his similar effects. A few hundred mg of either does tend to produce faster and deeper sleep in most people, and like melatonin thet are both safe and not habit-forming.
Valerian Root is somewhat less harmless. An old herbal standby, this herb in capsule form is used by millions as a sleep aid. While it does work, it can’t be recommended for any but the shortest-term use because it is a mild liver poison — long-term use damages liver function. Other herbal teas like chamomile also have some sedative effects without any obvious toxicities.
GABA is another amino acid and neurotransmitter which doesn’t seem to cross the blood-brain barrier, yet has some obvious effects, producing calm and deeper sleep and perhaps aiding production of growth hormone in older body builders who take it. I take a gram every night before bed and it seems to deepen sleep. It also has some side-effects reminiscent of the niacin flush for some, so be careful and experiment with small doses before trying more. A reliable low-cost provider of GABA powder which can be mixed into any drink is here.Capsules tend to provide less effective dosages.
Doxylamine succinate is an old standby which works fairly well and is cheap and safe as a sleep aid: as an antihistamine, it is obsolete because its side-effect of drowsiness is intolerable during the day. But while it’s unwise to take any drug regularly unless you really need to, it’s at least not addictive and is easy to buy OTC: as this Kirkland-label product from Costco, for example.
Everyone’s sleep problem is different, and with age staying asleep becomes the most common problem. Natural substances can help but good sleep hygiene should be tried first.
The FDA has finally approved Titan Pharmaceutical’s buprenorphine implant after years of unnecessary delay, letting doctors have another useful weapon in treating opioid addiction. The background is here:
— Who Killed Prince? Restrictions on Buprenorphine.
The implant provides a smooth low level of buprenorphine sufficient to relieve opioid cravings, but not enough to degrade mental functions; patients on the implant testify that, unlike opioids or pill forms of buprenorphine, it makes them feel normal so they can function in their daily lives.
The Reuters story mentions the neo-Puritan objections:
The first-ever implant to fight addiction to opioids, a class of drugs that includes prescription painkillers and heroin, was approved by the U.S. Food and Drug Administration on Thursday. The matchstick-sized implant, developed by Titan Pharmaceuticals Inc and privately owned Braeburn Pharmaceuticals, is by design less susceptible to abuse or the illicit resale that plagues existing oral therapies. Fewer than half of the estimated 2.2 million Americans who need treatment for opioid abuse are receiving help, according to the U.S. Centers for Human and Health Services (HHS).
Currently, two drugs are predominantly used to treat opioid addiction — methadone, which is dispensed only in government-endorsed clinics, and the less-addictive buprenorphine, which exists as a pill or strip of film. While effective, a pill or film may be lost, forgotten or stolen. Evidence suggests that the use of these medicines as part of the overall treatment program are more effective than short-term detoxification programs aimed at abstinence, the FDA said on Thursday….
“I intend to make this the most successful implant that’s ever been marketed … and I think it’s absolutely possible given the unmet need,” Braeburn Chief Executive Behshad Sheldon said in an interview ahead of the FDA decision.
However, some doctors are concerned that the implant may incentivise patients to rely solely on medication, and ignore the lifestyle changes they need to make.
This is the neo-Puritan impulse — if you lack the ability to get off entirely, you should just suffer and die because you don’t deserve a normal life. Addiction is not a “lifestyle choice,” it’s an addiction, and those prone to addiction are generally going to be addicted to something, or many things — the goal of treatment should be to move the addict to habits which don’t interfere with leading a productive and satisfying life. I am, for example, addicted to coffee, working out, eating well, and getting a good night’s sleep…
Since it’s an implant, if it isn’t replaced after six months the patient will taper off the drug fairly slowly, and it might well be easy enough to go off it completely as a result. But even if viewed as permanent maintenance, it is much better for the patient and society than allowing the peaks and valleys of opioid addiction to wreck the patient’s life and possibly kill them.
We are also seeing these perfectionists in the current effort to outlaw vaping, which is one of the best ways to get smokers off the much more damaging cigarette smoking habit — see FDA Wants More Lung Cancer.
The implant has a bright future now. Too bad tens of thousands of people died without treatment in the three years the FDA delayed it. The Reuters story continues:
Braeburn estimated the U.S. market for opioid addiction treatments at about $2 billion, excluding methadone and Vivitrol, Alkermes Plc’s treatment for the prevention of relapse after opioid detoxification.
CEO Sheldon declined to specify a price for the implant on Thursday, but said it would be substantially cheaper than Vivitrol. “We are hoping that our first patient will have received the implant by the first day of summer or June 21,” she added.
The market for long-acting therapies such as Probuphine could be even larger if attempts to raise the limit on the number of opioid addicts a doctor can treat are successful. Under the current law, a doctor can treat only 30 opioid addicts within a year of obtaining a waiver, rising to a maximum 100 after procurement of a second waiver. The Congress and the HHS are working toward increasing this limit. Of particular interest is a proposal that exempts from the patient limit any treatment directly administered by a physician, such as an implant or injection.
UPDATED 2 JUNE 2016:
The preliminary autopsy report has been released showing cause of death as an overdose of Fentanyl, an opioid stronger than morphine or heroin. The report is minimal and gives no hint of what investigators might have found or what legal actions Prince’s doctors may face.
Death by HR: How Affirmative Action Cripples Organizations
The first review is in: by Elmer T. Jones, author of The Employment Game.Here’s the condensed version; view the entire review here.
Corporate HR Scrambles to Halt Publication of “Death by HR”
Nobody gets a job through HR. The purpose of HR is to protect their parent organization against lawsuits for running afoul of the government’s diversity extortion bureaus. HR kills companies by blanketing industry with onerous gender and race labor compliance rules and forcing companies to hire useless HR staff to process the associated paperwork… a tour de force… carefully explains to CEOs how HR poisons their companies and what steps they may take to marginalize this threat… It is time to turn the tide against this madness, and Death by HR is an important research tool… All CEOs should read this book. If you are a mere worker drone but care about your company, you should forward an anonymous copy to him.
First, the public release of the autopsy report is likely to be delayed, possibly for months. The complex issues and possible prosecution of the doctors involved are said to be causing authorities to take more time before concluding their investigation of the death. The Minneapolis Star-Tribune has more:
Prince appeared to have been dead for at least six hours before his body was found in a Paisley Park elevator last month, a responding paramedic told staff members, law enforcement officers and others at the scene….
Sources with knowledge of the investigation have told the Star Tribune that despite putting on a calm face after his emergency treatment for an opioid overdose in Moline, Ill., on April 15, Prince grew increasingly agitated in the following days. That prompted one member of his staff to place a call to New York at 6 a.m. on April 20 — the day before the musician’s body was found — seeking advice from someone who had recently worked with the musician, a source said.
Later that day, Prince was given an intravenous treatment at a local hospital, a source with knowledge of the investigation said.
It’s not clear whether that visit came before or after the doctor treating him for withdrawal symptoms made a house call that evening at Paisley Park.
According to several sources, Prince’s staff eventually reached out to Phaedra Ellis-Lamkins, a well-known environmental and labor activist in the San Francisco Bay Area who has been credited with helping Prince recover the rights to his early catalog of songs from Warner Bros.
Ellis-Lamkins called Dr. Howard Kornfeld, a pain and addiction specialist in Mill Valley, Calif., seeking his help to get the musician off prescription painkillers, the sources said.
Her call would have been placed less than 12 hours before Prince’s body was discovered.
Ellis-Lamkins, reached by phone, declined to comment. “I cared deeply about him, and I am not ready to speak publicly,” she wrote the Star Tribune in a follow-up e-mail. “I also know how much he valued his privacy and want to respect his wishes.”
Ellis-Lamkins is a close associate of Van Jones, a Yale-trained lawyer and environmental and social activist who briefly served as a special adviser to the Obama administration. Jones, now a commentator for CNN, was close to Prince and his surviving siblings and attended a recent probate hearing in Carver County District Court to lend his support….
Bill Mauzy, a Minneapolis attorney who has spoken on Kornfeld’s behalf, has said that Kornfeld is widely known for his use of buprenorphine to help wean users from opioids….
In earlier interviews, Mauzy said that Kornfeld couldn’t leave California immediately to meet with Prince, so he sent his son Andrew — who works with his father’s clinic — to Minnesota to explain the treatment. Mauzy represents Andrew Kornfeld.
Court records show that Andrew Kornfeld arrived at Paisley Park the morning of April 21. Sources have told the Star Tribune that he arrived with Kirk Johnson — Prince’s longtime friend, drummer and business associate — and Meron Bekure, Prince’s assistant. It was Johnson and Bekure who found Prince unconscious in an elevator and began screaming.
Andrew Kornfeld called 911 at 9:43 a.m. and said that Prince appeared to be dead, according to the transcript of the call. Dr. Michael Todd Schulenberg arrived at Paisley Park a short time later and after paramedics were on the scene, according to one source. A search warrant filed in the death investigation said Schulenberg told investigators that he had treated Prince twice in April — including the day before Prince’s body was found — and that he had arrived at Paisley Park to deliver some test results.
The painkiller Percocet was present in Prince’s body when he died, and pills were found at the death scene, sources with knowledge of the investigation previously told the Star Tribune….
Andrew Kornfeld was carrying buprenorphine with him when he arrived at Paisley Park, though he is not licensed to administer prescription drugs. Mauzy has said Howard Kornfeld gave the drug to his son to bring to another, unidentified Minnesota doctor who is specially certified to prescribe the drug and who had planned to see Prince the morning he was found dead. Mauzy said the Kornfelds never provided buprenorphine to Prince, however.
“Andrew did not deliver or dispense or administer any medication to Prince,” Mauzy said Friday. “It is obvious that Andrew had nothing whatsoever to do with Prince’s death.”
TMZ has suggested a conspiracy theory based on leaked police reports — we’ll soon know more when the autopsy report is made public, but they suggest (contrary to Dr. Kornfeld’s son’s lawyer’s statements) that buprenorphine might have been given to Prince before his death. If that were true, it’s well-known that incautious addition of buprenorphine to an existing high level of opiates can precipitate a withdrawal crisis. While I doubt this version of events is what happened, if it turns out to be true we will have another celebrity doctor trial fiasco a la Michael Jackson’s. Kornfeld’s son is on shaky legal ground and Prince’s local doctor could reasonably be accused of malpractice.
As we reported, Prince’s doctor, Michael Schulenberg, told authorities he went to Prince’s home to personally deliver test results. Andrew Kornfeld, the son of California rehab Dr. Howard Kornfeld, was also present and had Buprenorphine pills in his backpack. The pills are used to treat opiate addiction.
Andrew’s lawyer held a news conference saying Andrew was not there to personally administer the drug, but he was there to deliver the pills to a local doctor. That’s why cops think it might be more than coincidental Kornfeld and Dr. Schulenberg were there at the same time … when Prince died.
That’s all speculation. But until the autopsy report is released, we can imagine the celebrity doctor trial that may be coming. Big stars seem to feel safer with doctors who will bend the rules to give them what they want. Sometimes that means they die prematurely because their doctor doesn’t want to confront them about their addictions.
UPDATED 2 JUNE 2016:
The preliminary autopsy report has been released showing cause of death as an overdose of Fentanyl, an opioid stronger than morphine or heroin. The report is minimal and gives no hint of what investigators might have found or what legal actions Prince’s doctors may face.
Death by HR: How Affirmative Action Cripples Organizations
The first review is in: by Elmer T. Jones, author of The Employment Game.Here’s the condensed version; view the entire review here.
Corporate HR Scrambles to Halt Publication of “Death by HR”
Nobody gets a job through HR. The purpose of HR is to protect their parent organization against lawsuits for running afoul of the government’s diversity extortion bureaus. HR kills companies by blanketing industry with onerous gender and race labor compliance rules and forcing companies to hire useless HR staff to process the associated paperwork… a tour de force… carefully explains to CEOs how HR poisons their companies and what steps they may take to marginalize this threat… It is time to turn the tide against this madness, and Death by HR is an important research tool… All CEOs should read this book. If you are a mere worker drone but care about your company, you should forward an anonymous copy to him.
Pop music legend Prince likely died of an overdose of opioid pain reliever, which he got hooked on after injuring a hip during a performance. Results of the autopsy are pending, but we know he was seeking treatment from one of the few doctors certified to prescribe a drug that can help addicts get off opioids. The doctor arrived too late — he was just in time to help discover Prince’s body in an elevator.
Who killed Prince? He was partly responsible for his own death. But he could have been saved had Congress, the FDA, and the DEA not restricted access to buprenorphine, the anti-addiction drug the doctor was bringing to help him.
It’s a long and complicated tale, and we’ll get back to Prince after explaining what buprenorphine is and why authorities made it so hard to get.
Opioids are the class of opium-derived and opium-like drugs, from opium itself to derivatives like morphine, codeine, heroin, oxycodone, oxycontin, and methadone. Opioids are commonly prescribed for pain under trade names like Percocet, Vicodin, Darvon, Dilaudid, and Demerol, and they are routinely prescribed for every surgical patient as part of aftercare.[1] Attempts to limit prescribing run up against pain management advocates, who quite reasonably don’t want some to suffer unnecessary and medically-damaging chronic pain.
Street opioids like heroin are illegal and addicts are often jailed, usually for the other unlawful activities they pursue as their ability to work declines and feeding their habit grows expensive. Middle and upper-class addicts can reach a stable state where they manage their addictions for long periods and stay out of the justice system. It’s far from clear that legalization would do any additional harm to poor addicts, who might then be expected to stabilize their lives more easily when their drug is cheap and easy to get.
But prescribed opioids are becoming a public-health epidemic, causing at least half of the 28,000 US overdose deaths in 2014.[2] Many legally-produced pills are diverted to the black market. Screening tests done to detect abuse cost about $2 billion in 2013, and US sales of opioids rose from $3.97 billion in 2001 to $8.34 billion in 2012.[3] Thus legally-prescribed opioids are an enormous business for US drug companies.
President Obama recently hosted pop star Macklemore to raise awareness on the topic. Of course his suggested solution is to spend $1.1 billion more, which would hire more therapists and pay for treatment.[4]
But getting people off opioids is a solved problem. Buprenorphine, an opioid itself originally approved by the FDA in 1985 as a scheduled narcotic for pain relief, was discovered to relieve cravings for other opioids in low doses which didn’t produce the highs of typical opioids. Let the The National Alliance of Advocates for Buprenorphine Treatment explain it:
Buprenorphine (BYOO-pre-NOR-feen) (‘bu-pre-‘nor-feen) is an opioid medication used to treat opioid addiction in the privacy of a physician’s office. Buprenorphine can be dispensed for take home use, by prescription. This in addition to buprenorphine’s pharmacological and safety profile makes it an attractive treatment for patients addicted to opioids.
Buprenorphine is different from other opioids in that it is a partial opioid agonist. This property of buprenorphine may allow for;
• less euphoria and physical dependence*
• lower potential for misuse*
• a ceiling on opioid effects*
• relatively mild withdrawal profile*
At the appropriate dose buprenorphine treatment may:
• Suppress symptoms of opioid withdrawal
• Decrease cravings for opioids
• Reduce illicit opioid use
• Block the effects of other opioids
• Help patients stay in treatment
* When compared with full opioid agonists (such as oxycodone and heroin)
Buprenorphine (‘bu-pre-‘nôr-feen) (C29H41NO4) is a semi-synthetic opioid derived from thebaine, an alkaloid of the poppy Papaver somniferum. Buprenorphine is an opioid partial agonist. This means that, although Buprenorphine is an opioid, and thus can produce typical opioid effects and side effects such as euphoria and respiratory depression, its maximal effects are less than those of full agonists like heroin and methadone. At low doses Buprenorphine produces sufficient agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. The agonist effects of Buprenorphine increase linearly with increasing doses of the drug until it reaches a plateau and no longer continues to increase with further increases in dosage. This is called the “ceiling effect.” Thus, Buprenorphine carries a lower risk of abuse, addiction, and side effects compared to full opioid agonists. In fact, Buprenorphine can actually block the effects of full opioid agonists and can precipitate withdrawal symptoms if administered to an opioid-addicted individual while a full agonist is in the bloodstream. This is the result of the high affinity Buprenorphine has to the opioid receptors. The affinity refers to the strength of attraction and likelihood of a substance to bind with the opioid receptors. Buprenorphine has a higher affinity than other opioids and as such will compete for the receptor and win. It will “knock off” other opioids and occupy that receptor blocking other opioids from attaching to it. If there is enough Buprenorphine to knock the opioids off the receptors but not enough to occupy and satisfy the receptors, withdrawal symptoms can occur; in which case the treatment is more Buprenorphine until withdrawal symptoms disappear.[5]
For motivated and conscientious patients, doctor-supervised treatment with buprenorphine is very effective, and prescriptions for the drug have risen into the millions yearly despite restrictions on the doctors allowed to prescribe it and the number of patients they can treat with it. Why the restrictions? After all, the more dangerous opioids are prescribed to much larger numbers of patients, and no special training of doctors is required….
The answer: Congress wrote the law to allow opioids to be prescribed for addiction treatment in 2000, but included special licensing and training requirements for doctors and limited the number of patients each doctor could treat, imagining that this would reduce the already-known problem of “pill mills” where doctors abuse their licenses to prescribe to addicted patients. This turned out to make it difficult to find a doctor to treat addiction since it would only be a small part of any doctor’s practice and the hassle of getting certified, and the association with addiction, made it a losing proposition for most doctors. So while large numbers did get treated, the problem continued to grow far beyond the treatment slots available.
Abuse did turn out to be a problem. Many patients are undergoing treatment involuntarily after being charged with drug possession or other crimes related to their addiction, and this population is quite capable of grinding up the pills and snorting or injecting them, or selling them to feed their original addiction. In an effort to block this, naloxone (an opioid antagonist which eliminates the high) was added to the pills. This didn’t solve the problem, and compliance by patients who are “justice system involved” continued to be poor, with only 8% of those treated staying clean.
The New York Times and the DEA spun these problems as fatal to use of the drug in treatment of addiction. Here’s the DEA in July 2013:
Like other opioids commonly abused, buprenorphine is capable of producing significant euphoria. Data from other countries indicate that buprenorphine has been abused by various routes of administration (sublingual, intranasal and injection) and has gained popularity as a heroin substitute and as a primary drug of abuse. Large percentages of the drug abusing populations in some areas of France, Ireland, Scotland, India, Nepal, Bangladesh, Pakistan, and New Zealand have reported abusing buprenorphine by injection and in combination with a benzodiazepine.
The National Forensic Laboratory Information System (NFLIS) is a DEA database that collects scientifically verified data on drug items and cases submitted to and analyzed by state and local forensic laboratories. The System to Retrieve Information from Drug Evidence (STRIDE) provides information on drug seizures reported to and analyzed by DEA laboratories. In 2012, federal, state and local forensic laboratories identified 10,804. In the first quarter of 2013, 1,905 buprenorphine exhibits were identified.
According to the Drug Abuse Warning Network (DAWN ED), an estimated 21,483 emergency department visits were associated with nonmedical use of buprenorphine in 2011, nearly five times the 4,440 estimated number of buprenorphine ED visits in 2006. The American Association of Poison Control Centers Annual Report indicates that U.S. poison centers recorded 3,625 case mentions and three deaths involving toxic exposure from buprenorphine in 2011.[6]
Crisis! Three deaths! As compared to the 28,000 dead from other opioids. This can’t be allowed.
The New York Times spun their 2013 story to emphasize buprenorphine abuse:
Mr. Schneider was staying in his parents’ basement when he washed down 40 sleeping pills with NyQuil and beer. His father heard him gasping and intervened, a reprieve that led Mr. Schneider into rehab, not his first program, but the one where he discovered buprenorphine, a substitute opioid used to treat opioid addiction.
In the two years since, by taking his “bupe” twice daily and meeting periodically with the prescribing psychiatrist, Mr. Schneider, 38, has rebounded. He is sober, remarried, employed building houses, half of a new acoustic duo and one of the many addicts who credit buprenorphine, sold mostly in a compound called Suboxone, with saving their lives.
Suboxone did not save Miles Malone, 20; it killed him. In 2010, a friend texted Mr. Malone an invitation to use the drug recreationally — “we can do the suboxins as soon as I give them to u, right, dude?” — and he died that night in South Berwick, Me., of buprenorphine poisoning. The friend, Shawn Verrill, was sentenced this summer to 71 months in prison.
“I didn’t know you could overdose on Suboxone,” Mr. Verrill said in an interview at a federal prison in Otisville, N.Y. “We were just a bunch of friends getting high and hanging out, doing what 20-year-olds do. Then we went to sleep, and Miles never woke up.”
Suboxone is the blockbuster drug most people have never heard of. Surpassing well-known medications like Viagra and Adderall, it generated $1.55 billion in United States sales last year, its success fueled by an exploding opioid abuse epidemic and the embrace of federal officials who helped finance its development and promoted it as a safer, less stigmatized alternative to methadone.
But more than a decade after Suboxone went on the market, and with the Affordable Care Act poised to bring many more addicts into treatment, the high hopes have been tempered by a messy reality. Buprenorphine has become both medication and dope: a treatment with considerable successes and also failures, as well as a street and prison drug bedeviling local authorities. It has attracted unscrupulous doctors and caused more health complications and deaths than its advocates acknowledge.
It has also become a lucrative commodity, creating moneymaking opportunities — for manufacturers, doctors, drug dealers and even patients — that have undermined a public health innovation meant for social good. And the drug’s problems have emboldened some insurers to limit coverage of the medication, which cost state Medicaid agencies at least $857 million over a three-year period through 2012, a New York Times survey found.[7]
Thus the need for a drug delivery system that didn’t allow for easy diversion or abuse, and delivered a constant dose of the medication without requiring the patient to remember to take it. Titan Pharmaceutical’s Probuphine, an implantable form of buprenorphine, started development in 2000, was rejected by the FDA in April 2013 for what appear to be murky reasons, and is up for approval again in 2016 after a three-year delay to gather more data to answer FDA questions. The episode looks like an instance of Bootleggers and Baptists overregulation, with vested interests blocking a much-needed new drug implant to protect their interests while throwing up a cloud of “concerns” to justify their actions.
Titan began development of the drug implant in 2000 after licensing the patent from MIT in 1996. At the beginning of development, buprenorphine was approved and in use for anti-addiction treatment in France and Australia, but was awaiting more studies and FDA approval in the US. When the FDA approved buprenorphine tablets in 2002 under the then-new law allowing opioids to be prescribed for addiction treatment, Titan appeared to have a winning idea on its hands after the DEA and FDA soured on the bright early hopes for tablet-delivered buprenorphine — Titan’s implantable form would address all of the issues that so concerned the DEA and improve success rates among addict populations.
But the FDA rejected Titan’s application in April of 2013 despite the positive recommendation of their panel of outside medical experts, a rare event. The company’s stock dropped by 80%, typical when a small drug company’s key development project is rejected. One biotech publication outlined the FDA’s position:
In the end, a vote by an outside panel of FDA experts favoring approval of Titan Pharmaceuticals’ Probuphine didn’t influence the outcome at all. Agency staffers stuck with the opinions outlined in a harsh internal review and rejected the opioid addiction drug, outlining some extensive demands for new clinical data that would be needed for an approval.
In a statement, Titan ($TTNP) outlined three key requirements on new efficacy data. Titan will have to offer clear evidence of:
• The ability of Probuphine to provide opioid blockade of relevant doses of agonists.
• The effect of higher doses of Probuphine, ideally doses more closely approximating the blood plasma levels associated with sublingual doses of buprenorphine of 12 to 16 mg/day.
• Human factors testing of the training associated with Probuphine’s insertion and removal.
The FDA’s panel had voted 10 to four in favor of an approval, but the agency had no problem overlooking the majority support along with Titan’s claim that Phase III data demonstrated that Probuphine, an implant that releases buprenorphine over a period of 6 months, was better than a placebo at preventing addicts from using illicit opioids. Investigators also said it was noninferior to the approved therapy. But staffers picked apart that argument in the internal review.[8]
The outside panel recognized that while results were not perfect, Titan’s product was needed immediately and offered enough advantages over alternatives to merit approval. FDA staff decided to reject the drug and require several more years of studies and delays before looking at it again.
Remember, this is a widely-used drug since 2002, and the company had been at work on the required studies for many years before bringing it to the FDA for approval in 2013. The delay nearly killed the company and the implant product, and Titan was forced to sell rights to the drug to another company, Braeburn Pharmaceuticals, to get enough money to continue.
Because the FDA is an unelected, unaccountable bureaucracy, no one knows how often their decisions are swayed by politics and under-the-table influence-peddling. Doctors can be stubborn and view themselves as protecting the public, or require even more proof of efficacy, or perhaps can be influenced by communications from Big Pharma interests who might see opioid revenues decline if better treatments for opioid addiction became available. No one knows or can know whether improper influence occurred in this case — it’s best to assume erroneous belief, rather than corruption, causes this kind of damaging mistake.
Titan came back to the FDA with the requested new studies, and a hearing was held January 13, 2016. The Psychopharmacologic Drugs Advisory Committee again has recommended approval, this time by a vote of 12-5. But again, some panelists were against approval, working hard to come up with reasons to deny a new treatment to people with life-threatening addictions:
Probuphine works like a contraceptive implant, such as Norplant. Four implanted rods, each smaller than a matchstick, provide a steady amount of medication for up to 6 months. The FDA is considering approving it for a specific population: “stable” patients who are already taking the dissolvable buprenorphine film at a low dose. The committee voted 12-5 in favor of probuphine.
“I think this will save some folks’ lives,” said advisory committee member David Pickar, an adjunct professor of psychiatry at Johns Hopkins Medical School in Baltimore.
Doctors who want to prescribe probuphine would have to refer patients to providers trained to implant medical devices, or undergo training to learn how to safely implant and remove it, said Behshad Sheldon, president and CEO of Braeburn Pharmaceuticals, who spoke at Tuesday’s advisory committee hearing.
Implanting probuphine takes 10 to 15 minutes and removing it takes about 20 minutes, said Steven Chavoustie, a physician involved in a clinical trial of the device.
Pharmacist Tracy Rupp urged the committee to reject probuphine, noting that its manufacturer presented only one clinical study showing the drug was effective.
In the study, doctors compared the use of probuphine implants and buprenorphine film, Sheldon said. Patients in the study were considered “stable” because they had been safely using the films. After 6 months, 85% of those given probuphine tested negative for illegal drugs, compared to 72% of those given the film.
The study had multiple flaws, said Rupp, director of public health policy initiatives at the National Center for Health Research, a nonpartisan group that analyzes health data.
Some missing urine tests were counted as negative, as if the patient had no drugs in their system. But Rupp noted that people addicted to opiates “often skip tests to avoid a positive test.” That could skew the results, Rupp said.
“It is disappointing that the advisory committee set such a low bar for safety and effectiveness,” Rupp said after the vote. “Is probuphine effective? We still don’t know because the study was poorly designed and missing data.”
Judith Kramer, the committee’s acting chairwoman, said she voted against recommending probuphine’s approval because doctors don’t yet know if it’s effective for more than 6 months. Many people who are addicted to opiates need to take medication for years, she added.[9]
Notice the proposed use is now restricted to patients already on the film form of the drug, and the advantages—six months guaranteed compliance, for example—are ignored in favor of nitpicking, as if the efficacy of the drug itself has to be proven all over again. The goalposts have been moved. The FDA will rule soon, and may well reject the drug again despite the positive panel recommendation.
Meanwhile, the magnitude of the opioid addiction crisis has only grown, with recent headlines about flat life expectancy among older white women which some blame on epidemic opioid addictions among the poorer folk of the depressed parts of the US. The New York Timesweighed in again as Congress and the White House prepared to try again to address the crisis:
Methadone, a liquid opioid that patients must drink every day under supervision at a methadone clinic, has been in use since the Vietnam War; it was approved to help the many soldiers coming back with heroin addiction. Before that, “treatment” usually consisted of a) jail and b) nothing else…
Waiting lists for these therapies are enormous. According to research by the RAND Corporation, 90 percent of the counties in the United States have no methadone clinic or fall very far short of the need, even though having a local clinic is crucial, because patients must visit daily. The shortage is especially acute in rural areas, where opioid and heroin addiction are spreading fast.
As for Suboxone, 43 percent of counties don’t have doctors who can prescribe it, or have far fewer than needed. According to the Pew Charitable Trusts, while 900,000 doctors across the United States are licensed to write prescriptions for opioid painkillers, only 32,000 are allowed to prescribe Suboxone….
Just as a contraceptive implant in a patient’s arm releases a steady dose over time, the new Probuphine implant releases a consistent, low dose of buprenorphine for six months. Three studies — this one,this one and a not-yet peer-reviewed study — found that Probuphine was better than a placebo implant and better than Suboxone pills at reducing illicit drug use, measured by urine tests…. Probuphine was designed to solve three problems with Suboxone. One was the chance of resale or accidental exposure to the pills. “Also, there’s the opportunity for non-adherence — people forget, or don’t take their dose, which leaves them vulnerable again,” [Richard Rosenthal, medical director of addiction psychiatry at Mount Sinai Behavioral Health System in New York] said. The other issue is that medicines have peaks and troughs. “People on various medications may have increased cravings during those troughs.”
…I spoke with a man named David, a firefighter in a Boston suburb who wanted to be identified only by his first name. After doing well on Suboxone, he participated in the latest trial of Probuphine. When he was taking the pill, he said, he could feel it kick in every morning, “like drinking a good cup of coffee,” he said. “With the implant there was a much more consistent feeling of normalcy. I just felt perfectly normal all the time.”[10]
On May 11th, Congress passed a new package of bills aimed at fighting the epidemic — and the White House asked for $1.1 billion in new money to fund the effort:
House members are expected to overwhelmingly approve a total of 18 bills this week focused on opioid addiction, treatment and prevention.
On Wednesday, the House easily passed 10 of those bills, including legislation by Rep. Susan Brooks, R-Ind., and Joe Kennedy, D-Mass., to create an inter-agency task force to update standards for doctors to manage their patients’ pain and prescribe painkillers. Lawmakers also approved a bill requiring states that receive federal grants for child protective services to have laws or programs in place to ensure that infants born to opioid-addicted mothers will be cared for safely when they leave the hospital.
More bills will be taken up Thursday.
“This historic package of anti-drug bills will deliver critical funds to address the abuse of heroin and opiates, support our loved ones on their path towards recovery, and slow the flow of drugs into our country,” said Rep. Vern Buchanan, R-Fla.
Rep. Jim McGovern, D-Mass., praised the bipartisan action but said it must be fully funded to do any good. Democrats offered an amendment Wednesday to provide $600 million in emergency funding, but it was blocked by Republicans who said the money will come later when Congress passes its 2017 spending bills for federal agencies.[11]
Eighteen bills! That will surely fix the problem, and $1.1 billion will fund thousands more social workers and functionaries to administer new programs.
Simple folk may wonder why all doctors can’t prescribe buprenorphine as they do Oxycontin and Percocet, which are more dangerous to life and health. Or why Titan’s implant form has been so long delayed by the FDA. More dead people is apparently preferred to letting the doctors and suffering patients start treating the addictions.
Prince was found dead one day before he was scheduled to meet with a California doctor in an attempt to kick an addiction to painkillers, an attorney with knowledge of the death investigation said Tuesday.
Dr. Howard Kornfeld, a national authority on opioid addiction treatment, was called by Prince representatives the night of April 20 because Prince “was dealing with a grave medical emergency,” said William Mauzy, a prominent Minneapolis attorney working with the Kornfeld family.
Kornfeld, who runs Recovery Without Walls in Mill Valley, Calif., could not clear his schedule to meet with Prince the next day, April 21, but he planned to fly out the following day.
So he sent his son, Andrew Kornfeld, who works with him, to Minnesota, with plans for him to go to Paisley Park to explain how the confidential treatment would work, Mauzy said.
“The plan was to quickly evaluate his health and devise a treatment plan,” Mauzy said, speaking on behalf of the Kornfelds. “… The doctor was planning on a lifesaving mission.”
…When Andrew Kornfeld arrived at Paisley Park at 9:30 a.m. Thursday, Prince’s representatives could not find him, Mauzy said. Andrew Kornfeld was one of three people at Paisley Park when the musician’s body was found in an elevator a few minutes later — and it was Andrew Kornfeld who called 911.[12]
Too late by a day. Meanwhile, some Minneapolis doctors are darkly critical of Kornfeld for not getting in touch with one of them.[13] It’s not known why Prince or his staff chose to seek treatment from Kornfeld’s California clinic instead of local doctors, but presumably the local doctors Prince had seen weren’t proactive in getting him off opioids, for whatever reason.
Prince had been treated at an ER six days before his death, apparently for an overdose. This is probably what started the search for a private clinic that could treat him for opioid addiction.[14] He may also have had the flu, and the immune system involvement may have turned his customary dose deadly.[15]
78 people a day die from opioid overdose[16]. 28,000 people a year, more than all non-suicide deaths from guns. Yet life-saving treatments are being bottled up by regulatory delay and a strange if-you-can’t-kick-the-addiction-you-deserve-to-die attitude. Congress and the FDA need to give doctors the freedom to help patients, and give patients the freedom to get treatment free of bureaucratic delays and costly requirements.
The FDA was founded to assure consumers that the foods and drugs they were purchasing were pure and as labelled, unadulterated, and useful for the ailments they claimed to treat — remember that the FDA was originated in 1906 by passage of the Pure Food and Drug Act.[17] Mission creep and continued expansion of safety and efficacy-proving study requirements led to the current morass, where new drugs take a decade and hundreds of millions of dollars to win approval. This is the underlying reason for high drug prices and reduced competition, as small companies like Titan are crushed by vested interests. Many life-saving drugs are available overseas for many years before they are approved in the US.
Prince — and hundreds of thousands of other overdose victims — might still be alive and creating music today if it were not for the commissars at the FDA and the drug warriors of the DEA, aided by a Congress easily pressured into limiting the people’s freedom to decide what they want to put into their own bodies. Having well-paid bureaucratic busybodies decide every aspect of your life for you is what brought us to this learned helplessness that is slowing growth and leading to lives of unemployed and aimless despair and addiction.
—
UPDATED 2 JUNE 2016:
The preliminary autopsy report has been released showing cause of death as an overdose of Fentanyl, an opioid stronger than morphine or heroin. The report is minimal and gives no hint of what investigators might have found or what legal actions Prince’s doctors may face.
Postscript: Others are reporting further speculation about the two doctors on scene when Prince’s body was discovered. TMZ has spun up a conspiracy theory based on leaked police reports — we’ll soon know more when the autopsy report is made public, but they suggest (contrary to Dr. Kornfeld’s son’s statements) that buprenorphine might have been given to Prince before his death. If that were true, it’s well-known that incautious addition of buprenorphine to an existing high level of opiates can precipitate a withdrawal crisis. While I doubt this version of events is what happened, if it turns out to be true we will have another celebrity doctor trial fiasco a la Michael Jackson’s. Kornfeld’s son is on shaky legal ground and Prince’s local doctor could reasonably be accused of malpractice.
As we reported, Prince’s doctor, Michael Schulenberg, told authorities he went to Prince’s home to personally deliver test results. Andrew Kornfeld, the son of California rehab Dr. Howard Kornfeld, was also present and had Buprenorphine pills in his backpack. The pills are used to treat opiate addiction.
Andrew’s lawyer held a news conference saying Andrew was not there to personally administer the drug, but he was there to deliver the pills to a local doctor. That’s why cops think it might be more than coincidental Kornfeld and Dr. Schulenberg were there at the same time … when Prince died.
As for the drugs … medical experts say a combination of Percocet and Buprenorphine can be fatal because both drugs suppress breathing, and the combination creates a dangerous synergistic effect.
If the toxicology results show both drugs were in Prince’s system and contributed to his death, Dr. Schulenberg and Andrew Kornfeld would be questioned again to determine if either of them gave Prince the Buprenorphine and what tests were done to determine the level of Percocet in his system.
Stay tuned — much of this speculation may evaporate when the autopsy report is released.
The first review is in: by Elmer T. Jones, author of The Employment Game.Here’s the condensed version; view the entire review here.
Corporate HR Scrambles to Halt Publication of “Death by HR”
Nobody gets a job through HR. The purpose of HR is to protect their parent organization against lawsuits for running afoul of the government’s diversity extortion bureaus. HR kills companies by blanketing industry with onerous gender and race labor compliance rules and forcing companies to hire useless HR staff to process the associated paperwork… a tour de force… carefully explains to CEOs how HR poisons their companies and what steps they may take to marginalize this threat… It is time to turn the tide against this madness, and Death by HR is an important research tool… All CEOs should read this book. If you are a mere worker drone but care about your company, you should forward an anonymous copy to him.
Death by HR: How Affirmative Action Cripples Organizations
