07/29/16

Be Careful of Where You’re Going

© : J�rg St�ber | 123rf.com

© : J�rg St�ber | 123rf.com

On July 9, 2015 eight Senators sent a letter to the Department of Health and Human Services (HHS), Office of National Drug Control Policy (ONDCP), and the Drug Enforcement Administration (DEA) asking for information on their efforts to facilitate scientific research into the benefits of medical marijuana. The Senators asked for answers to a series of questions, stating that relevant federal agencies had to play a leadership role in coordinating and facilitating research into medical marijuana. This began a process culminating in the administrators of the three agencies sending a detailed reply to their questions in an April 4, 2016 response … 26 pages long. And so speculation began that the DEA would decide whether or not to change the controlled substance status of marijuana “in the first half of 2016.”

This was part of the inquiry made by the Senators’ letter, in noting the need to remove “extraneous regulatory barriers for researchers who wish to perform scientific studies on the sue of marijuana for various diseases.” They pointed to the need of the federal government to make a concerted effort to understand how marijuana works and what the appropriate doses and methods of treatment are, “like any prescribed medicine.” Within Appendix C of the HHS, ONDCP, DEA response, was the following graphic and text delineating the process to schedule or re-schedule any drug.

DEAThe Controlled Substance Act requires eight factors as part of its scientific review: 1) the actual or relative potential for abuse; 2) the scientific evidence of its pharmacological effect; 3) the state of current scientific knowledge regarding the substance; 4) the history and current pattern of abuse; 5) the scope, duration and significance of abuse; 6) the risk to the public health; 7) the psychic or physiological dependence liability; and 8) the immediate precursor of a substance already controlled.

Writing for the Huffington Post in April 2016, Matt Ferner noted the FDA completed its review of the medical evidence of the safety and effectiveness of marijuana, and forwarded it to the DEA. But the FDA recommendations are still not public. In the Washington Post, Christopher Ingraham interviewed John Hudak of the Brookings Institution, who said the small amount of researchers currently working with marijuana is not due to the government turning down applications to do the research. Rather, it is a function of the application process itself. “People just aren’t applying because of all the headaches involved. . . . It’s a huge disincentive for the academic community.”

The bureaucratic hurdles also mean that colleges and universities are often hesitant to fund marijuana research for fear of running afoul of complex federal regulations. One ongoing study on the use of marijuana to treat veterans with PTSD has been struggling to get off the ground for more than five years, for instance.

There was an unconfirmed rumor by an “anonymous” DEA attorney that the DEA planned to reschedule marijuana as a Schedule II controlled substance and make medical marijuana legal with a doctor’s prescription in all 50 states. This is simply not true. Rescheduling would merely make it easier to get permission to do research with marijuana, not make it legal for doctors in all 50 states to prescribe marijuana. If that were the case, why can’t doctors prescribe cocaine legally? It is a Schedule II Controlled Subtance. Writing for The Fix, McCarton Ackerman noted the skepticism about the validity of the source.

In response to the rumors, DEA staff coordinator Russ Baer would not confirm the rumored rescheduling by August 1st in an interview with aNewDomain. Baer pointed out the complexity of what is referred to as “medical marijuana.” While THC and CBD are the two main cannabinoids, there are an estimated 480 compounds in cannabis. “What is under-reported right now is how complex the marijuana plant is.”

Baer said the DEA wants to remove the roadblocks to further research into the effectiveness of medical marijuana. However, he said the DEA doesn’t support decisions made on anecdotal evidence.

We want there to be research on marijuana and its component parts, there needs to be (more) studies about both the benefits and the adverse effects about marijuana. . . . We want to know more about cannabis— we need rigorous scientific research — the DEA stands behind the scientific process.

He added that safe medical cannabis requires rigorous peer-reviewed studies. He singled out current research into the benefits of cannabinol (CBD). “We are told by NIDA, also, that there are medical studies out there also preliminarily indicate CBD is beneficial.” But the opioid crisis has captured most of the DEA’s attention. “Marijuana is important, but our efforts are mainly focused on the nation’s growing opioid crisis. . . . We’re focusing on fentanyl, fentanyl compounds and on preventing the deaths caused by opioid addiction.”

A June 24th article by Kate O’Keeffe for the Wall Street Journal said Baer didn’t expect an answer by June 30th, but the agency was in the final stages of deciding whether to reschedule marijuana. He added that a decision is expected sometime soon.

On July 13, 2016 Dr. Douglas Throckmorton of the FDA appeared before the Judiciary Subcommittee on Crime and Terrorism. In his written statement to the committee, he reiterated its standing 2006 recommendation that marijuana remain as a Schedule I controlled substance because of a high potential for abuse; no currently-accepted medical use; and that it lacks accepted safety for use under medical supervision. However, “DEA is currently in the process of evaluating a number of other Citizen Petitions regarding the scheduling of marijuana.”

He noted there are three drugs approved for human use that contain active ingredients present in or similar to those in botanical marijuana: Marinol Capsules, Syndros and Cesamet Capsules. These products have undergone the FDA’s approval process and have been determined to be safe and effective for their respective indications. The future of medical marijuana lies in “classical drug development.”

If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems.

Throckmorton pointed to three Fast Track designations for Savitex (April 2014), Epidiolex (June 2014) and a CBD formulation of Insys Therapeutics to treat Dravet syndrome (February 2015). All three are drugs derived from marijuana. He said the FDA is working with researchers who are conducting studies on the development of potential new drugs derived from marijuana.

FDA encourages and supports medical research into the safety and effectiveness of marijuana products through adequate and well-controlled clinical trials conducted under an IND [Investigational New Drug] and consistent with DEA requirements for research on Schedule I substances. FDA has provided scientific advice to representatives from several states considering support for medical research of marijuana and its derivatives, including CBD, to help ensure that their research is rigorous and appropriate.

Another date floated on the rumor pond for a DEA decision on rescheduling marijuana was August 1st, which is fast approaching. Will there be an answer? Who knows? According to Russ Baer, the DEA is not bound to give its answer within some artificially determined timeframe. So I suggest those anxious for an announcement by the DEA (senators and marijuana activists alike) apply a mash up of a famous Yogi-ism here: “Marijuana ain’t re-scheduled till it’s rescheduled.” Perhaps the DEA is just trying to be careful in its decision making process about the rescheduling. Yogi Berra has some further words of wisdom to apply there: “You’ve got to be very careful if you don’t know where you are going, because you might not get there.”

07/26/16

Thirty Pieces of Silver

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© Bigalbaloo | stockfresh.com

To be a “Judas” or hear a reference to “thirty pieces of silver” has long been part of Western culture’s portrayal of betrayal. Classically, we think of the price paid to Judas by the chief priests and elders to betray Jesus (Matthew 26:14-16; 27:3-10).  Matthew said this was done to fulfill “what had been spoken by the prophet Jeremiah.” But if you want to get technical, Matthew was actually giving a rather loose translation of a passage from another prophetic book—Zechariah. So what’s going on here?

The first of two possible explanations suggests that Matthew was making a composite quotation of Jeremiah and Zechariah. He considered the sections taken from Jeremiah to be significant enough that he cited the better-known and more prominent prophet as his authority. Second, and what seems to be the more likely explanation, Matthew is citing Jeremiah because the book of Jeremiah was first in the manuscript that contained the collection of the Prophets. Luke 24:44 has a similar composite reference by Jesus as he spoke to the disciples on the road to Emmaus, “that everything written about me in the Law of Moses and the Prophets and the Psalms must be fulfilled.”

However there are some difficulties with Matthew’s use of the Zechariah passage. Some details of Zechariah’s behavior don’t seem to fit with the historical account in Matthew. In The Hard Sayings of the Bible, Kaiser et al. noted how the prophet delicately posed his request for payment for his services, saying in effect: “If you don’t care to pay me, fine; don’t bother!” Zechariah apparently assumed that because of the bad feelings between them (Zechariah 11:8), they would refuse to pay him. But they paid him the “princely” sum of thirty pieces of silver! Zechariah understood this to be an insult, so at the Lord’s direction, he threw the thirty pieces of silver into the house of the Lord, “to the potter.”

Leon Morris said the Syriac rendition of “Throw it to the Potter” in Zechariah 11:13 is translated as “Throw it into the Treasury.” Kaiser et al. noted where “to cast it to the potter” was an idiomatic expression meaning “Throw it to the dogs” or “Get rid of it.” They concluded it would be an unlikely meaning here because of its connection to the house of the Lord. But if the amount was negligible, as some commentators have suggested, then for Zechariah to accept it would have dishonored his role as their shepherd.

Consistent with this understanding, “thirty shekels of silver” was the price set for compensation for a slave that was gored by an ox (Exodus 21:32).  The value Israel placed on Zechariah’s services was akin to that of gored slave. Consider also that Zechariah was enacting the annulment of the relationship between the flock (Israel) and their Shepherd (ruler). Here is the connection Matthew makes with the passage in Zechariah. The transaction was symbolic of the flock’s rejection of their future messianic Shepherd-King, Jesus (Zechariah 11:4-14).

Leon Morris said in his commentary on Matthew that whichever way we understand the message of Zechariah to his readers, Matthew is saying the money used to pay Judas was in accord with the words of the prophecy. In Zechariah, thirty pieces of silver was the amount paid to annul Israel’s relationship with its symbolic Shepherd. In Matthew the same amount was given for Judas to betray Jesus, who is the true Shepherd.

Whichever reading we accept and however we understand the message of Zechariah to his readers, Matthew is saying that the use of the money paid to Judas took place in accordance with the words of the prophecy; the purpose of God was not overthrown in the deeds that Zechariah was recording, and it was not overthrown in the actions of Judas and the Sanhedrin that disposed of his bribe money.

A further connection exists with “the potter” and “the treasury” in Matthew. After his betrayal of Jesus, Judas returned to the Sanhedrin and tried to undo his actions by saying he had betrayed innocent blood (Matthew 27:4). This was an attempt by Judas to get them to reconsider their handing over of Jesus to the Romans for possible execution. Would their acceptance of Judas returning the money they paid him have been an acknowledgment they also accepted his opinion that Jesus was innocent of what he was accused of?

Judas seems to have betrayed Jesus in an ill-fated attempt to precipitate events he believed would reveal Jesus to be the Messiah and ultimately lead them to Jewish independence. It quickly became evident that Jesus would not use any of his powers to deliver himself from his enemies. “So it was quite clear that what Judas had done led inexorably to the condemnation of Jesus.” He didn’t understand what Jesus meant when he said he was not of this world (John 8:23).

Judas’s confession was not enough for the Sanhedrin to change their course. So Judas threw down the money given to him and went and hanged himself (Matthew 27:5). The chief priests and elders then debated the lawfulness of placing the money into the temple’s treasury. Ironically, it would have been from the temple treasury that they took the thirty pieces of silver originally. Where it was no crime to use money from the temple treasury to bring about a death, it was apparently wrong to return that same money to the treasury (Matthew 27:6). John Calvin commented that they were hypocritically attending to nothing more than the outward appearance.

If it was unlawful to put into the sacred treasury the price of blood, why was it lawful for them to take the money out of it? For all their wealth was derived from the offerings of the temple, and from no other source did they take what they now scruple to mingle again with it as being polluted. Now, whence came the pollution but from themselves?

Their decision was to buy a field—a potter’s field—that would serve as a burial place for strangers. It is more likely these ‘strangers’ were Jews from other lands who died in Jerusalem, rather than people who did not attempt to live according to the law who were from other lands. So we come around again to the application of the prophecy in Zechariah to the Matthew passage.

The Jewish leaders willfully rejected Jesus as their true Shepherd just as they had rejected Zechariah as their symbolic Shepherd. The cost to them to get rid of Jesus was the same as that for severing their relationship with Zechariah—thirty pieces of silver. They willingly paid the price both times, but were woefully ignorant of the true cost of their actions. What was but a symbolic rejection of the flock’s shepherd-king in Zechariah 11:4-14, became a prophecy of how they would eventually throw their messianic Shepherd-King to the dogs.

07/22/16

The Not-So-Golden Years

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© lisafx | stockfresh.com

Dr. Stephen Barnes wrote a thoughtful article on the so-called golden years of adulthood. In case you’re wondering when (or if) you reach said span of time, he said it begins with retirement and ends with the beginning of “age-imposed physical, emotional, and cognitive limitations; roughly between the ages of 65 and 80+. This can be a time of self-fulfillment, with many positive outcomes related to aging. Of course there are some variables to consider: do you have good physical and psychological health; do you have adequate financial resources; do you now have fewer family and career responsibilities.  If you do, then there are opportunities for “self-fulfillment, purposeful engagement, and completion.” However, there is another perspective on the golden years for us to consider—that of Dr Seuss:

The Golden Years have come at last.

I cannot see.

I cannot pee.

I cannot chew.

I cannot screw.

My memory shrinks.

My hearing stinks.

No sense of smell.

I look like hell.

My body is drooping.

I have trouble pooping.

The Golden Years have come at last.

The Golden Years … can kiss my ass.

There was a study done by Gray et al. published in JAMA Internal Medicine for March of 2015 that caught some media attention. It looked at the cumulative use of anticholinergics and dementia. This class of drugs blocks a neurotransmitter called acetylcholine (ACh), which is found throughout the body. Dr. Sandra Steingard noted: “It is involved in gut motility, visual acuity, heart rate, and secretions. In the brain, its activity is linked to memory and movements.” There are a wide variety of drugs with an anticholinergic effect, from antihistamines like Chlor-Trimeton, Unisom (diphenhydramine), Vistaril and Benedryl to antidepressants like Paxil, antipsychotics like Seroquel and Zyprexa, and even Detrol (oxybutinin).

Anticholinergics often cause dry mouth, constipation, rapid pulse, urinary retention, blurred vision and impaired memory. Notice how they correspond to four of Seuss’ complaints. Dr. Steingard also commented on the Gray et al. study and said there were two major findings of the study. “The first is that total exposure to anticholinergic drugs increases the risk of developing dementia. But of further concern, these effects were seen even if the drugs had been stopped years before the onset of dementia.” The study found a dose response risk for developing dementia—a greater exposure to anticholinergics meant a greater risk.

Steingard thought the study was carefully done. Her one complaint was it didn’t have a very complete list of anticholinergic drugs. She provided a link to a chart on AgingBrainCare.org with a more complete listing. As a psychiatrist, she thought the study had particular implications for psychiatry since many psychiatric drugs have anticholinergic effects. Several antipsychotics were in the most severe category.

Many people are now being exposed to psychiatric drugs at very young ages, and are taking them for many years. “We need to use these drugs with caution. Dose matters. Length of time a person is on them matters. Polypharmacy matters.”

The Gray et al. study concluded that there was an increased risk for dementia in people with higher use of anticholinergics. The findings suggested that someone taking even one such drug for more than three years “would have a greater risk for dementia.”

Prescribers should be aware of this potential association when considering anticholinergics for their older patients and should consider alternatives when possible. For conditions with no therapeutic alternatives, prescribers should use the lowest effective dose and discontinue therapy if ineffective. These findings also have public health implications for the education of older adults about potential safety risks because some anticholinergics are available as over-the-counter products. Given the devastating consequences of dementia, informing older adults about this potentially modifiable risk would allow them to choose alternative products and collaborate with their health care professionals to minimize overall anticholinergic use.

Another area of concern within the so-called golden years is substance abuse. Ironically, the initial step into the golden years via retirement is seen as a contributing factor into senior substance abuse. Paul Gaita, writing for The Fix, indicated several aspects of retirement could lead to greater drug and alcohol use among seniors. The circumstances leading to retirement as well as the economic and social nature of retirement are two possible features. A substance abuse counselor added: “In retirement, there can be depression, divorce, death of a spouse, moving from a big residence into a small residence.”

There are issues of loneliness, anxiety and boredom to consider. Then there is the reality of the increased likelihood of medical issues and the death of family or friends who are older. And don’t forget changes in body metabolism. The liver slows down as does kidney filtration. Both of these factors lead to alcohol and drugs staying active in the body for longer periods of time. Then there are medical issues like menopause, limited mobility, sleeping problems and chronic pain.

SAMHSA publishes a free volume in its Treatment Improvement Protocol (TIP) Series entitled: “Substance Abuse Among Older Adults” (TIP 26). It contains chapters on alcohol use and abuse, prescription and over-the-counter drug use and abuse, referral and treatment approaches, as well as appendixes of assessment tools. Here I will highlight the Executive Summary and chapter 1, “Substance Abuse Among Older Adults: An Invisible Epidemic.”

TIP 26 also noted that physiological change and changes in kinds of responsibilities and activities pursued are factors in substance abuse with older adults. Individuals 65 and over consume more prescribed and over-the-counter medications than any other age group in the U.S. Concerns with benzodiazepine use and sleep aides were noted. Limited use of both drug classes was given. Antihistimines and anticholinergics were highlighted as well.

Older persons appear to be more susceptible to adverse anticholinergic effects from antihistamines and are at increased risk for orthostatic hypotension and central nervous system depression or confusion. In addition, antihistamines and alcohol potentiate one another, further exacerbating the above conditions as well as any problems with balance. Because tolerance also develops within days or weeks, (bold the remaining) the Panel recommends that older persons who live alone do not take antihistamines.

Substance misuse among adults 60 an older is one of the fastest growing health problems in the country. Yet the situations is underestimated, underidentified and undertreated. “Until relatively recently, alcohol and prescription drug misuse, which affects up to 17 percent of older adults, was not discussed in either the substance abuse or the gerontological literature.” Diagnosis or identification can be difficult because symptoms of substance abuse in older adults will sometimes mimic symptoms of other medical and behavioral concerns such as diabetes, dementia and depression. Adding to this issue is that drug trials of new medications rarely include older adults. So even recognizing the presence of adverse drug reactions with older adults often doesn’t happen until enough adverse events accumulate after the drugs have been approved.

Alcohol abuse can accelerate the normal decline of physiological functioning that happens with aging. There is also the probability of an increased risk of injury, illness and socioeconomic decline. Increased benzodiazepine use with older adults also causes problems. The BMJ indicated that the mass of evidence suggested the benefits of benzodiazepines in older adults rarely outweigh their risks.

Benzodiazepine risks, whether short-term or chronic, include cognitive impairment, delirium, respiratory insufficiency, falls, fall-related injuries such as hip fractures, motor vehicle crashes, and death. Most patients are not warned of these risks before starting these medications. The main risk factor for chronic benzodiazepine use is any previous use, so an intended short-duration prescription of these habit-forming medication is likely to lead to their long-term use. Chronic benzodiazepine users are rarely prompted to discontinue, despite good evidence for the safety and tolerability of tapering protocols.

Ageism also contributes to the problem. “There is an unspoken but pervasive assumption that it’s not worth treating older adults for substance use disorders.” Behaviors that are seen as problematic in younger adults may not inspire the same urgency for treatment with older adults. Also, there can be an attitude that treatment for this population is a waste of health care resources. Attitudes like these are callous and based on misperceptions. For example, most older adults live independently. Only 4.6% of adults over 65 are in nursing homes or personal care facilities.

The reality is that misuse and abuse of alcohol and other drugs take a greater toll on affected older adults than on younger adults. In addition to the psychosocial issues that are unique to older adults, aging also ushers in biomedical changes that influence the effects that alcohol and drugs have on the body.

Health care and social service providers working with older Americans will mainly encounter abuse or misuse of alcohol or prescribed drugs. Although a smaller population, illicit drug users over 60 are increasing. This trend is at least partly due to aging baby boomer whose rates of illicit drug use have historically been higher than previous generations. The following chart from a NIDA report tracks past month use of illicit drugs among adults aged 50 to 64.

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Here is a more intimate and personal look at this issue. Patrick O’Neil, described coping with his 79 year-old mother’s recovery from hip surgery in “I Can’t Watch My Mom Detox.” Incidently, her HMO had been heavily prescribing Vicodin for seven years. Before the surgery. The medical team is considering detoxing her from her dependency on hydrocordone WHILE she’s recuperating from her hip surgery “for her own good.”

A doctor I’ve never met takes me aside and explains the process, how the patient will appear to be suffering but it’s for her own good.

I look at her skeptically. “So you’re going to detox my mom in the middle of her recovering from one of her most painful surgeries ever, because you’re having a knee-jerk reaction to your HMO being at fault for keeping her addicted?”

“It’s a little more complicated than that,” replies the doctor.

“Well, try and explain it then,” I say. “Because it looks exactly like that to me.”

O’Neil is himself a recovering heroin addict and author of his own journey through addiction in Gun, Needle, Spoon. So he really understands what his mother is going through. He suggests they not attempt a detox until after she’s healed from her surgery. It seems they finally agreed.

When I was growing up, my mom never had an obvious substance abuse problem. Even though her father was an alcoholic and addiction is thought to be hereditary, she never exhibited any outright addictive behaviors. And until recently, she hadn’t displayed the sort of desire to overmedicate that I had. Only with age, her retiring, my stepfather dying and close friends passing, she’d lost interest in life. These days she sits at home, alone. Her health, having never been great, is deteriorating even more. When her knee went out, she had it replaced and the doctor prescribed Vicodin. And suddenly, the same monster that lives in me was awakened in my mom and she took to them like they were the solution to all her problems.

“The Golden Years have come at last. The Golden Years … can kiss my ass.”

07/19/16

The Tale of the OxyContin Lie

© Jaroslaw Kilian | 123rf..com

© Jaroslaw Kilian | 123rf..com

To tell the tale of OxyContin, we should start with the Sackler family, named by Forbes Magazine as the 16th richest family in the U.S. for 2015 with an estimated net worth of $14 billion dollars. The Sacklers own 100% of Purdue Pharma, which generated more than $3 billion in sales for 2015, most of which came from OxyContin.  Separate Sackler-owned companies outside the U.S. with a similar product profile were said to generate as much money in sales to Europe, Canada, Asia and Latin America. In 2007 Purdue Pharma paid $600 million to settle charges it misbranded OxyContin as safer and less addictive than it actually was. Currently, Purdue faces a civil lawsuit in Kentucky with the potential to exceed $1 billion in damages. But I am getting ahead of the story. It all begins with the traditional American success story of an immigrant family who came to America in the early 20th century.

Isaac Sackler immigrated from what is now the Ukraine and Sophie Sackler came from Poland. They ran a grocery in Brooklyn and had three sons: Arthur (1913-1987), Mortimer (1916-2010) and Raymond (1920-). All three brothers became psychiatrists. Arthur Sackler was said by the New Yorker to be the “founder” of modern pharmaceutical advertising. His thinking inspired the marketing strategy that would be applied to Oxycontin after his death. The brothers bought a small drug manufacturer in 1952 that would eventually become Purdue Pharma, L.P.

Purdue Pharma initially sold products like laxatives and earwax remover. Then in 1972, the Contin® controlled drug-release system was developed. In 1987, MS Contin®, a controlled release morphine formula was launched. In 1991 Purdue Pharma L.P. was formed, with a focus on pain management. It currently manufactures pain medicines containing hydromorphone, oxycodone, fentanyl, codeine and hydrocodone. In 1993 Purdue established Partners Against Pain® to help alleviate unnecessary suffering of chronic pain care through education. Then in 1996, Purdue launched OxyContin®. In 2010 the reformulated version of OxyContin® was launched. In 2010 the company launched the Butrans® Transdermal system, a buprenorphine-based pain reliever. In 2012 it launched the Intermezzo® sublingual tablet. In 2015 Purdue launched Hysingla® ER, extended release hydrocodone tablets. Also in 2015, Purdue launched TeamAgainstOpioidAbuse.com.

The Contin® controlled drug-release system was marketed as having the potential to minimize or stymie abuse concerns with oxycodone by spreading the drugs effects over 12 hours. Before OxyContin®, oxycodone had only been used for pain relief with cancer patients. “Not long after OxyContin’s launch in 1995, primary-care doctors were prescribing it for an array of painful symptoms.” Mortimer Sackler’s obituary in the New York Times said that by 2001, sales of OxyContin had reached almost $3 billion and accounted for 80% of the Purdue Pharma revenue.

But OxyContin wasn’t as abuse-resistant as it claimed. Reporting for Forbes, Alex Morrell described how the pills could be crushed and the time release mechanism neutralized. Then the drug could be snorted (or dissolved in water and injected) for a heroin-like high. I’ve thought for years that the FDA should have a panel of opioid addicts review every newly proposed abuse-resistant pain medication to brainstorm about possible ways to work around the abuse-resistant technology. The company finally reformulated OxyContin in 2010, which has been speculated by some as contributing to the migration of prescription opioid users to the cheaper and more used heroin.

In 2007 Purdue Pharma, its president, top lawyer and former chief medical officer pleaded guilty to misleading the public about the drug’s risk of addiction. They agreed to pay a total of $635 million in fines. CNBC reported the plea agreement came two days after Purdue agreed to pay $19.5 million to 26 states and the District of Columbia to settle complaints the company had encouraged physicians to overprescribe OxyContin. The state of Kentucky launched an independent lawsuit against Purdue in 2007 alleging false marketing, which is just now coming before a judge. It has the potential for over $1 billion in damages.

Purdue learned from focus groups with physicians in 1995 that doctors were worried about the abuse potential of OxyContin. The company then gave false information to its sales representatives that the drug had less potential for addiction and abuse than other painkillers, the U.S. attorney said.

The LA Times did an investigation of Purdue Pharma and OxyContin and just recently printed their findings. They began by pointing out Purdue Pharma made a bold claim with OxyContin—that it would relieve pain for 12 hours, “more than twice as long as generic medications.” But it seems that for many people, the drug does not last that long and that Purdue knew it. “Even before OxyContin went on the market, clinical trials showed many patients weren’t getting 12 hours of relief.” Since the launch in 1996, Purdue was confronted with additional evidence from a variety of sources, including complaints from doctors, independent research and even reports from its own sales reps.

But Purdue persisted in its claim that OxyContin provided 12-hours of pain relief. It’s high price and huge market was based on this claim. “Without that, it offers little advantage over less expensive painkillers.” When doctors began prescribing OxyContin at shorter intervals than 12 hours, Purdue sent out sales reps to “refocus” doctors on 12-hour dosing. They suggested the doctors prescribe stronger doses, not more frequent ones. But this has the potential to increase the possibility of overdose and death.

Over the last 20 years, more than 7 million Americans have abused OxyContin, according to the federal government’s National Survey on Drug Use and Health. The drug is widely blamed for setting off the nation’s prescription opioid epidemic, which has claimed more than 190,000 lives from overdoses involving OxyContin and other painkillers since 1999.

The LA Times reviewed internal Purdue documents in its investigation spanning three decades, from the conception of OxyContin in the mid-1980s to 2011. The documents painted a clear picture of the development and marketing of OxyContin, how Purdue responded to the complaints about its product, “and their fears about the financial impact of any departure from 12-hour dosing.” Experts said the withdrawal symptoms from OxyContin’s less than 12-hours pain relief, followed by the next 12-hour dose created a cycle of pain and euphoria that fostered addiction. Theodore Cicero, a neuropharmacologist, and researcher into how opioids effect the brain, said this was “the perfect recipe for addiction.”

Now let’s return to the late 1980s. The patent for MS Contin, Purdue’s main source of income, was running out. Executives expected a significant drop in income when the patent ran out. A 1990 memo read: “MS Contin may eventually face such serious generic competition that other controlled-release opioids must be considered.” So they decided to use the Contin technology on oxycodone. Over the next ten years, the company put over $40 million into developing OxyContin.

Multiple clinical trials indicated that OxyContin wasn’t giving 12-hour pain relief. “In study after study, many patients given OxyContin every 12 hours would ask for more medication before their next scheduled dose.” This even happened in the study ultimately used by Purdue to get OxyContin approved as a 12-hour pain relief drug. The official who led the FDA’s review of OxyContin left the agency shortly after the drug’s approval. Within two years, he was working for Purdue in new product development.

Before Oxcontin, doctors were hesitant to prescribe narcotic painkillers, seeing them as dangerously addictive. Through organizations like Partners Against Pain doctors were re-educated to “alleviate the unnecessary suffering of chronic pain.” Before the drug’s debut, the minutes of a 1995 meeting indicated a Purdue marketing executive said: “We do not want to niche OxyContin just for cancer pain.” Sales reps urged doctors to try OxyContin with common conditions like backaches and knee pain. “The company invited doctors to dinner seminars and flew them to weekend junkets at resort hotels, where they were encouraged to prescribe OxyContin and promote it to colleagues back home.”

Then came the 2007 lawsuits. Curiously, in all the inquiries into Purdue and OxyContin, the short acting problem was not looked at. Purdue drug reps reported that doctors said the drug didn’t last and many were prescribing it for use three or four times a day. Company officials worried that if OxyContin wasn’t seen as a 12-hour drug, hospitals and insurance companies would resist paying its premium price. So they trained sales reps to convince doctors OxyContin provided 12-hour pain relief. “Purdue held closed-door meetings to retrain its sales force on the importance of 12-hour dosing, according to training documents.”

If a doctor complained that OxyContin didn’t last, Purdue reps were to recommend increasing the strength of the dose rather than the frequency. There is no ceiling on the amount of OxyContin a patient can be prescribed, sales reps were to remind doctors, according to the presentation and other training materials.

There’s more to see in the LA Times article, but you get the sense of the issue. Purdue Pharma responded to the LA Times report, saying it was “long on anecdotes and short on facts.” And it was based on a “long-discredited theory.” They said scientific evidence amassed over more than 20 years supports the FDA’s approval of 12-hour dosing for OxyContin. “The OxyContin label has been updated more than 30 times and at no point did FDA request a change to the dosing frequency.” By the way the medication guide for OxyContin says: “Take your prescribed dose every 12 hours at the same time every day. Do not take more than your prescribed dose in 12 hours. If you miss a dose, take your next dose at your usual time.”

None of the Sackler family has ever been charged in the litigation against Purdue. These days, the family is not involved in the day-to-day running of the company. Throughout their history they have been philanthropic, with donations resulting in the Sackler Library at Oxford University; the Sackler Faculty of Medicine in Tel Aviv, Israel; the Sackler Institute of Biomedical Science at New York University; and the Sackler School of Graduate Biomedical Sciences at Tufts University. But the Sacklers may not be able to be as generous if they lose a major chunk of their $14 billion fortune. A Kentucky judge has ordered the unsealing of secret documents about the marketing of OxyContin in June of 2016, according to STAT.  But that’s a tale for another time.

07/15/16

Vengeance Belongs to God

© Jovanche Vitanovski | 123rf.com

© Jovanche Vitanovski | 123rf.com

The Islamic State (ISIS) is reigning destruction on archeological treasures they deem to be sacrilegious. In 2014, they destroyed what was said to be the tomb of Jonah. The tomb itself was inside a Sunni mosque, the Mosque of the Prophet Yunis (Jonah). The site has some religious significance to Christians and Moslems. Jonah is considered to be a prophet by Christianity, Islam and Judaism. A witness to the destruction of the mosque and tomb said: “They first stopped people from praying in it, they fixed explosive charges around and inside it and then blew it up in front of a large gathering of people.” The site was even said to have once held the remains of the whale that swallowed Jonah. Well, at least one of its teeth.

You can see a video of the explosion in an article by NPR. Towards the end of the short video, you can hear a man saying in Arabic, “No, no, no. Prophet Jonah is gone. God, these scoundrels.” The militants kept locals away from the mosque and closed the roads up to 500 meters away from the shrine while they rigged the shrine with explosives. The destruction was said to be even drawing criticism from Sunni allies of ISIS. Reporting for NPR, Leila Fadel said: “It may cause a deep rift in the uneasy alliances the Sunni extremist group has made with other Sunni fighting groups.”

The mosque is in the town of Mosul, Iraq’s second-largest city. And if you are wondering why a tomb alleged to be that of Jonah would be in Mosul, you should know that Mosul is also near the site of Nineveh, the ancient capital of the Assyrian Empire. “Now the word of the Lord came to Jonah the son of Amittai, saying, ‘Arise, go to Nineveh, that great city, and call out against it, for their evil has come up before me” (Jonah 1:1-2).

The story of the Prophet Yunis in Islam is different than the story familiar to Christians and Jews from the book of Jonah. What follows is from the website Islam 101. The Prophet Yunis, has two additional surnames: “Dhun-Nun” (Lord of the Fish) and Sahibil-Hot” (Companion of the Fish). After he became a prophet, he was sent to Nineveh to preach the true faith of God. But its people were arrogant and conceited; they led sinful lives. Although he tried his best to reform them, they turned a deaf ear to his advice and warnings. He became disgusted, flew into a rage, and invoked Allah’s wrath on the people of Nineveh.

Without waiting for further instructions from Allah, he left Nineveh. He went to the sea and took passage on a boat, and like the biblical story the boat was caught in a storm. The sailors, holding him responsible for their misfortune, wanted to throw Prophet Yunis into the sea, but the passengers initially opposed their plan. Instead they drew lots, and the name of Prophet Yunis came out. So then he was thrown into the sea for the safety of the boat and swallowed by a great fish.

Now in extreme distress, Yunis realized he was suffering because of his dereliction of duty as a prophet. He repented and supplicated himself to Allah. His repentance was accepted and he was delivered ashore. There he was provided the shelter of a spreading plant. When he had regained his health, he was commanded to go back to Nineveh and fulfill his mission. This time the people of Nineveh repented and followed their prophet. And the result was they had a new lease on life.

Gradually the people of Nineveh again adopted evil ways of life. They indulged in idol-worship and debauchery.  Eventually they were destroyed by the Scythians. The Prophet Yunus (peace be upon him) died in Nineveh and was buried there. According to the story of some of the historians his tomb is in the village Halmol about ten miles away from Hebron.

The above-mentioned alternate site for the Tomb of Yunis is near Hebron, in the modern West Bank. According to Stephen Vicchio in Biblical Figures in the Islamic Faith, it is part of a site known as “The Cave of the Patriarchs.” See Genesis 25:9. In Islam, Ibrahim (Abraham) purchased the land, “and a number of biblical prophets are said to be buried there.”  There is still yet another site proposed as the tomb of the Prophet Yunis in el Mesched, a few miles north of Nazareth. Mesched is the ancient site of Gath-Hepher, said to be the birthplace of Jonah. Contemporary Judaism and Christianity hold to Gath-Hepher as the birthplace for Jonah/Yunis.

So why destroy a tomb and mosque revered as the burial site of one of Islam’s prophets? An Assyrian temple, a Christian monastery and a church once stood on the site before the mosque was erected during the time of the Muslim conquest in the middle of the first millennium. There is a long history of Christian tradition in Iraq. According to church tradition, Christianity was introduced to the region now called Iraq by the apostles Thomas and Thaddeus.

The Monastery of Mar Behnam , founded in the 4th century, about 20 miles away from Mosul, was destroyed by ISIS on March 19, 2015. Joel Baden and Candida Moss, both religion professors, reported in their blog for CNN that ISIS refused to let the monks take any of their relics or manuscripts, some which dated back over 1,400 years. They said despite its antiquity and rich tradition, Christianity in Iraq is on the brink of extinction.

The heirs to those who first discovered the tomb of Jonah, and those who helped to keep Greek philosophy alive in the medieval period, are being ejected from their homes and from a land they have held sacred for centuries. This is the face and reality of Christian persecution.

But Mark Movsesian, writing for First Things, had a different take. He said that to see why ISIS destroyed the tomb, you have to understand something about the version of Islam it holds to. “ISIS is part of the Salafi movement, a branch of Sunni Islam that seeks to return to the practices of the earliest Muslims—the salaf—who lived at the time of the Prophet Mohammed and just after.”  They reject the subsequent developments in Islam since that time as ‘pagan’ innovations that adulterated the faith. They oppose the veneration of the graves of Islamic prophets, which is most frequently associated with Sufi Islam.

So Movesesian believes we should see ISIS’s destruction of the tomb of Jonah as an attack at directed at other Muslims, not Christians. But ISIS hasn’t stopped there. In April of 2016 it was confirmed by National Geographic that ISIS had destroyed the Mashki and Adad Gates at the ancient site of Nineveh. You can see pictures of the reconstructed Adad Gate, now destroyed, here. The extremism of ISIS has led to the formation of a coalition of Muslim nations to fight against terror done in the name of Islam.

In addition to Saudi Arabia, the coalition will include Jordan, the United Arab Emirates, Pakistan, Bahrain, Bangladesh, Benin, Turkey, Chad, Togo, Tunisia, Djibouti, Senegal, Sudan, Sierra Leone, Somalia, Gabon, Guinea, the Palestinians, Comoros, Qatar, Cote d’Ivoire, Kuwait, Lebanon, Libya, Maldives, Mali, Malaysia, Egypt, Morocco, Mauritania, Niger, Nigeria and Yemen.

When reading about this growing opposition to ISIS and their tactics among its geographic and religious neighbors, I was struck by parallels between ISIS and Assyria. Like Assyria, ISIS has incurred the wrath of not only of the people they conquered, but other nations as well. Reflections made by the historian Simon Anglim about Assyria could easily be applied to ISIS: “Though the Assyrians and their army were respected and feared, they were most of all hated.”  When the region of the over-extended Assyrian Empire began to rebel, their struggles were not just for freedom, but for revenge.

Assyria practiced what could be called a cultural ‘scorched earth’ policy of relocating the political and cultural elites of the lands they conquered. As we described above, ISIS has systematically practiced a similar cultural policy in the areas they control. Ironically, despite their bloodthirsty empire-building practices, the ancient Assyrians are well known today for the grandeur of their capital city, Nineveh—the remains of which ISIS is systematically destroying.

In 612 BCE Nineveh was sacked and burned by a coalition of nations. We haven’t yet seen the destruction of ISIS, but the political storm clouds of its doom do seem to be forming. Looking beyond the book of Jonah in the Bible to that of another prophet, Nahum, we find a judgment oracle against Nineveh that can be easily applied to ISIS.

Nineveh is mentioned in other passages of the Bible besides the book of Jonah. In fact, the entire book of Nahum is a prophetic judgment of the impending fall of Nineveh. Biblical scholars with a high view of Scripture date the writing of Nahum to just before the fall of Nineveh in 612 BCE. The striking parallels between the fall of Nineveh and Nahum’s prophecy have led some to conclude the book to have been written after its destruction. In his commentary on Nahum, Kenneth Barker said: “History soon played out the threats Nahum so vigorously offered.” Consider how these passages might apply to the future of ISIS and the peoples it has conquered:

Thus says the Lord, “Though they are at full strength and many, they will be cutdown and pass away. Though I have afflicted you, I will afflict you no more. And now I will break his yoke from off you and will burst your bonds apart.” (Nahum 1:12-13)

Behold, I am against you, declares the Lord of hosts, and I will burn your chariots in smoke, and the sword shall devour your young lions. I will cut off your prey from the earth, and the voice of your messengers shall no longer be heard. (Nahum 2:13)

But there is a two-edged message for us in Nahum when applying it to the modern situation with ISIS. God calls us to care for the needy of the world and work to correct oppression. We ARE CALLED to the humanitarian aide required as a consequence of their actions, even taking in refugees. While we can easily point the finger of guilt at ISIS, as Nahum did with Nineveh, God calls us to an additional perspective. Vengeance is best left in the hands of God. There cannot be ‘an eye-for-an-eye’ response to the atrocities of ISIS. In his concluding paragraph, Barker said:

Those who read the Book of Nahum should not miss the point that God cares for the weak and needy of the world and is working in history to correct oppression. Let us make sure that we recognize God’s work and seek to correct oppression and participate in the work of God in his world. For us who read the Book of Nahum today, a strong message comes through. We can easily stand with Nahum and point the finger of guilt at our enemies. We quickly volunteer for God’s army, hardly able to wait for his call to battle against the hated enemy. God calls us to another listening post as we read Nahum. He calls us to stand with the court of the king of Nineveh and listen to God’s description of who we are in his sight. He calls us to take off our battle uniforms and watch God at work. “We must never forget that the whole Book of Nahum is a celebration of divine, not human, action. Nahum leaves vengeance in the hands of God.”

07/12/16

Common Sense with Lithium

© Suljo | stockfresh.com

© Suljo | stockfresh.com

Lithium carbonate (not the element lithium) is used as a psychiatric medication primarily with bipolar disorder. It can be used with other psychiatric disorders such as major depression and schizophrenia, when first line medications are not effective. There are several advantages to lithium, particularly when it comes to cost. Available as a generic medication, a typical daily dose costs between 90 cents and $1.20. Major downsides are that therapeutic doses are just lower than toxic doses and there is the potential of direct damage to the kidneys and thyroid.

The website drugs.com said that since the toxic levels for lithium are so close to the therapeutic levels, patients and their families should watch for early symptoms, then discontinue the drug and inform the physician should they occur. Indications of lithium toxicity may include: diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination. There are a host of other potential side effects that include: confusion, dry mouth, muscle twitching or trembling, vertigo, increased urination, memory problems and weight gain. These are only a few of the side effects found in 10% or more of the persons using lithium. See drugs.com or the Wikipedia listing for a more detailed discussion of lithium side effects.

In the late 1800s lithium was a popular ingredient in elixirs and tonics. It was even added to beer and other beverages. The theory was that it dissolved uric acid, so it could break up kidney stones and the uric acid crystals associated with gout. It was found to have no such effects. Lithium was eventually banned by the FDA in 1949 when it was found to cause cardiovascular problems.

Coincidentally, that same year an Australian physician named John Cade published a paper describing his treatment of 10 patients with mania with lithium. Cade had noticed that lithium made guinea pigs docile, so he thought it could have a therapeutic effect in manic patients. He announced dramatic effects in his paper and claimed they were specific to mania. What he failed to mention was that one patient died, two others had to discontinue lithium because of severe toxicity and one patient refused to take it. None of this was reported in his paper. Side effects were noted 41 times in the clinical records, but only 1 time in the published article. See The Myth of the Chemical Cure by Joanna Moncrieff for a more detailed description of lithium as a psychiatric treatment.

In Anatomy of an Epidemic, Robert Whitaker noted that psychiatrists in the U.S. had little interest in lithium until manic-depression was distinguished into unipolar and bipolar forms. Only a few placebo-controlled trials of lithium had ever been done up to that point. In 1985 UK researchers could only identify four with any merit. But within those studies, lithium was said to have a good response rate in 75% of the patients. This was much higher than the response rate in the placebo group.

A 1994 meta-analysis of nineteen studies by J.P. Baker of patients who were on lithium and had their lithium withdrawn showed that 53.7% of the patients relapsed, versus 37.5% of the lithium-maintained patients. This was seen as clear evidence that lithium prevented relapse. However, only 29% of patients who were gradually withdrawn from lithium relapsed. Note how this rate was better than those in the drug-maintained group.

Whitaker said this wasn’t very robust evidence of lithium’s benefit to patients, especially when you considered the additional studies raising concerns about lithium’s long-term effects. There was also a high rate of patients who stopped taking lithium—over 50%—because of how the drug dulled their minds and slowed their physical movements. In 1999 Baldessarini et al. found that almost half of all patients relapsed within five months of quitting lithium, while individuals who did not use lithium took nearly three years to reach that percentage of relapse. “The time between episodes following lithium withdrawal was seven times shorter than it was naturally.” Whitaker noted:

Although lithium is still in use today, it lost its place as a first-line therapy once “mood stabilizers” were brought to market in the late 1990s.

Now there has been a growing body of evidence that suggests lithium prevents suicide. In 2003 Baldessarini and others found that long-term lithium maintenance patients had lower suicide rates than individuals who did not. Cipriani et al. found lithium was an effective treatment for reducing the risk of suicide in people with mood disorders as well as bipolar disorder. Lewitzka et al. did a comprehensive review of more than 20 years of studies investigating the anti-suicide effect of lithium in patients with affective disorders. They also concluded lithium to be “an effective treatment for reducing the risk of suicide and suicide attempts in patients with affective disorders over the long-term course.”

Joanna Moncrieff reviewed several meta-analyses indicating the anti-suicide effects of lithium in The Myth of the Chemical Cure and said the studies included in these analyses had conflicting results. An article on her website, “Lithium and Suicide: What Does the Evidence Show?” said the proposed effect of decreased mortality rates was inexplicable since lithium was a toxic drug that made most people feel rather depressed. She wondered if the sedating effect of the lithium sapped people of the will to act. “A closer look at the evidence, however, suggests the idea [lithium reducing suicidality] is simply not justified.”

The first issue was that the evidence supporting this idea consisted of follow-up studies with individuals on long-term lithium, as with Copper et al. Moncrieff commented how these people are a particularly compliant group with medication. “People who follow their lithium regime religiously are, in general, not likely to be the people who are chaotic, impulsive, desperate and most likely to commit suicide.” One study, by Gonzalez-Pinto et al., showed that people who were highly compliant with their lithium were five times less likely than those who were ‘poorly compliant’ to commit suicide. A second issue was that given small margin of error between therapeutic and toxic doses of lithium, people with suicidality tendencies are less likely to be given lithium.

Another confounding issue is that people with medical conditions are less likely to be given lithium. Not only can lithium cause kidney and thyroid problems, but it interacts with many commonly prescribed drugs like diuretics, ACE inhibitors and NSAIDS like aspirin and ibuprofen. This can result in dangerously high lithium levels. So caution is used when starting lithium with someone who is physically sick or taking other medication. Moncrieff said better randomized controlled trials are needed.

She thought it curious that a meta-analysis by Cipriani et al. in 2013 did not include a single placebo-controlled trial where the suicide rate was zero, so she looked more closely at its methology. Moncrieff discovered that the authors excluded any trial whose treatment arm was uninformative, namely those whose suicide rates were zero. “This decision is totally unsound, however, as it reduces the denominator (the total number of participants) and thereby makes the events included appear more common than they actually were.” She speculated this was why some well-known studies were not included in the analysis of suicides. When the studies with no suicides were included, “the number of participants would have been much larger and the proportion of suicides in the placebo group much smaller.”

 So there is the evidence on lithium and suicide. The meta-analysis that has been accepted as demonstrating that lithium prevents suicide spuriously inflated the suicide rate on placebo by excluding studies in which no suicides occurred. The only double blind, prospective study designed to test whether lithium reduces suicide in people at high risk, ended up unblinding many of its participants, and in any case suicidal events were low in both groups.

The fact that studies of suicide prevention have been so difficult to recruit to, suggests patients may have more sense than researchers in this field!

07/8/16

Another Empty Promise

© wavebreak_media | stockfresh.com

© wavebreak_media | stockfresh.com

I’ve been following the news on the development of a buprenorphine implant for the medication-assisted treatment (MAT) of opioid dependence.  An early January 2016 article on The Fix related that a new drug, Probuphine, was scheduled for FDA review on January 12, 2016. Braeburn Pharmaceuticals and Titan Pharmaceuticals jointly developed and brought Probuphine to market. A week later an advisory committee of the FDA recommended approval of the implant by a 12 to 5 vote. The President and CEO of Braeburn Pharmaceuticals was quoted as saying their vision is to “bring change to this underserved population.” But the jury is still out on whether or not that change will ultimately help or harm individuals with opioid use disorders.

Not surprisingly, on May 26, 2016, the FDA announced the approval of Probuphine as the first buprenorphine implant. The main benefit touted seems to be that it provides another way to use buprenorphine. Nora Volkow, director of the National Institute on Drug Abuse was quoted as saying: “This product will expand the treatment alternatives available to people suffering from an opioid use disorder.” FDA Commissioner Robert Califf said: “Today’s approval provides the first-ever implantable option to support patients’ efforts to maintain treatment as part of their overall recovery program.” Is it just me, or do those endorsements seem to be a bit lukewarm?

The first thing to know is that Probuphine was reviewed by the FDA in 2013, and despite recommendations by an advisory committee for approval, it was not approved at that time. The FDA said it needed additional data supporting the efficacy of Probuphine. The executive chairman for Titan Pharmaceuticals said they were “extremely surprised and disappointed” at the action of the FDA. One of the issues then was “human factors testing of the training associated with Probuphine’s insertion and removal.” In other words, 23% of Probuphine patients had implant site adverse events, compared to only 13.5% of the placebo control group. Another concern seems to have been that the Probuphine dose was too low for the kind of patients who were being tested.

Another report on the initial clinical trials indicated that only 8% of patients were opioid-free throughout the treatment, also suggesting the dosage wasn’t adequate. And 25% of the Probuphine-treated patients failed to provide as few as four opioid-negative urine samples over the course of six months. Continued use of illicit substances was not defined as “treatment failure” in the trial, but needing additional buprenorphine beyond preset amounts was. “Overall, 35 percent of the Probuphine patients and 72 percent of the placebo patients in the controlled trials did not complete the six-month treatment course.” Writing for FierceBiotech, John Carroll noted similar concerns—expressed by FDA staffers BEFORE the advisory committee voted to approve Probuphine in 2013.

While the placebo group had even more discouraging results, supporting the conclusion that Probuphine does have an effect on drug use, overall, the response was not what one might hope for, given that the product ensures compliance with medication for six months. It prompts speculation that the dose is simply not high enough. … Potentially, Probuphine could deliver just enough buprenorphine to allow patients to continue to use illicit opioids without experiencing withdrawal when they stop.

A total of 40% to 62% of Probuphine-treated patients needed supplemental buprenorphine; another 11-12% needed supplemental buprenorphine even after receiving a fifth implant. Ironically, one of the voiced advantages for the implant was that the pill and film forms of buprenorphine wouldn’t be accessible to children. The trial was also too small to fully access the safety risks with inserting the implants. Plus there were unanswered questions regarding what happens if addicts never get the implants removed; or how long treatment would continue with the implants; or what happens to patients when they stop treatment.  So why did the 2013 advisory committee vote to approve Probuphine with all of these concerns? Carroll provided a link to the full staff review in his article.

The January 12, 2016 FDA report on Probuphine is available here. The trial was revised at the recommendation of the Psychiatric and Drugs Advisory Committee as a treatment for patients stabilized on sublingual buprenorphine at doses of 8 mg or less. The efficacy results demonstrated that the Probuphine-treated patients met the selected margin criteria for non-inferiority. In this study Probuphine was compared to sublingual burprenorphine instead of a placebo. The rationale was that it was inappropriate to expose stable patients to the risk of relapse with a placebo-controlled trial. The non-inferiority margin was the smallest acceptable decrease in effect from that of sublingual buprenorphine. However, the responder rate used in determining the results used a number of assumptions about missing data; and it assumed that using supplemental buprenorphine did not indicate an inadequacy of treatment.

When analyzed under different assumptions, the response rates are lower than reported by the Applicant, and also differ from the expected response rate used to calculate the non-inferiority margin. Therefore, under some sets of assumptions, one might question whether enough of the effect size has been maintained to conclude efficacy of Probuphine. Moreover, because Probuphine ensures compliance, one would expect a clearer demonstration of superiority over sublingual buprenorphine than was demonstrated in this trial.

There were also issues with the data on urine samples. The sampling schedule was less frequent than is customary for efficacy studies. The rationale was that since the population was of stabilized patients, more frequent urine testing could lead to patients dropping out. Only ten samples per patient were to be collected. Nevertheless, 12% in each group missed visits and thus missed giving a urine sample. And 22% (25% in the Probuphine group and 18% in the sublingual buprenorphine group) were missing data from one or more samples because of sampling handling issues.

So even though Probuphine was approved, there doesn’t seem to be an indication that it was clearly superior to sublingual buprenorphine as an opioid maintenance drug. And there are concerns noted within the FDA announcement of its approval. The boxed warning within the medication guide cautions that the insertion and removal of Probuphine can be associated with the risk of implant migration, expulsion and nerve damage. There were additional concerns mentioned by the FDA.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

The cost for the implant will be between $1,000 and $1,500 per month, significantly more than the cost of sublingual buprenorphine products. STAT quoted Dr. Carl Sullivan, the director of addiction services as West Virginia University Medicine, as saying: I just don’t see how this is going to help fight the opioid epidemic at all.” Dr. Sarah Wakeman, the medical director for substance use disorders at Massachusetts General Hospital said: “I’d probably still err on the side of prescribing it that way [by tablet or film].”

Some critics don’t think the implant is needed or ready for release. Diana Zuckerman, president of the National Center for Health Research, a nonprofit think tank, said: “We don’t need another product on the market that’s not been tested very well to see how safe it is and how effective it is.” Titan Pharmaceuticals has been trying to get Probuphine approved for over six years, and the voiced concerns about it from abstinence-based recovery go back as far.

In October of 2010, JAMA published an article by Ling et al., “Buprenorphine Implants for Treatment of Opioid Dependence.”  Although the study was 24 weeks long, the primary outcome measure was for negative urine samples for illicit opioids during the first 16 weeks of the trial. The rationale for this shortened period was said to because “of the interest in examining early-treatment response in the context of this longer-term treatment.” My question is what were the results of the urine tests for the final 8 weeks, and would they negatively effected the outcome results? The study concluded that: “Among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples.”

So it’s not clear that Probuphine has a greater treatment efficacy than sublingual buprenorphine. There are concerns with adverse effects related to the insertion and removal of the implant. There also seems to be a potential for accidental or intentional misuse of the implant, which contains “a significant amount” of a drug that the FDA Advisory Committee report for January 2016 acknowledged is a growing product on the illicit drug market.

Unfortunately, despite these features, buprenorphine sublingual products have been increasingly identified in the illicit drug market, and it is known that they are diverted, abused, and misused. Additionally, they have been implicated in a number of cases of accidental poisonings of small children. Therefore, a depot injection or an implantable product which would be difficult to divert or abuse, and would be less likely to be accidentally ingested by small children, offers potential advantages. In addition, if a depot or implantable product provided a sufficient plasma level of buprenorphine to block the effects of exogenous opioids, the nature of the product would enforce compliance so that patients could not periodically discontinue use to allow the blocking effect to dissipate in order to experience the effects of their opioids of choice.

The clinical trials used to approve Probuphine used sublingual buprenorphine to supplement its dose for some individuals, which neutralizes the rationale of it being less likely for small children to ingest buprenorphine. Adding a benzodiazepine to Probuphine would be a quick work-around for anyone looking to “experience the effects of their opioids of choice.” Trying to remove an implant for the high may seem to be a highly unlikely event. Yet I’ve heard of individuals who would lick or chew fentanyl patches and others who would crush and shoot Suboxone tablets despite the alleged abuse deterrent of it containing naloxone. I even read of one individual who faked a terminal illness to get hospice care for the pain meds.

It won’t take long for stories of removing the implant to get high or sell the drug it contains to emerge. The temptation will be too great for some individuals. Screening for appropriate Probuphine patients will be crucial, but the existing failure to prevent illicit sublingual buprenorphine abuse doesn’t encourage me that will work. And was the question of what happens to patients after implant treatment ever answered? What about people who drop out of treatment after receiving the implant? Probuphine is more likely to become a profitable drug for Titan and Braeburn than it is to bring change to the underserved population of opioid addicts. It seems to be just another empty promise to help the still-suffering addict for financial gain.

07/5/16

Digging Deeper

© bowie 15 | 123rf.com

© bowie 15 | 123rf.com

The trial of Galileo has been used to illustrate the assumed conflict between science and religion for the last four hundred years. But there is a false dichotomy here. It’s really not about science versus religion. Francis Bacon, an early scientist and Christian said: “Let no woman or man, out of conceit or laziness, think or believe that anyone can search too far or be too well informed in the Book of God’s Works or the Book of God’s Words.” Galileo himself said: “The glory and greatness of Almighty God are marvelously discerned in all His works and divinely read in the open book of Heaven.” God reveals His glory and greatness in the Book of His Works just as He does within the Book of His Word.

For many years, Galileo pointed his telescope at the heavens and demonstrated that Jupiter had moons, Venus had phases, and the moon had mountains, among other astronomical discoveries. He became convinced from his observations that the sun-centered theory of Nicholaus Copernicus was correct. But in 1616, the Inquisition declared heliocentrism to be heretical, and Galileo was ordered to refrain from holding, teaching or defending such ideas. He was able to hold his tongue until 1632, when he published Dialogue Concerning the Two World Systems. He almost got away with it, as he had cleverly woven his arguments into a fictional dialogue between three individuals. This hypothetical discussion had been permitted by the Inquisition. His mistake was putting a concluding argument used by the pope in the mouth of the character named Simplico. You don’t need to know Italian to guess what that name means.

Galileo’s enemies were able to convince Pope Urban that if the statement came from Simplicio, Galileo had intended to make fun of it and Urban himself. Ironically, church censors had directed Galileo to include the argument in the book as a standard papal argument against heliocentrism. This led to Galileo’s trial for heresy on June 22, 1633. Under the threat of torture, imprisonment and even being burned at the stake, he was forced to renounce his belief “that the sun, not Earth, was the center of the universe and that Earth moved around the sun and not vice versa, as ecclesiastical teaching dictated.” It wasn’t until October 31, 2009 that the Vatican formally corrected the record with a “not guilty” finding.

To be fair, it seems Galileo could be arrogant at times, and it might be that enemies he made from his sharp tongue were responsible for his coming before the Inquisition. Here is one example of his acerbicness from a letter he wrote to the German astronomer Johannes Kepler in 1610, six years before heliocentrism was first declared to be heresy. He complained to Kepler, that some philosophers had refused to even look through his telescope to see for themselves what he had discovered about the heavens.

My dear Kepler, I wish that we might laugh at the remarkable stupidity of the common herd. What do you have to say about the principal philosophers of this academy who are filled with the stubbornness of an asp and do not want to look at either the planets, the moon or the telescope, even though I have freely and deliberately offered them the opportunity a thousand times? Truly, just as the asp stops its ears, so do these philosophers shut their eyes to the light of truth.

Today, among Christians that false dichotomy is not between astronomy and the Bible, but with evolution and the Bible. Some Christians affirm what is called a “creation science” understanding of the Bible. They hold that God “created the world quickly and completely through dramatic, miraculous interventions.” According to Denis Lamoureux, an evolutionary creationist (yes there can be bible-believing Christians who believe in evolution):

The greatest problem with young earth creation is that it completely contradicts every modern scientific discipline that investigates the origins of the universe and life. There are very few scientists working in the disciplines of cosmology, geology, and biology who accept this anti-evolutionary position. (Lamoureux, I Love Jesus & I Accept Evolution, p. 22).

Creation science holds to a hermeneutic for determining the age of the earth that was influenced by Anglican bishop James Ussher. He based his chronological calculations on the questionable assumption that the genealogical lists in Genesis (5:1-4; 11:10-32) and other passages of Scripture described a literal, unbroken succession. Assuming there to be no gaps in the generations, he calculated the exact date of creation to be Sunday, October 23, 4004 BC. Deborah and Loren Haarsema noted that even if the genealogies had gaps, the date of creation wouldn’t be more than 8 or 10 thousand years ago.

In order to explain the acceptance of evolution by modern science, creation scientists like Henry Morris say Satan blinds the minds of hundreds of thousands of scientists. This would include many Christians who accept evolution as God’s method of creation, setting the stage for uncharitable exchanges and even division in the church. In an article titled “Strong Delusion,” Henry Morris marveled that the pseudo-scientific evolutionary worldview, which he said was not based on any real scientific evidence, could be believed so passionately. He wondered how those who believe in evolution can be won to Christ “when their minds have been blinded by Satan and are under such strong delusion that they have become sincerely committed to the false worldview of evolution?”

The Two Books idea, the Book of God’s work in nature, and the Book of God’s Words in Scripture is where Christians can go for help in resolving this dilemma. Deborah and Loren Haarsma, the authors of the book Origins, have put together a series of short videos on topics discussed at length in their book. Session 2, “Origins: It’s Not About Science versus Scripture,” tackles this issue and even includes Galileo in their discussion. Since God is the Author of revelation in nature and Scripture, there is no conflict. “We trust that God would not tell one story in nature, and a contradictory story in Scripture.”

Even in the midst of difficult conflict, we trust that God is telling us one story. There is a harmony. And it gives us a strategy. When the two sides seem to conflict, we don’t simply throw out one and hold on to the other. Instead, we hold onto both sides and dig deeper to test our human interpretations. . . . By listening to both nature and Scripture, we gain a fuller understanding of God’s story in creation.

Extracting the story of Galileo and his trial from history as “proof” of the war between science and religion is akin to proof texting with Biblical passages isolated from the whole of Scripture. The full story shows how science was able to clearly demonstrate the universe was not earth-centered. And we see that what occurred with Galileo was a misinterpretation of Scripture by the church. When Psalm 93:1 says: “The world is established; it shall never be moved”, it was using phenomenological language, and not affirming an earth-centered universe. “The conflict arises when we get one or both interpretations wrong.”

God tells us one story. He would not contradict himself by saying one thing in Scripture and another in nature. Creation science seems to hold on so tight to Scripture, that they willingly deny well-received scientific findings like the age of the earth and universe.

When there is apparent conflict, as seems to be occurring with Scripture and science over evolution, we need to hold onto both. We can’t jettison Scripture or its hard won doctrines for a dystelological version of evolution. And we can’t shoe horn scientific truth into—or between—the passages of Scripture. We have to hold on to and dig deeper into both.

In a post script, NASA’s Juno mission entered orbit around the planet Jupiter on July 4th and began a two year study of the planet. On board are three specially constructed LEGO figurines including one of Galileo, who discovered the four largest moons of Jupiter. When its mission is complete, Juno will take a suicide plunge into Jupiter’s atmosphere. NASA doesn’t want to take a chance of any rogue microbes on the spacecraft unintentionally contaminating Jupiter’s moons, especially Europa and Ganymede, which are believed to have oceans and the possibility of life.

07/1/16

Misleading Info on ADHD

© Ivelin | stockfresh.com

© Ivelin | stockfresh.com

Three Swedish researchers did a study on the information published online by the National Institute of Mental Health (NIMH) on ADHD. What is intriguing about their study is that they were looking at how the NIMH document sought to persuade its readers to take action to address their child’s ADHD problem. They suggested there was a circular argument wherein ADHD was defined according to the presence of certain behaviors, which the diagnostic label of ADHD was said to explain. They also pointed out how ADHD is presented as legitimate medical disorder, despite the fact that “diagnostic criteria are subjectively interpreted from the behavior of the child.”

The authors, Erlandsson, Lundun and Punzi, linked this Easy-to-Read NIMH document on ADHD in their study. However, their citations appear to be from this NIMH document, “What is Attention Deficit Hyperactivity Disorder (ADHD, ADD)?” They noted where the image of ADHD as a legitimate medical disorder was established by the first sentence of the article, “ADHD is one of the most common childhood disorders [and can continue through adolescence and adulthood].” This is word-for-word in the latter article, where the Easy-to-Read one is slightly different: “ADHD is a common mental disorder that begins in childhood and can continue through adolescence and adulthood.” The bracketed phrase was not quoted by Erlandsson, Lundun and Punzi, possibly because they were looking at ADHD in children; or when they examined the document in October of 2015, it wasn’t there.

Erlandsson et al. noted how the repeated use of the term “disorder” (at least 15 times) and a number of references to brain imaging and brain chemicals gave the impression of a chronic, long-term disability.  The rhetoric is clearly suggestive that ADHD is a brain disorder. And yet, because symptoms vary from person to person, the ‘disorder’ can be difficult to diagnose. The so-called ‘key behaviors of ADHD’ are also found in all children—inattention, hyperactivity, and impulsivity. “But for children with ADHD, these behaviors are more severe and occur more often.” They have to be present for at least six months, and be present to a degree “that is greater than other children of the same age.” Erlandsson et al. said:

In fact, as shown in the document, there are no biological markers, environmentally defined categories, or objective tests to distinguish “ADHD” as a discrete condition. Rather, diagnostic criteria are subjectively interpreted from the behavior of the child: “No single test can diagnose a child having ADHD. Instead, a licensed health professional needs to gather information about the child, and his or her behavior and environment.” Professionals as well as teachers and parents are involved in the evaluation and examination process, and subsequently in the diagnostic process.

There is a clear bias in presenting ADHD as a biomedical problem. While saying scientists aren’t sure what causes ADHD, NIMH then said many studies suggest genes play a large role. Twin studies show ADHD runs in families. “Children with ADHD who carry a particular version of a certain gene have thinner brain tissue in the areas of the brain associated with attention.” But the differences were not permanent and as the children with this gene grew up, the brain developed to a normal level of thickness and the ADHD symptoms improved. As Erlandsson et al. commented: “The biomedical discourse assumes that there is a consensus among professionals on how to interpret the behaviors of the child, which means that pharmacological treatment is the preferred intervention.” But this is not the case.

In “ADHD: an Imbalance of Fire over Water or a Case of the Fidgets?” I reviewed several different sources questioning whether ADHD was a biochemical disorder. Psychiatrist Peter Breggin said the search for a genetic and biological cause for ADHD would never succeed because the researchers are looking in the wrong place. Neurologist Fred Baughman said:

 Despite regular pronouncements that its biologic roots have been discovered, no proof of a definite physical or chemical abnormality is ever found. All such research and all such claims … have been a sham, meant to create illusions of science and disease while proving nothing.

The NIMH material also did not mention there was a lack of consensus on the safety of using medication to treat children. Rather, medication is said to be a safe treatment:  “Under medical supervision, stimulant medications are considered safe.” The potential for substance abuse or dependence is downplayed, saying: “there is little evidence of this.” ADHD stimulants are classified as Schedule II controlled substances, which have “a high potential for abuse, with use potentially leading to severe psychological or physical dependence.” See “ADHD: an Imbalance of Fire over Water or a Case of the Fidgets?” for more information on ADHD medications and addiction.

The consequences of a biomedical view of ADHD were addressed in a recent study by the CDC of ADHD treatment among children between 2 and 5 years of age. While the American Academy of Pediatrics and other organizations recommend behavior therapy ahead of stimulant medication for children under 5, only 53% of children had received behavior therapy in the year prior to the survey, while 47% had received stimulant medication during the previous week.  Between 75% and 78.5% of children aged 2-5 with ADHD received one or more ADHD medications.

ADHD is a highly prevalent condition that can lead to poor health and social outcomes. Despite 2007 and 2011 guidelines recommending behavior therapy as first-line treatment for children aged <6 years with ADHD, during 2008–2014 only about half of children aged 2–5 years with ADHD received psychological services. To effectively mitigate impairments associated with ADHD and minimize risks associated with ADHD medications, it is important to increase the percentage of young children with ADHD who receive evidence-based psychological services, especially parent training in behavior therapy.

Around 30% of children aged 3-5 experienced adverse effects from ADHD medications. The most common ones were appetite suppression and sleep problems. But other commonly reported side effects were: abdominal pain, emotional outbursts, irritability, lack of alertness, repetitive behaviors and thoughts, social withdrawal, and irritability when the medication wears off. In one large study, of methylphenidate (Ritalin or Concerta) over 10% of children 3-5 had to stop treatment because of adverse effects. They were also 20% lower for height and 55% lower for weight. Anne Schuchat, the CDC’s Principle Deputy Director, said:

We are still learning about potential side effects of long-term use of ADHD medicine on young children. Until we know more, the recommendation is to refer parents for training in behavior therapy for children under 6 years of age with ADHD.

We recognize that these are not easy treatment decisions for parents to make. We know that behavior therapy is effective, and the skills they learn through behavior therapy can help the whole family be successful. Building these skills in parents and children both empowers families and helps young children with ADHD live up to their full potential.

An article in The Washington Post, “CDC Warns that Americans May Be Overmedicating Youngest Children with ADHD,” addressed this concern as well. The long-term effects of the drugs of choice for treating ADHD, Adderall and Ritalin, were not well studied. An estimated 2 million of the 6 million children diagnosed with ADHD were so labeled between the ages of 2 and 5. While ADHD medications don’t work for everyone, in many cases they take effect almost immediately. In contrast, behavior therapy can take several months to have an impact. However, it can be long lasting; and has no side effects.