11/20/18

Kratom Ping-Pong

A 25 year-old man was driving to work on the Pennsylvania Turnpike in Chester County PA on June 27, 2018 when his car veered into the right lane, struck a curb and flipped over. The West Chester County coroner ruled he died of “acute mitragynine intoxication.” With the exception of the equivalent amount of caffeine in a cup of coffee, there were no other drugs in his system. A Montgomery County Pennsylvania woman died in May of 2018 from multiple drug intoxication. She had cocaine, heroin, fentanyl and mitragynine (kratom) in her system.

According to The Inquirer in “Deaths from kratom,” there have been at least four kratom-related overdose deaths reported in the Philadelphia area since 2016. Two of those deaths in Chester County occurred in 2018 and listed kratom as the sole cause of death. The website OverdoseFreePA, which tracks overdose fatalities, reported there have been 27 deaths in 2017 where kratom was present. NMS Labs, a nationally known forensic lab in Willow Grove PA, reported that from January to June in 2018 they found kratom in the postmortem toxicology cases of 303 deaths. Often the kratom was in combination with other opioids.

Kratom activists and the federal government have been playing “scheduling ping-pong” since August of 2016 when the DEA announced its intention to temporarily schedule kratom as a Schedule I controlled substance. Public and political outcry at this proposed action resulted in the DEA reversing itself, saying it would await the FDA’s “scientific and medical evaluation” of the proposed scheduling. Since then the FDA has released information on the adverse events when using kratom and its opioid properties. The agency took actions to address a multistate salmonella outbreak related to kratom. And there were FDA reports on kratom-related deaths. See: “Kratom Regulation Is Coming,” “Kratom: Part of the Problem or a Solution?” and “What Is the Future of Kratom?” on this website.

Then in May of 2018 the FDA announced it was warning three marketers and distributers of kratom products for illegally selling unapproved kratom products with unproven claims the products could treat opioid addiction and withdrawal. “The companies also make claims about treating pain, as well as other medical conditions like lowering blood pressure, treating cancer and reducing neuron damage caused by strokes.” The FDA Commissioner Scott Gottlieb said the agency had determined kratom is an opioid analogue that “may actually contribute to the opioid epidemic and puts patients at risk of serious side effects.” He added the FDA was open to review data on the benefits of kratom through its new drug approval process. “In the meantime, I promised earlier this year that the FDA would step up our actions against unapproved and unsafe products that are being deceptively marketed for the treatment of opioid addiction and withdrawal symptoms.”

The FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse and dependence. There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom.

Similar to the days of patent medicines, the companies receiving the warning letters said kratom could be used to lower blood pressure, relieve pain, boost a person’s metabolism, increase their sexual energy, improve the immune system, prevent diabetes, ease anxiety, eliminate stress, and help you get a good night’s sleep.

At the beginning of September of 2018 the FDA sent warning letters to two additional companies selling kratom because of their illegal claims that kratom treats or cures opioid addiction and withdrawal. The two companies receiving FDA warning letters, Mitra Distributing and Chillin Mix Kratom, were reported by MarketWatch to be selling kratom at cheap wholesale prices. The FDA letters indicate both companies claimed their kratom products could be used to “treat or cure” opioid addiction and withdrawal symptoms. The FDA warning letters also cited specific examples from the company websites they reviewed, including the following:

“Kratom can render both mildly stimulating effects and mildly relaxing effects depending upon the measurement used. At smaller amounts, the effects tend to be slightly more stimulating; and at larger amounts, the effects tend to be more relaxing.”
“Some [kratom users] have reported an increase in focus, attentiveness, and social confidence resulting from the responsible use of kratom.”
“Due to the rise in opium costs and the discovery that kratom could relieve opium withdrawals, many users turned to kratom as a means to cure their addiction.”
“It has been long reported that kratom has been used to treat a myriad of ailments including but not limited to: diarrhea, depression, diabetes, obesity, high blood pressure, stomach parasites, diverticulitis, anxiety, alcoholism, and opiate withdrawal.”

Beginning in February of 2018 the FDA began an investigation into the link of several kratom-containing products contaminated with salmonella. “Interviews conducted by state and local health departments in coordination with the CDC found that a high proportion of the ill people reported recent consumption of kratom, either as capsules, powders or herbal remedies.” One of the three companies receiving warning letters from the FDA was also implicated in an FDA investigation of kratom products tainted with salmonella. This led to multiple recalls, with most marketers being cooperative. In one case, a marketer failed to conduct a voluntary recall and the FDA was forced to issue a first-ever mandatory recall order. On July 2, 2018 the agency announced the results of their investigation, saying it appears the salmonella problem has probably been occurring for some time, and was even still happening.

As of the end of May 2018, a total of 199 cases of salmonellosis in 41 states have been linked to kratom consumption; 38 percent of those illnesses led to hospitalizations. Fortunately, there have been no known deaths related to these illnesses. In addition to Salmonella I 4, [5],12:b:-, illnesses have been linked to Salmonella Heidelberg, Salmonella Javiana, Salmonella Okatie, Salmonella Thompson and Salmonella Weltevreden. A total of 81 samples of kratom were collected and tested as a direct result of the outbreak investigation, and 42 (52 percent) were found to be contaminated with salmonella. This means that users of these products had essentially a one in two chance of being exposed to this pathogen.

While kratom hasn’t been scheduled as a controlled substance yet, the DEA does list it as a “Drug of Concern.” At low doses, it produces stimulant effects like increased alertness, physical energy and talkativeness. At higher doses, it has sedative effects and can lead to addiction. “Several cases of psychosis resulting from use of kratom have been reported, where individuals addicted to kratom exhibited psychotic symptoms, including hallucinations, delusion, and confusion.”

Kratom’s effects on the body include nausea, itching, sweating, dry mouth, constipation, increased urination, tachycardia, vomiting, drowsiness, and loss of appetite. Users of kratom have also experienced anorexia, weight loss, insomnia, hepatotoxicity, seizure, and hallucinations.

At the end of July 2018 the National Institute of Drug Abuse (NIDA) released an official position on kratom that was quoted as saying: “Kratom by itself is not associated with fatal overdose.” The American Kratom Association said this clarified that it was “only when the natural ingredient is contaminated or “laced with other compounds” has it been associated with death.” The AKA then repeated its previous claim that the original data used by the FDA to warn the public about using kratom was tainted by “adulterated or contaminated kratom.” The president of the AKA said:

NIDA’s statement was consistent with these findings, and we call upon the two agencies to work together to remove the FDA’s scheduling recommendation for natural kratom and focus on protecting the rights of Americans who rely on it by removing adulterated and dangerous counterfeit products from the market.

But the AKA celebration was short-lived. According to The Washington Times, when NIDA was alerted to the AKA statement, it quickly edited the information cited by the AKA. For the FAQ, “Can a person overdose on kratom?” the website now reads: “There have been multiple reported deaths in people who had ingested kratom, but most have involved other substances.” An email inquiry to NIDA from The Washington Times said the AKA’s statement was inaccurate. “Currently, no Government agency views Kratom as a safe drug. Just because a drug is not routinely fatal does not mean it is safe.” In response to the revisions to the NIDA website, the AKA sent a letter to the NIDA director, claiming it bowed to political pressure from the FDA.

We are concerned that NIDA may be under pressure from purely political requests or demands being made by the FDA related to kratom that are not supported by the science, including research done by NIDA and its research contractors.

The science supporting adverse effects from kratom use and its scheduling as a controlled substance is not as weak or corrupted as the AKA claims. See discussions in the above linked articles on this website. It seems we might soon see the “kill shot” in the ping-pong match on kratom if the FDA recommends for the DEA to schedule it.

09/14/18

Machiavellian Drug Approval

photo by JoJan; Creative Commons Attribution 3.0 Unported license.

ProPublica noted that when the FDA’s responsibilities expanded in the 1970s, the review times for new drug approvals began to lag to more than 35 months on the average. The AIDS crisis came soon after, leading activists to accuse the FDA of holding back cures and then press the agency for faster drug approval times. One of the then activists, now an assistant professor of epidemiology at Yale, said they were desperate back then and naively thought there were drugs behind the FDA approval curtain being held back by its slow process. “Thirty years of our rash thinking has led us to a place where we know less and less about the drugs that we pay more and more for.”

The activists’ protests helped bring about the Prescription Drug User Fee Act in 1992, which began drug industry contributions to fund FDA salaries. In return, the FDA promised to speed up review times for drugs—within 12 months for normal applications, and 6 months for priority cases. You can probably guess what happened. The more the FDA relied upon industry fees to pay for drug reviews, the greater was its tendency towards approval. “The virginity was lost in ’92,” according to Jerry Avorn, who is a professor at Harvard Medical School. “Once you have that paying relationship, it creates a dynamic that’s not a healthy one.”

In 1993 Pharma funded 27% of the FDA’s scientific review budgets for branded and generic drugs. In 2017, that had increased to 75% or $905 million. Staffers know you don’t get promoted if you aren’t pro-industry. A former FDA medical team leader said: “You don’t survive as a senior official at the FDA unless you’re pro-industry.” He added the FDA has to pay attention to what Congress says, and the industry will lobby to replace you if they don’t like you. The attitude at the agency is: “Keep Congress off your back and make your life easier.”

The FDA’s Center for Drug Evaluation and Research gives internal awards annually to review teams. Former FDA employees said they never saw an award granted to a team that rejected a drug application. Congratulatory emails are sent to review teams by higher-up administrators when a drug is approved. “Nobody gets congratulated for turning a drug down, but you get seriously questioned.” FDA rejections of all drug applications have fallen over 50% since 2008. See the following graph from the above linked article in ProPublica.

Over the past thirty years Congress authorized the FDA to implement at least four major routes to faster approvals. Initially, these pathways were supposed to be the exception to the rule, but now they seem to have become the rule. In 1988 Congress authorized the FDA to create “fast track” regulations. In 1992 the Prescription Drug User Fee Act formalized “accelerated approval” and “priority review.” Then when the law was reauthorized in 1997, the goal for review times was lowered to ten months. Finally, in 2012, the designation of “breakthrough therapy” enabled the FDA to waive normal procedures for drugs “that showed substantial improvement over available treatments.”

Sixty-eight percent of novel drugs approved by the FDA between 2014 and 2016 qualified for one or more of these accelerated pathways, Kesselheim and his colleagues have found. Once described by Rachel Sherman, now FDA principal deputy commissioner, as a program for “knock your socks off, home run” treatments, the “breakthrough therapy” label was doled out to 28 percent of drugs approved from 2014 to 2016.

The industry’s lobbying group, Pharmaceutical Research and Manufacturers of America (PhRMA), is pressing for even faster approvals. A policy memo on its website warns of “needless delays in drug review and approval that lead to longer developmental times.” Aaron Kesselheim, an associate professor at Harvard Medical School said he thought it was reasonable to want to move drugs faster, particularly for “an extremely promising new product, which treats a serious or life-threatening disease.” When you do that, he said the key factor “is that you’ve got to make sure you closely follow the drug in a thoughtful way and unfortunately, too often we don’t do that in the U.S.” FDA approvals of novel drug applications have nearly doubled since 2008. See the following graph from the above linked article in ProPublica.

Nuplazid, a drug for hallucinations and delusions associated with Parkinson’s disease, was an example of the potential consequences from this accelerated approval process in Caroline Chen’s article for ProPublica. The drug was created in 2001 by a chemist at Acadia Pharmaceuticals. In 2009 it failed to prove its benefit over a placebo in the first of two Phase 3 clinical trials; two successful Phase 3 trials are required. The company halted the second trial and asked the FDA for permission to revise the scale used to measure benefit. They argued the original scale was typically used for schizophrenia assessments and thus wasn’t appropriate for Parkinson’s-related psychosis.

Given that Acadia didn’t raise this issue with the FDA until after its failed clinical trial, their objection seems like sour grapes to me. Why didn’t they use the revised scale from the beginning? Nevertheless, the FDA agreed to this new scale—even though it had never been used before in a study for drug approval! Then, since there were no treatments approved for Parkinson’s-related psychosis, the FDA granted Acadia’s request for break-through therapy status, meaning Nuplazid now only needed one positive Phase 3 clinical instead of two for approval. “In 2012, Acadia finally got the positive trial results it had hoped for. In a study of 199 patients, Nuplazid showed a small but statistically significant advantage over a placebo.”

An FDA medical reviewer was skeptical of Nuplazid. In analyzing all of the drug’s trial results, he calculated you would have to treat 91 patients to get seven who would receive the full benefit. Five of those 91 would suffer “serious adverse events,” including one death. He recommended against approval, citing “an unacceptably increased, drug-related, safety risk of mortality and serious morbidity.” So the FDA convened an advisory committee to help it decide. That committee eventually voted 12-2 to recommend accelerated approval.

Fifteen members of the public testified at its hearing. Three were physicians who were paid consultants for Acadia. Four worked with Parkinson’s advocacy organizations funded by Acadia. The company paid for the travel of three other witnesses who were relatives of Parkinson’s patients, and made videos shown to the committee of two other caregivers. Two speakers, the daughter and granddaughter of a woman who suffered from Parkinson’s, said they had no financial relationship with Acadia. However, the granddaughter is now a paid “brand ambassador” for Nuplazid. All begged the FDA to approve Nuplazid. . . . The only speaker who urged the FDA to reject the drug was a scientist at the National Center for Health Research who has never had any financial relationship with Acadia.

Since Nuplazid was approved in 2016, Acadia raised its price twice from the original base price of $24,000 to more than $33,000. “There have been 6,800 reports of adverse events for patients on the drug, including 887 deaths” as of March 31^st of 2018. In more than 400 instances Nuplazid was associated with worsening hallucinations—“one of the very symptoms it was supposed to treat.” After a CNN report about adverse events related to Nuplazid in April of 2018, the FDA began an evaluation. There are more examples of drugs-gone-bad after approval in the article.

Although the FDA expedites drug approvals, it will wait ten years or more for the post-marketing studies manufacturers agree to do when their drug is approved. Studies on Nuplazid aren’t expected until 2021. One of the reasons post-marketing studies take so long to complete is the fact it’s harder to recruit patients to risk being given a placebo when the drug is available on the market. In addition, the manufacturer no longer has a financial incentive to study its impact since the drug is on the market and could lose money if the results are negative. “Of post-marketing studies agreed to by manufacturers in 2009 and 2010, 20 percent had not started five years later, and another 25 percent were still ongoing.”

The FDA has the authority to issue fines or pull a drug from the market if a manufacturer doesn’t meet its post-marketing requirements. “Yet the agency has never fined a company for missing a deadline.” The agency would have the burden to show the company was dragging its feet, which could be difficult to prove. “It’d be an administrative thing that companies could contest,” according to the FDA director of the Center for Drug Evaluation and Research.

Michael Carome, the director of the health research group for Public Citizen, a nonprofit advocacy organization, said instead of a regulator and a regulated industry, we now have a partnership. “That relationship has tilted the agency away from a public health perspective to an industry friendly perspective.”

In “FDA’s revolving door,” Charles Piller pointed out how many former FDA employees end up working or consulting for the drug makers they previously regulated. There are safeguards that are supposed to prevent the prospect of industry employment from affecting an employee’s decisions while at the agency. And there are others to discourage them from exploiting relationships with former colleagues after they leave. But the reality seems to be somewhat different. Piller cited a 2016 BMJ article that found 15 of 26 FDA employees who had conducted reviews over a 9-year time period in the hematology oncology field later worked or consulted for the biopharmaceutical industry.

Science has discovered that 11 of 16 FDA medical examiners who worked on 28 drug approvals and then left the agency for new jobs are now employed by or consult for the companies they recently regulated. This can create at least the appearance of conflicts of interest.

The co-author of the 2016 BMJ study thought that weak federal restrictions and the expectation of future employment inevitably biases how FDA staffers conduct drug reviews. “When your No. 1 major employer after you leave your job is sitting across the table from you, you’re not going to be a hard-ass when you regulate. That’s just human nature.” No, that’s not human nature, it’s just plain Machiavellian behavior—whether you’re doing whatever it takes to get your drugs on the market or whether you’re trying to position yourself for a future job with Pharma as you regulate their drugs.

09/11/18

JUUL is Not a Gem

licensed under the Creative Commons Attribution-Share Alike 4.0 International license.

An eighteen-year-old waitress was admitted to a Pittsburgh intensive care unit with difficulty breathing, sudden stabbing pains in her chest and a worsening cough. Her condition continued to deteriorate even after the hospital put her on antibiotics. A doctor said: “She was unable to get enough oxygen into her blood from her lungs and required a mechanical ventilator (respirator) to breathe for her until her lungs recovered.” She needed to have fluid drained from her lungs and was diagnosed with hypersensitivity pneumontis, or “wet lung.” Her medical problem was attributed to a two or three week habit of vaping.

Her case study appeared in the medical journal Pediatrics and received local and national media attention. KDKA-TV, which was quoted above, and CNN are just two of the media outlets covering the story. The treating physician and lead author of the case study said chemicals in e-cigarettes led to lung damage and inflammation. “As electronic cigarette use increases, we will be seeing more case reports and side effects.” CNN reported that the 2016 National Youth Tobacco Survey reported that 1.7 million high school students said they had used e-cigarettes in the previous 30 days.

The specific e-cigarette product used by the teen was not mentioned in any of the articles. However, Time and CNBC noted that a product known as “JUUL” accounted for about 33% of the e-cigarette market as of late 2017. The JUUL Labs product has become so popular, that using it is now known as “juuling.” Like tobacco products, JUUL is legally available only for adults 18 and over. But JUUL devices are reported to be wildly popular with teens.

Ironically, the chief administrative officer for JUUL Labs said: “We really don’t want kids using our product.” He said two former smokers created JUUL to help adults quit smoking. However, each JUUL cartridge contains as much nicotine as a pack of cigarettes. The JUUL device fits in the palm of your hand, as illustrated in the above photo. A JUUL starter kit contains the device, four cartridges and a USB charger in order to charge it in a USB port. Time said:

Because of their sleek design and resemblance to USB drives, JUUL products are easy for students to conceal and use in school — sometimes even in the middle of class. (JUULs also produce less smoke than many similar devices, making them even more discreet.) The problem has grown widespread enough that school districts in states including Kentucky, Wisconsin, California and Massachusetts have voiced their concerns and, in some cases, begun amending school policy to address the issue. Some college publications, including those at New York University and the University of Illinois, have also reported on the trend.

In “What is Juul?” Truth Initiative noted that while JUUL Labs says JUUL is just for adults, it comes in flavors that have a proven appeal to young people. And many young people do not realize they are inhaling nicotine with e-cigarettes. A study published in the American Journal of Public Health found that 99% of all the e-cigarettes sold in 2015 contained nicotine. “Youth are more likely to try flavored e-cigarettes, and believe that they are less harmful than tobacco-flavored e-cigarettes.”

In 2015, 16 percent of high school students and 5.3 percent of middle school students used e-cigarettes, the most commonly used tobacco product among U.S. youth. This research provides further evidence that restrictions and warning labels for products containing nicotine are necessary to protect and inform youth.

Truth Initiative did a survey in April of 2018 to assess where teens are getting their hands on JUUL. The most common way was through a store or retail outlet. Another common source was from friends or family members; 52% received JUUL from a social source. Only 6% bought it online, yet “nearly all youth who tried to buy the product online were successful.” Truth Initiative and five other public health and medical groups filed suit in federal court in March of 2018 for the FDA to take action against JUUL.

On April 24, 2018, the FDA issued a statement from Commissioner Scott Gottlieb, who said the FDA “will not tolerate the sale of any tobacco products to youth.” They issued 40 warning letters to retailers known to have sold JUUL products to youth. They also sent an official request to JUUL Labs requiring the company to submit documents related to product marketing and whether certain product features, ingredients or specifications appeal to different age groups. “We don’t yet fully understand why these products are so popular among youth. But it’s imperative that we figure it out, and fast.”

Commissioner Gottlieb said the FDA was planning additional enforcement actions against companies they believed were marketing products in ways that were misleading to kids. These were just the first in a series of efforts within the FDA’s newly formed Youth Tobacco Prevention Plan. He hoped this sent a clear message to all tobacco product manufacturers and retailers. “If kids are flocking to your product or you’re illegally selling these products to kids, you’re on the agency’s radar.”

The youth-focused steps we’re taking are consistent with our responsibility to protect kids and significantly reduce tobacco-related disease and death, and I intend to do everything within my power to fulfill that duty.

Then on May 17, 2018 and again on June 21, 2018 the FDA sent out official requests to a total of six additional e-cigarette manufacturers requiring them to submit information like that requested of JUUL Labs to help the agency better understand the youth appeal to these products. The companies had until July 12, 2018 to respond to the FDA. The companies were selected based on product attributes that overlapped with those of JUUL. These attributes included the use of e-liquids with high nicotine concentration; a small size, making them easily concealable; and intuitive product design features for ease of use. Commissioner Gottlieb said:

Too many kids continue to experiment with e-cigarette and vaping products, putting them at risk for developing a lifelong nicotine addiction. These products should never be marketed to, sold to, or used by kids and it’s critical that we take aggressive steps to address the youth use of these products. This includes taking a hard look at whether certain design features and product marketing practices are fueling the youth use of such products.

A study published in PLOS One by Weaver et al. said ENDS (electronic nicotine delivery systems) were not helping adult smokers quit. The study randomly sampled 1,284 adult smokers in August/September of 2015 and re-contacted them one-year later. Adults who didn’t use ENDS were more likely to have quit smoking at the end of the study than those who has used ENDS at some point during the study. The researchers, Weaver et al., said:

We found no evidence that ENDS use, within context of the 2015–2016 US regulatory and tobacco/vaping market landscape, helped adult smokers quit at rates higher than smokers who did not use these products. Absent any meaningful changes, ENDS use among adult smokers is unlikely to be a sufficient solution to obtaining a meaningful increase in population quit rates.

The Wall Street Journal quoted the lead author of the study as saying, “These products have not been fulfilling the public health promise of helping people in the U.S. quit smoking.” He added that changes in design, marketing and regulation may help them become more effective as smoking cessation tools. The researchers speculated that older ENDS might be ineffective because they fall short of the “real world” of smoking. It other words, they don’t have a high enough nicotine content to tempt smokers to switch from cigarettes completely. Disturbingly, while this speculation is not yet supported by research, it could be used to present higher nicotine ENDS like JUUL as harm reduction tools, subtly changing the public health dialogue away from smoking cessation. “Any amount of smoking is harmful, and it’s really not benefiting them if they don’t quit entirely.”

The senior author of the study was alarmed with the large percentage of dual users noted at the end of the study. More than half of those who also vaped at the beginning of the study were still smoking a year later. And over half of those smokers were also vaping. The study also found that none of the flavors used in ENDS other than menthol or mint were associated with lower odds of quitting when compared to non-ENDS users. “We need to be much more consistent in our guidance to smokers about how to use these products and that they need to quit smoking and avoid dual use.”

NPR noted how San Francisco banned the sale candy-flavored e-cigarettes, “but a tobacco industry-funded campaign” forced a voter referendum on the ban. The measure, known as Prop E, was opposed by “No on Prop E,” which received its funding from R.J. Reynolds—“to the tune of nearly $12 million.” Some of their slogans included “bans don’t work” and “voting no preserves adult choice.” The referendum took place on June 5, 2018, wheere Prop E was soundly supported, with 68% voting “yes” on Prop E to ban candy-flavored e-cigarettes.

Surprisingly, on January 5, 2018, Philip Morris International announced its plan to stop selling cigarettes in Britain at an unspecified future date. The managing director of PML said: “We believe we have an important role to play in helping the U.K. become smoke-free.” Yet like other tobacco companies, Philip Morris has been developing alternatives to conventional cigarettes. The company currently sells a technology called iQOS in about 24 countries. “It heats tobacco without burning it, reducing levels of harmful chemicals found in cigarette smoke.”

Former Philip Morris employees and contractors told Reuters about “a number of irregularities” in the clinical trial studies submitted by the company in its application to the FDA for approval of its iQOS device. One principal investigator failed to get informed consent from participants, a basic procedure during clinical trials, and the experiment had to be excluded. A review of hundreds of pages of publically available study reports also uncovered “shortcomings in the training and professionalism of some of the lead investigators, as well as their knowledge of the study results.”

A group of tobacco research and policy experts reviewed detailed summaries of Reuters’ reporting and Philip Morris’ response. The experts, including a former head of the FDA and two former scientific advisers for the agency, said those findings raise concerns about Philip Morris’ clinical trial program.

The New York Times reported on January 25, 2018 that an advisory committee recommended the FDA reject the Philip Morris International application to market the iQOS as safer than traditional cigarettes by an eight-to-one vote. The committee rejected the company’s claim that “scientific studies have shown that switching completely from cigarettes to the IQOS system can reduce the risks of tobacco-related diseases.” Although the committee did agree the device would limit exposure to the harmful chemicals in conventional cigarettes, it expressed doubt smokers would completely switch to use only iQOS. Rather, many on the committee thought smokers could become long-term dual users of the device and cigarettes.

An FDA decision on IQOS had not been made public by the beginning of July. But Reuters noted that ten U.S. Senators sent a letter to FDA Commissioner Gottlieb in February of 2018 calling on the agency to reject the Philip Morris application to market the iQOS device as less risky than cigarettes. They encouraged the FDA to avoid rushing through new products like the iQOS “without requiring strong evidence that any such product will reduce the risk of disease, result in a large number of smokers quitting, and not increase youth tobacco use.” A thorough review of the application was “especially critical given the tobacco industry’s deceitful history of marketing products under the guise of lower risk.” So far, the company has spent more than $3 billion developing new smoking technologies like iQOS.

JUUL Labs just announced it will sell cartridges with 40% less nicotine beginning in August of 2018. Initially only mint and Virginia tobacco flavored JuulPods will be available in the lower nicotine cartridges. In October there will be a wider release. I wonder if they will offer their top selling fruity flavored cartridges in a lower nicotine option?

The Verge noted JUUL Labs carefully avoided saying whether the lower nicotine cartridge will eventually lead to no nicotine at all. The company describes its product as a “switching tool” to help adults stop smoking cigarettes. And a 40% reduction isn’t enough to make JUUL less addictive. An expert said nicotine levels would have to be cut by 85 to 95 percent to make cigarettes (and by implication JUULs) significantly less addictive. If the company goal is to get smokers to switch from cigarettes to JUUL, cartridges with low enough concentrations of nicotine to be less addictive and a real harm reduction technology are unlikely.

Public health efforts have drastically curtailed the use of tobacco and cigarettes over the past several decades. Cigarette use has become stigmatized. So companies like Philip Morris International and JUUL Labs are trying to position their new nicotine delivery systems as harm reduction devices. But they may be as bad for you as the tobacco products they seek to replace. JUUL and iQOS are not really public health gems.

08/24/18

Misleading Pharma Ads

Pfizer had a killer direct-to-consumer ad for its anti-cholesterol drug Lipitor in 2006-2008. Robert Jarvik, identified as the inventor of the artificial heart, turns to the camera and says, “Just because I’m a doctor doesn’t mean I don’t worry about my cholesterol.” After recommending that people use Lipitor, the commercial shows him rowing across a lake. While the ad cost Pfizer $260 million, it played fast and loose with several facts. Robert Jarvik had never been licensed as a medical doctor so he could not legally prescribe anything. He didn’t actually invent the artificial heart; and he didn’t even row the boat in the commercial. “Welcome to the world of direct-to-consumer advertising.”

Television direct-to-consumer (DTC) ads have become the most ubiquitous means of Pharma advertising. It is estimated that a person in the U.S. watching an average of 4.3 hours of broadcast television per day will see nine drugs ads, totaling around 30 hours of direct-to-consumer (DTC) ads each year. In 2017, spending on DTC ads in the U.S. reached $6.1 billion; a 4.6% decrease from 2016 ($6.4 billion).

The FDA has oversight of DTC ads by the pharmaceutical industry through the Food, Drug and Cosmetic Act of 1938. Congress approved the Act in an effort to protect the health and safety of U.S. citizens by regulating the food and medical supply. “The Act regulates the pharmaceutical industry to ensure the safety and efficacy of drug produced and sold in the United States, and it gives the FDA authority to carry out its legislative directives.” Amendments in 1962 by Congress to the Food, Drug and Cosmetic Act transferred the regulatory authority of prescription drug advertising from the Federal Trade Commission to the FDA. “With the addition of the 1962 amendments, the regulation of drugs became the most consuming, and at times the most controversial, aspect of all the FDA’s activities.”

As a result of these actions, drug companies are required to submit all their promotional materials to the FDA’s Office of Prescription Drug Promotion (OPDP). However, limitations on the capacity and resources of the OPDP mean it cannot review every single ad. Nevertheless, there was not a significant amount of DTC advertising even after the FDA made it possible in 1985.

The Food, Drug and Cosmetic Act has been traditionally understood by the FDA to restrict unapproved or “off-label” promotion use. FDA regulations explicitly prohibit DTC ads from even suggesting any off-label use. While print ads must state all of the risks in the drug’s FDA-approved label in a “brief summary,” broadcast DTC ads are only required to include the major risks, as long as those risks are verbally communicated and the ad provides a source for consumers to access the FDA-approved labeling for the drug.

In 1997, the Division of Drug Marketing, Advertising, and Communications (DDMAC), a sub-division of the Center for Drug Evaluation and Research (CDER), which is a division of the FDA, released guidelines which allow prescription drug manufacturers to comfortably satisfy the legal requirements for advertising their products to the general public. As a result, pharmaceutical companies have swelled their direct-to-consumer (DTC) marketing budgets and provided the advertising industry with a profitable new line of products to promote. Since the regulatory change was announced, name-brand prescription drug use in the United States has increased, drug prices have gone up, a debate over the effects, efficacy and wisdom of DTC ads has ensued, and scores of heath care issues that affect patients, doctors, insurers, and the federal government have risen to the surface.Despite the wide enforcement authority generally given to the FDA, the Act expressly prohibits any requirement that pharmaceutical companies submit drug advertising content for FDA pre-market approval (except in extraordinary circumstances). This provision, grounded in First Amendment doctrine, has led to a regulatory regime that can only offer a pre-market approval process and enforce compliance post-violation.

This protection of the pharmaceutical company’s right to speak has occasionally resulted in ads giving information that did not satisfy the Act’s requirement that all advertisements give a “fair balance” of the drug’s benefits and risks. Drug companies have also used this provision to challenge certain FDA restrictions on off-label marketing.”Recent federal court cases have permitted companies to promote off-label indications, thereby calling into question the FDA’s authority to regulate off-label marketing, even with respect to DTC advertising.”

“Adherence to FDA Guidelines in DTC Advertising” by Klara et al. noted where previous studies have found many Pharma companies do not follow the advertisement guidelines set forth by the FDA. They assessed the degree to which recently aired DTC ads (between January 2015 and July 2016) for prescription drugs adhered to FDA regulations and whether off-label use was suggested. They looked at both prescription and over-the-counter medications. Among the 67 ads with unique drug-indication combinations, the most commonly advertised conditions are noted in the following table.

Indication/Condition	DTC ads by number & (%)
Inflammatory conditions	12 (17.9%)
Diabetes	11 (16.4%)
Psychiatric/neurological	7 (10.4%)
Cardiovascular	7 (10.4%)
Bowel/bladder dysfunction	6 (9.0%)
Infections/allergic reaction	6 (9.0%)
Sexual dysfunction	4 (6.0%)
Lung	6 (9.0%)
Other	8 (12.0%)

More than ¾ of the ads were to treat chronic conditions; 18% were for intermediate conditions; and 6% were for acute conditions. Sixty percent referred to potential savings on or payment for the drug. And forty percent advertised drugs with black box warnings.

The median time spent describing drug risks was 45% of the ads, while the median time for other forms of communication, such as a description of the benefits or drug indication was 55%. The median number of risks mentioned was 16. Forty-two percent of ads used a different announcer for risk and benefit information. When all of the ads presented their risk information, there were distracting visuals like frequent scene changes or characters dancing or singing. Seventy-nine percent had running text on screen that was unrelated to the risks, like “See our ad in Weight Watchers.”

Our findings demonstrate that the quality of information in DTC television ads is low: none described drug risks quantitatively; only one-quarter described drug benefits quantitatively; and suggestions of off-label promotion were common for diabetes medications. Though proponents argue that DTC advertising is educational and empowering for consumers, our findings suggest that the information provided is unreliable and potentially misleading. The promotion of off-label indications, poor quality of information, distracting risk presentations, and the fact that risks are never quantified could distort the perception of benefit and risk information.Suggestions of off-label use, a practice that has been expressly prohibited in prescription drug DTC advertising, occurred in 13% of ads in our sample. All of these ads marketed drugs indicated for the treatment of type2 diabetes, and suggested potential benefits of use, including weight loss and blood pressure reduction.

Data were rarely provided to support the drug benefit claims, and the risks were never quantified. “Broadcast DTC advertising could lead patients to make healthcare decisions and request certain expensive, brand-name medications based on ads containing low-quality and incomplete information.” The researchers noted a suggestion that the FDA should review television commercials for prescription drugs before their release to ensure these ads are more informative for the public. They also suggested further study of the impact of off-label marketing by DTC ads on patient and prescriber decisions. “By enacting such a program and by enforcing more objective requirements for DTC advertisements, the FDA could better protect consumers.” Commenting on the above study for Mad in America, Shannon Peters said:

Patients deserve quality, comprehensive information about drug benefits and risks in order to provide informed consent and be truly empowered in their healthcare decisions. In their current form, most DTC advertisements are misleading rather than promoting informed consent.

The website Medical Marketing & Media provided data on DTC ad spending by pharmaceutical companies in 2017. There has been an overall increase of $2.6 billion yearly from 2012 to 2016. Broadcast TV spending for DTC in 2016 was $4.06 billion, with magazine spending ranking second with $1.7 billion. The top ten companies by U.S. DTC spending were: Pfizer ($1.2 billion); Bristol-Myers Squibb ($458.2 million); AbbVie ($433.3 million); Eli Lilly ($414.7 million); Allergen ($352.3 million); Johnson & Johnson ($292 million); Merck ($285.2 million); Novartis ($254.8 million); AstraZeneca ($226 million); and Novo Nordisk ($206.7 million).

Pfizer eventually cancelled its Lipitor ad campaign with Robert Jarvik after there was a Congressional outcry over false impressions in the ad. But the marketing misstep didn’t stop Lipitor or Pfizer. Lipitor became the world’s best-selling drug with more than $125 billion in sales over 14.5 years. Pfizer also didn’t lose faith in DTC, as it was number one in DTC spending in 2015 and 2016. But I bet they’ve been shrewder in how they marketed their drugs. You can watch the Jarvik Lipitor ad here.

06/19/18

Loperamide Regulations Tightened

licensed under Creative Commons; photo by Tom Murphy VII

Loperamide, an over-the-counter anti-diarrheal drug (Imodium A-D), is back in the news, as the blog by FDA Commissioner Scott Gottlieb warned of adverse effects from high doses. Loperamide is an opioid agonist (it activates the opioid receptors) that is safe when taken at approved doses. “But when loperamide is abused and taken at extremely high doses, some of it can cross the gut lining, giving users an opioid like ‘high.’” Sometimes people report using as much as 100 times the recommended dose of 2-8 mg daily. Reportedly, 50-300 mg of loperamide may produce euphoria.

We’re aware that those suffering from opioid addiction see loperamide as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects. But at these very high doses, it’s also dangerous. We’ve received reports of serious heart problems and deaths, particularly among people who intentionally misuse or abuse high doses.

The above warning, posted on May 9, 2018, referred back to a FDA Drug Safety Communication Update from January 30, 2018. It said the FDA was working with manufacturers to limit the number of doses of loperamide in their packages and revise OTC labeling to warn of the danger of serious heart problems associated with high doses. OTC loperamide is currently approved in packages of 8 to 200 tablets, which can be sold in multipack of more than 1,000 two mg capsules at a time. If the drug is taken as prescribed, that is more than a three-year supply of the drug. One of the FDA’s recommended packaging changes to discourage abuse was for manufacturers to use blister packs. “Evidence suggests that reasonable packaging limitations and unit-of-dose packaging may reduce medication overdose and death.”

There have been expressed concerns that packaging changes would drive up the cost. However the FDA does not expect the steps they’ve taken to have much, if any impact on cost, “given that loperamide is available as a generic drug and manufactured by a range of competitors.” Commissioner Gottlieb said the FDA would carefully evaluate the impact their actions could have on the cost of loperamide.

We’re currently evaluating the maximal package size appropriate for OTC use, and plan to take into account data manufacturers provide on consumer use and needs; current OTC labeling and indications; the dose-response relationship of loperamide to cardiac events and known adverse event data; and importantly, the feedback of patients who rely on this medicine.

Concerns with adverse effects and abuse with loperamide have been appearing for a few years. In 2012, there was a web-based study of extra-medical use of loperamide. The intent of the researchers, Daniulaityte et al., was to collect user-generated content on one such website to assess emerging drug use practices and trends with loperamide. The first post on the website that mentioned loperamide appeared in 2005. By 2010-2011 there was a notable increase in discussions related to loperamide. See the following figure taken from the study.

Approximately 70% of the posts dealt with loperamide self-medication for opioid withdrawal. About 25% of the posts discussed the drug’s potential to produce euphoric or analgesic effects. Most of the posts about the drug’s use to manage withdrawal were positive (79%), while posts about using loperamide to get high or control pain were negative (69%). The most commonly discussed side effects were constipation, dehydration, and other types of gastrointestinal discomforts. “Some people also reported mild withdrawal symptoms from using loperamide for an extended period of time.”

A May 2016 New York Times article, noted how “Addicts Who Can’t Find Painkillers” turn to loperamide, “the poor man’s methadone.” They cited an online report, later published in the Annals of Emergency Medicine: “Loperamide Abuse Associated with Cardiac Dysrhythmia and Death.” The NYT article said overdoses had been linked to deaths or life-threatening irregular heartbeats in over a dozen cases in the previous eighteen months. “Some toxicologists argue that the sale of loperamide should be limited, much as the nonprescription drug pseudoephedrine was restricted a decade ago to help prevent the manufacturing of crystal meth.”

The lead author of the Annals of Emergency Medicine report, William Eggleston was quoted as saying: “We’ve seen patients who have been on loperamide for months at a time.” He added that while a subset of patients take it to get high another subset uses it to ease withdrawal symptoms. One 39-year-old male collapsed at home and was pronounced dead at the hospital. He had previously used buprenorphine to manage his opioid misuse disorder, but had been self-medicating with loperamide.

A Morbidity and Mortality Weekly Report for the CDC by Eggleston et al. on November 18, 2016 noted the abuse of loperamide for its euphoric effect and as a self-treatment of opioid withdrawal was increasing. Eggleston and his colleagues found that the average daily dose of New York City residents who were abusing loperamide was 358 mg (their range was 34 to 1,200 mg). Prior opioid abuse was reported by 15 of the 22 abuse cases identified. Eight individuals reported previous treatment with methadone or buprenorphine. Heart abnormalities were found in eight to 15 individuals of the identified cases of abuse.

The researchers also looked at loperamide abuse data reported to the National Poison Database System (NPDS). The average dose in this population was 196.5 mg of loperamide (the range was 2-1,200 mg). Cardiac problems were also found with some patients. Outcomes reported for 132 patients were coded as major (life-threatening symptoms or residual disability) for 66 individuals (50%); four deaths were reported. “These cases support the reported association between loperamide abuse and cardiac toxicity.”

At a 2015 Clinical Toxicology Conference, Eggleston and two others presented a poster that described, “a case of buprenorphine induced acute precipitated withdrawal in a patient presenting with loperamide toxicity.” At the time, to their knowledge, withdrawal had not been reported with loperamide abuse. A 30 year-old male was seen at the hospital after passing out. Tests indicated he had some heart irregularities, but he left against medical advice. He was later found without a pulse and not breathing. He was given CPR and readmitted to the hospital.

Within 24 hours of his readmission, he complained of withdrawal symptoms and was given 12 mg of buprenorphine for the withdrawal. “He became agitated and combative with hallucinations.” He had to be resuscitated, sedated with propofol and intubated. The researchers said toxicologists should be aware of the increasing trend of loperamide abuse. Further, administering high-dose buprenorphine “in patients actively intoxicated with loperamide can acutely precipitate opioid withdrawal.”

The FDA Commissioner noted in his blog article how several retailers have already responded to the FDA’s request. Walmart/Sam’s Club have limited online purchases of 200 count tablet products to a single package and moved the sale of bundled products at Sam’s Club behind the pharmacy counter. Amazon has taken steps to address the FDA recommendations and eBay intends to do the same. Several manufacturing companies have committed to implementing the FDA packing changes or purchasing safeguards.

But the FDA actions come too late for a Western Pennsylvania man who died in November of 2017. When the Allegheny County medical examiner finally revealed in March of 2018 that the cause of the man’s death was from an overdose of loperamide, several media sources picked up the story, including the Daily Mail from the United Kingdom, the Miami Herald, the New York Post, and local Pittsburgh news outlets such as the Trib Live. I’m not sure his family will get much comfort from the FDA actions, but I hope rapid implementation of the recommendations will limit the number of future loperamide overdoses and other adverse events.

06/1/18

Pure Caffeine Crackdown

Pexels Creative Commons Zero (CC0) license

On April 13, 2018 the FDA announced new restrictions on the sale of so-called dietary supplements containing high amount of caffeine. The new guidelines restrict the sale of pure or highly concentrated caffeine products in powder or liquid form directly to consumers in bulk quantities. They were said to pose a significant public health threat because of the high risk they will be used in excessive, potentially dangerous doses. A single teaspoon of powdered caffeine contains approximately 3,200 mg of caffeine—the equivalent to about 20 to 28 cups of coffee—a potentially fatal dose of caffeine. The FDA said it was prepared to take immediate steps to begin removing illegal products from the market.

The recommended serving of highly concentrated or pure caffeine products is 200 mg, equal to 1/16 of a teaspoon of pure powder, or 2.5 teaspoons of liquid. The FDA press release said the risk of overuse and misuse is high when these products are sold in bulk quantities, given the expectation of the buyer making small, precise measurements per recommended serving. Despite the small serving sizes, “powdered forms of caffeine are sold in large bags and liquid forms are sold online in bottles that can contain a gallon or more.” Often consumers don’t have the right tools to correctly measure the small dosage amounts so they are at risk of ingesting too much concentrated or pure caffeine.

Another concern is these products can resemble safe, household items like water, distilled vinegar, flour or powdered sugar. “The consequences of a consumer mistakenly confusing one of these products could be toxic or even lethal.” The new guidance does not apply to products such as prescription or over-the-counter drugs containing caffeine or conventional caffeinated beverages. The FDA commissioner, Scott Gottlieb, was quoted as saying:

Despite multiple actions against these products in the past, we’ve seen a continued trend of products containing highly concentrated or pure caffeine being marketed directly to consumers as dietary supplements and sold in bulk quantities, with up to thousands of recommended servings per container. We know these products are sometimes being used in potentially dangerous ways. For example, teenagers, for a perceived energy kick, sometimes mix dangerously high amounts of super-concentrated caffeine into workout cocktails. The amounts used can too easily become deceptively high because of the super-concentrated forms and bulk packaging in which the caffeine is being sold. . . . We’re making clear for industry that these highly concentrated forms of caffeine that are being sold in bulk packages are generally illegal under current law. We’ll act to remove these dangerous bulk products from the market.

Concern with the public health risk of products containing concentrated, high levels of caffeine is not new. In September of 2015 the FDA issued a warning that “Pure and highly concentrated caffeine products present a significant public health threat and have contributed to at least two deaths in the United States.” The FDA then issued warning letters to five distributors of pure powdered caffeine. In March of 2016 the FDA sent two additional warning letters to manufacturers. See the 2015 FDA announcement for links to the warning letters.

The FDA warnings about dietary supplements with high concentrations of caffeine reported knowledge of at least two confirmed deaths attributed to these products. This was apparently referring to a 2014 FDA article, “Tragic Deaths Highlight the Dangers of Powdered Pure Caffeine.” The article described the unfortunate deaths of two men, an eighteen-year-old high school senior and a 24-year-old college graduate who died after using pure powdered caffeine products. These aren’t the only two deaths linked to these products. The Washington Post highlighted the case of a South Carolina teen who died in April of 2017 of a “caffeine-induced cardiac event” after drinking a latte and a Mountain Dew, then chugging an energy drink within the span of two hours.

In 2015 a group of US senators sent a letter to the FDA requesting the agency require clearer labeling on powdered caffeine products and a ban on the retail sale and marketing of such products to consumers. They renewed their call to the FDA to take action on the 2015 requested ban on April 26, 2016 as the FDA still had not taken any action. In the 2016 letter, the senators said:

It is disturbing that despite two unintended and untimely deaths associated with powdered caffeine, the FDA has done little to regulate these products or adequately enforce the standards in place to protect Americans from the substantial risk associated with ingesting powdered caffeine in any form. . . . Unfortunately, in the absence of strong regulatory action, companies are continuing to develop new delivery mechanisms and creative advertising ploys to attract new powdered caffeine users and are doing so without relaying the serious health consequences of improper use.

The senators also sent information to the FDA on data from the nonprofit organization, the Center for Science in the Public Interest (CSPI), supporting the requested ban on the retail distribution of pure and highly concentrated caffeine products. In their April 26, 2016 letter to the FDA, CPSI noted while the five dietary supplement companies who received warning letters by the FDA in 2015 voluntarily removed pure caffeine products from their retail sales, “pure caffeine in powdered (PPC), liquid (PLC) and now inhalable (IC) forms is still widely available for purchase online.” A basic internet search found at least fifteen online suppliers. Five of these were domestic suppliers and ten were international suppliers based in Canada, the United Kingdom, India and China.

This compelling evidence demonstrates why a ban is the only step that will protect consumers from the hazards of PPC. Moreover, a ban would prevent legal importation of this dangerous substance into the country from foreign suppliers.Given the evidence, and vocal support from experts, parents, and trade associations, CSPI reiterates the need for a complete ban on the retail distribution of highly concentrated caffeine marketed as a dietary supplement. This includes specifying limits on the form in which caffeine is sold, including its labeling, serving sizes, and potency, to minimize the risk of accidental overdose by all potential users, including young consumers.

Senators Sherrod Brown (D-OH), Richard Blumenthal (D-CT), and Dick Durbin (D-IL) voiced their support to the FDA ban they have been seeking for the past four years. Senator Brown said: The FDA’s decision to ban the direct sale of pure, lethal powdered caffeine will finally bring about the consumer protections we have been demanding for years.” Senator Blumenthal said: “The FDA has rightly heeded our call to take swift action to get highly concentrated bulk caffeine products off the market. Pure caffeine is simply unsafe and has long posed dangerous – even deadly – risks to unsuspecting consumers. Robust enforcement action will go a long way towards stopping senseless and tragic caffeine overdoses.” Senator Durbin concurred with these sentiments, saying he was glad to see the FDA heeded their call to action, adding that when sold in bulk, “it is nearly impossible for consumers to tell the difference between a safe dose of pure powdered caffeine and a lethal one.”

For more information on problems with energy drinks and other products with high caffeine concentrations, see: “Overdosing On Energy Drinks” and “Killer Caffeine.”

04/6/18

Foolishness with Gabapentin

Scott Gottlieb, the Commissioner of the FDA, recently expressed concern about the potential misuse and abuse of gabapentinoids, gabapentin (Neurontin) and pregabalin (Lyrica). Although abuse of gabapentinoids is not widespread yet, use continues to increase, especially for gabapentin. He said the FDA is investigating whether their abuse is growing and what should be done about the problem. “Although limited, the data suggest that gabapentinoid misuse and abuse may be growing, both when taken alone and when taken with opioids, benzodiazepines, or other central nervous system depressants.” Data from GoodRx indicated gabapentin was the sixth-most prescribed drug in the nation in November of 2021, warning of the potential for misuse and overdose deaths.

He said the FDA has looked at social media sites where opioid users share descriptions on methods for misusing or abusing gabapentinoids. “And we’ve tasked our surveillance and epidemiology group inside FDA – who are focused on spotting early patterns of abuse of controlled substances – with investigating the use patterns of the gabapentinoids.” Stay tuned; he said the FDA will have more to say on this soon. Swift attention to this matter is partly a consequence of the lessons of history. “We need to get ahead of these problems.”

In July of 2017, STAT News published an article on gabapentin abuse in the town of Athens, Ohio. The Ohio Board of Pharmacy reported sales of gabapentin prescriptions surpassed oxycodone by 9 million doses in December of 2016. An Athens pharmacist noticed signs of gabapentin misuse five years ago when patients began picking up their prescription refills several days before the prescription ran out. She said: “Gabapentin is so readily available. . . . That, in my opinion, is where a lot of that danger is. It’s available to be abused.” In May of 2017, her pharmacy filled approximately 33 prescriptions of gabapentin per week, dispensing 90 to 120 pills per client.

As providers dole out the drug in mass quantities for conditions such as restless legs syndrome and alcoholism, it is being subverted to a drug of abuse. Gabapentin can enhance the euphoria caused by an opioid and stave off drug withdrawals. In addition, it can bypass the blocking effects of medications used for addiction treatment, enabling patients to get high while in recovery.

This is not simply a new problem or concern. Doctors and researchers have been pointing out the potential for gabapentin abuse for at least six years. In 2012 Smith et al. in “Substance Misuse of Gabapentin” noted gabapentin was prescribed without restriction and escalating doses were recommended. This made it easy to misuse or develop an addiction of the drug. They recommended introducing routine testing for gabapentin in urine screens. “This will inform clinical and political approaches to this possible new and dangerous type of substance misuse, as well as safe management of the distress caused by neuropathic pain.”

A 2014 a Medscape article by Sarah Melton asked, “Has Gabapentin Become a Drug of Abuse?” She summarized a 2004 report describing gabapentin misuse in Florida correctional facilities. A recall at one of the larger facilities revealed that: “only 19 of 96 prescriptions were in the hands of the intended patients.” She then reviewed several reported cases of gabapentin abuse dating back to 2001. There also was a report of “Gabapentin Abuse in Order to Potentiate the Effect of Methadone.”

More recent concerns with the abuse and misuse of gabapentinoids include three separate articles published in 2017. “Abuse and Misuse of Pregabalin and Gabapentin” did a systematic review of fifty-nine studies. The authors’ analysis indicated patients were self-administering higher than recommended doses for the high. “Evidence suggests gabapentinoids possess potential for abuse, particularly in individuals with a history of opioid abuse, and reports of such abuse are increasingly being documented. Prescribers should be aware of high-risk populations and monitor for signs of abuse.”

Shanthanna et al. looked at the “Benefits and Safety of Gabapentinoids in Chronic Low Back Pain.” The authors noted that while there was no clear rationale for using gabapentinoids to treat chronic low back pain (CLBP), they were increasingly used for nonspecific CLBP. They said that despite the widespread use, they found very few RCTs (random control trials) that attempted to assess the benefit of using gabapentin (GB) or pregabalin (PG) in patients with CLBP. “Use of GB and PG, compared to placebo and active analgesic comparators, respectively, were associated with significant increase in adverse effects [with] limited evidence for improvement in pain scores or other outcomes.”

In The New England Journal of Medicine Goodman and Brett said they believed gabapentinoids were being overprescribed in part as a response to the opioid epidemic. They said the FDA approved gabapentinoids for the treatment of postherpetic neuralgia (gabapentin and pregabalin), fibromyalgia (pregabalin) and neuropathic pain associated with diabetes or spinal cord injuries (pregabalin). Yet they have seen clinicians prescribing both for almost any type of pain; and their “experience is supported by national prescribing data.” They suspected “that clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain.”

They noted that past marketing practices of gabapentin (Neurontin) also help explain the growing use of gabapentinoids for various types of pain. After Neurontin was approved as an antiseizure medication in 1993, the manufacturer engaged in an extensive (and illegal) marketing campaign to increase off-label prescribing of Neurontin for pain. “Research had suggested that the drug had analgesic properties, but postherpetic neuralgia was the only pain-related indication for which there was sufficient evidence from clinical trials to justify FDA approval.” The company (Pfizer and its subsidiaries) eventually admitted to improper off-label marketing and paid $897 million in three separate cases (criminal and civil) of marketing for off label unapproved uses. Also see “Twentieth Century Snake Oil” and “The Evolution of Neurontin Abuse.”

Goodman and Brett thought there were several reasons to be concerned with the trend to prescribe gabapentinoids as supposedly safer alternatives to opioids. First, there was no reasonably robust evidence to support the use of gabapentinoids for off-label use. They found that most recently published studies of gabapentinoids for pain examined single-dose or short-course gabapentinoids for mitigating postoperative pain, “an indication that isn’t relevant to general outpatient practice.”

Relatively few clinical trials have assessed the use of gabapentinoids in the common pain syndromes for which they are prescribed off-label — and many of those trials were uncontrolled or inadequately controlled and of short duration. Among the few well-conducted, properly controlled, double-blind studies, results have been mixed at best. In a recent rigorously conducted placebo-controlled trial, pregabalin was ineffective for patients with painful sciatica.

Second, the side effects with gabapentinoids are not trivial ones. Sedation and dizziness are fairly common; and some patients have cognitive difficulties while taking these drugs. In a sciatica trail, 40% of patient taking pregabalin reported dizziness, as compared to 13% of those taking a placebo. The adverse effects are reversible and not always severe; and they are reversible when the drugs are discontinued. However, gabapentinoids are often taken with other medication with central nervous system side effects. “Such polypharmacy might affect neurologic function in subtle but clinically important ways.”

Third, evidence suggests that some patients misuse, abuse, or divert gabapentin and pregabalin. Some users describe euphoric effects, and patients can experience withdrawal when high doses are stopped abruptly. The likelihood of gabapentinoid abuse is reportedly heightened among current or past users of opioids and benzodiazepines. Whether misuse and abuse of gabapentinoids will become an important public health issue remains to be seen. [That is the FDA concern noted in the opening paragraph]

Fourth, “the indiscriminate off-label use of gabapentinoids reinforces the tendency to view the treatment of pain through a pharmacologic lens.” Goodman and Brett thought appropriate pain management of acute and chronic pain management should examine how the patient’s pain is affecting activity and function and set ‘realistic goals that may include coping with or mitigating pain,” but not necessarily eliminating it. “Writing a prescription and moving on is much easier and less stressful for clinicians.” And nonpharmacologic approaches may be unavailable or unaffordable for many patients.

Nevertheless, clinicians shouldn’t assume that gabapentinoids are an effective approach for most pain syndromes or a routinely appropriate substitute for opioids. Although gabapentinoids offer an alternative that is potentially safer than opioids (and presumably more effective in selected patients), additional research is needed to more clearly define their role in pain management.

Gabapentin can enhance the euphoria caused by opioids, including methadone or buprenorphine; and it staves off drug withdrawals. These factors make it an attractive supplement for individuals misusing or abusing opioid or benzodiazepines. In large enough quantities, it can also have its own euphoric effect. There can be withdrawal symptoms. And reports of misuse and abuse of gabapentinoids are increasing.

There is also no “reasonably robust evidence” for off-label pain relief at this time. It may be a matter of medical professionals looking at the treatment of pain through a pharmacologic lens (with the encouragement of pharmaceutical companies). More research is needed into the efficacy of gabapentinoids in pain management. Adverse effects can be problematic, especially if a gabapentinoid is taken with other medications with central nervous system side effects. Given the history of deceit and exaggerated claims made with gabapentin, let’s be cautious of how we use it. Remember that “fools rush in …”

03/27/18

Kratom Regulation is Coming

© Noppharat Manakul | 123rf.com; close up of a mitragyna speciosa (kratom) leaf

February of 2018 was not a good month if you are pro-kratom. The FDA released information on adverse events and “even stronger evidence of kratom compounds’ opioid properties.” Then the CDC announced a multistate outbreak of Salmonella infections related to kratom. Then FDA announced the destruction and recall of kratom products. And the icing on the kratom cake was the FDA stating the agency has seen their death count related to kratom increase from 36 to 44.

The February 6^th statement regarding additional adverse events associated with kratom said the agency used the PHASE (Public Health assessment via Structural Evaluation) methodology to simulate how the chemical elements of kratom are structured at a molecular level, how they behave inside the body and what they potentially do to the brain. In other words, PHASE used the molecular structure of a kratom to predict how it could biologically function in the body. “The new data provides even stronger evidence of kratom compounds’ opioid properties.” The 25 most prevalent compounds in kratom all share structural similarities with controlled opioid substances such as morphine derivatives.

The model predicted that 22 (including mitragynine) of the 25 compounds in kratom bind to mu-opioid receptors. This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors (“opioid agonists”).

Additionally, the computational model predicted some kratom compounds may bind to receptors in the brain thought to contribute stress responses contributing to neurologic function in seizures and cardiovascular function in respiratory depression. And the FDA “found that kratom has a strong bind to mu-opioid receptors, comparable to scheduled opioid drugs.” What all this means is that:

The data from the PHASE model shows us that kratom compounds are predicted to affect the body just like opioids. Based on the scientific information in the literature and further supported by our computational modeling and the reports of its adverse effects in humans, we feel confident in calling compounds found in kratom, opioids.

Kratom-related deaths have increased to 44, according to the FDA. The agency said they could not fully assess many of the cases because of limited information. Additionally, some of the cases with fatal outcomes indicate kratom was not the only substance used. “Cases of mixing kratom, other opioids, and other types of medication is extremely troubling because the activity of kratom at opioid receptors indicates there may be similar risks of combining kratom with certain drugs, just as there are with FDA-approved opioids.” Particularly troubling was a new report of death where the individual had no known history of toxicologic evidence of opioid use except kratom.

Taken in total, the scientific evidence we’ve evaluated about kratom provides a clear picture of the biologic effect of this substance. Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that kratom is safe or effective for any medical use. And claiming that kratom is benign because it’s “just a plant” is shortsighted and dangerous.

Writing for the HuffPost, Nick Wing questioned the reliability of the FDA’s conclusions on kratom-related deaths. He stated that almost all the FDA cases involved subjects using multiple substances at the time of death, “with the vast majority including either illicit or prescription drugs that carry well-known fatal risks.” He concluded when taken together, the case reports fail to provide a clear picture of the deadly risks claimed by the agency with kratom. He gave examples from FDA case studies to illustrate his conclusions, but there was not a link in his article or the FDA press release to the case reports. And the given link in the FDA press release did not connect to the reports of the “36 deaths.”

Wing commented on the irony that many of the deaths the FDA associates with kratom also involved prescription drugs. But that seems to be part of the FDA concern, since “kratom has a strong bind to mu-opioid receptors,” meaning that when used in conjunction with other drugs, the combined adverse effects could be serious and even fatal.

Wing also said: “most of the emerging science on kratom has found it to be largely benign, especially when taken in low or moderate doses.” Andrew Kruegel, a chemist who has authored a number of studies on kratom, thought it was better to say kratom is an “atypical opioid,” given the differences between kratom and classical opioids. Kratom used alone may be less likely to lead to adverse events, but consumers need to be aware that it is an opioid. Even if it does have a better side-effect profile than classical opioids, the potential for adverse events when it’s mixed with other drugs seems to be a clear danger.

There was an FDA report, “CAERS: Kratom Deaths,” released on December 13, 2017. The case reports corresponding to the examples given in the HuffPost article could not be readily identified. But you can review the CAERS report for several examples of the dangers of kratom’s primary opioid agonist, mitragynine. Here are a few examples.

The cause of an accidental death for case # 10698706 was: mixed drug toxicity primarily mitragynine. “Despite the detection of the other compounds at therapeutic concentrations, they were considered to have additive toxic central nervous system effects in the presence of mitragynine and were therefore felt to have contributed toward the death.”

Case # 10708286 was a 17 year-old male who was self-medicating with kratom to treat a history of heroin abuse and chronic back pain. No other compelling cause of death beside mitragynine was evident. He had “a well-established history of opioid abuse, including Kratom abuse.” Kratom was present at the scene “and the active compound of this substance was identified in the decedent’s blood. Other drugs found were not felt to be significantly related to death.”

Case # 12569892 was a middle-aged man with a history of substance abuse and psychiatric problems for which he was taking medication, including Celexa, Lamictal, and zopiclone. He was being drug tested at work, so in order to avoid testing positive for a mind altering substance, he ordered kratom from the internet. He commented that his most recent batch seemed more potent than what he had previously. The concentrations of his prescription medications were within therapeutic levels and were felt to be of little significance in causing his death. There was a high concentration of mitragynine in his blood. “Mitragynine intoxication was assumed to be the main cause of death.” However, it could be that the other medications present may have enhanced the effects of the mitragynine.

When it’s used as a dietary supplement, kratom is considered to be a new dietary ingredient by the FDA. Dietary supplements typically require a New Dietary Ingredient Notification indicating the product is reasonably expected to be safe. “To date, the FDA is not aware of any evidence of safety establishing that kratom (or any compounds derived from kratom) will reasonably be expected to be safe as a dietary ingredient.” Some individuals use it to treat pain or other medical conditions, but there are no FDA-approved therapeutic uses of kratom, while there is evidence of significant safety issues. “Before it can be legally marketed for therapeutic uses in the U.S., kratom’s risks and benefits must be evaluated as part of the regulatory process for drugs established by Congress.”

Some individuals use it to treat their opioid dependency. But again, there is no reliable evidence to support kratom’s effectiveness for this use.

The CDC announced on February 20, 2018 that it was investigating a multistate outbreak of Salmonella infections. “Epidemiologic evidence indicates that kratom is a likely source of this multistate outbreak.” Eight of 11 people interviewed reported consuming kratom. There were no common brands, or suppliers identified at the time of the announcement. “At this time, CDC recommends that people not consume kratom in any form. The investigation indicates that kratom products could be contaminated with Salmonella and could make people sick.” The investigation is ongoing and will be updated as more information becomes available.

This outbreak associated with kratom-containing capsules, teas and powders, underscores the risk that harmful bacteria may contaminate these products when not subjected to manufacturing controls to eliminate that risk, in addition to the overall safety concerns for kratom itself.

In a February 21, 2018 FDA News Release, the agency announced the voluntary destruction and recall of a large volume of kratom-containing products manufactured and distributed by Divinity Products Distribution of Grain Valley Missouri under the names: “Botany Bay, Enhance Your Life and Divinity.” The company has also agreed to stop selling all products containing kratom. The FDA encouraged all companies involved in the sale of products containing kratom for human consumption to take similar steps to take their products off the market. FDA Commissioner, Scott Gottlieb said that some individuals use kratom believing it can help them treat their opioid dependency, “but there’s no reliable evidence to support kratom’s effectiveness for this use.” He added:

To protect the public health, we’ll continue to affirm the risks associated with kratom, warn consumers against its use and take aggressive enforcement action against kratom-containing products. We appreciate the cooperation of companies currently marketing any kratom product for human consumption to take swift action to remove these products from circulation to protect the public.

Kratom then is an unregulated substance with 23 compounds that qualify as opioids—atypical opioids if you prefer. In high enough doses it can be abused and lead to all the adverse effects common with opioids—withdrawal, cravings, anxiety, sleep disturbance, etc. In combination with other substances it can lead to overdose and death. Marketed and sold as a dietary supplement for human consumption, it varies in strength with no real way for consumers to know the strength of what they are ingesting. Sounds like something the FDA would want to regulate.

For more on kratom, see: “The Secret of Kratom,” “Kratom: Part of the Problem or a Solution?” or “What is the Future of Kratom?”

02/23/18

Priming Young Adults with Vaping

The National Institute of Health announced that recent national survey research discovered that almost 1 in 3 (27.8%) 12^th graders reported some kind of use of a vaping device in the past year, while the use of hookahs and regular cigarettes is declining. When asked what they thought was in the mist they inhaled, 51.8% said it was just flavoring, 32.8% said the mist contained nicotine, and 11.1% said they were smoking marijuana or hash oil. Nora Volkow, the director of NIDA, said: “We are especially concerned because the survey shows that some of the teens using these devices are first-time nicotine users.” Recent research suggests some of them could move on to regular cigarette smoking … or other drugs. And some additional research suggests many teens don’t actually know what is in the device they are using.

Monitoring the Future (MTF) is a yearly survey of 8^th, 10^th and 12^th graders in school nationwide. The MTF survey is done by the Institute for Social Research at the University of Michigan for NIDA, the National Institute on Drug Abuse. When the survey asked about vaping over the past month, 11% of 12^th graders reported vaping nicotine and 4.9% reported vaping marijuana. See the following chart from the NIH news release.

According to the CDC, e-cigarettes are now the most commonly used form of tobacco by youth in the U.S. Dual use, using both regular cigarettes and e-cigarettes, is also common among young adults 18-25. The reasons reported by young people for trying e-cigarettes include curiosity, taste and the belief they are less harmful than other tobacco products. Over 80% of teens and young adults who use e-cigarettes said they use flavored e-cigarettes.

Back in June of 2016 the FDA finalized a rule that extended its regulatory authority to all tobacco products, including e-cigarettes, cigars, hookahs and pipe tobacco. The rule requires health warnings and bans free samples. It also restricts youth access to newly regulated tobacco products by not allowing their sale to those younger than 18 and requiring a photo ID. Manufacturers will have up to two years to continue selling their products while they submit a new tobacco product application (and an additional year while the FDA reviews the application).

The rule will help prevent young people from starting to use these products, help consumers better understand the risks of using these products, prohibit false and misleading product claims, and prevent new tobacco products from being marketed unless a manufacturer demonstrates that the products meet the relevant public health standard.

If the new technology in e-cigarettes helps reduce toxicity compared to conventional cigarettes, encourages current smokers to switch completely and/or are not widely used by youth, they potentially could reduce disease and death. “But if any product prompts young people to become addicted to nicotine, reduces a person’s interest in quitting cigarettes, and/or leads to long-term usage with other tobacco products, the public health impact could be negative.” The FDA encouraged manufacturers to explore product innovations that would maximize potential benefits and minimize risks. The revised rule allows the FDA to further evaluate the impact of these products on the health of both users and non-users.

Psychiatric Times reported e-cigarettes were first developed and commercialized in China in 2003. They entered the US market in 2006. During their first ten years on the market, before the FDA ruling discussed above, advertising and sales of e-cigarettes increased exponentially every year. “While tobacco advertising has been banned from television and radio since 1970, e-cigarettes are promoted widely on these media channels, on the web, and in social media, with many ads reaching youth.” Mislabeling has been a problem with some products labeled as nicotine-free containing nicotine and others having higher concentrations of nicotine than labeled.

The evidence for e-cigarettes as a cessation aid to quit regular cigarette smoking is limited. Dual use of regular cigarettes and e-cigarettes is common. One study reported half of current smokers report regular use of e-cigarettes. A meta-analysis of twenty controlled studies found the odds of quitting cigarettes was 28% lower in individuals who used e-cigarettes. However only 2 randomized controlled trials have been done, and: “The quality of evidence was judged to be low grade, and in both trials, e-cigarettes with nicotine were no different in efficacy for quitting smoking than placebo (nicotine-free) e-cigarettes.”

So at this point in time, the evidence does not support the use of e-cigarettes as an aid to stop smoking regular cigarettes. It should be noted that the American Heart Association’s policy statement of e-cigarettes does not recommend their use. However, if a patient has tried and failed other cessation methods or is unwilling to try them, the AHA does recommend trying e-cigarettes for smoking cessation.

There is evidence that smoking e-cigarettes increases the risk of cardio vascular problems. Swedish researchers, in Antoniewicz et al., demonstrated that in healthy volunteers, ten puffs from an e-cigarette caused an increase in endotheial progenitor cells (EPSs) of the same magnitude as smoking one traditional cigarette. The average e-cigarette user takes 230 puffs per day, raising the prospect that prolonged use could result in serious health consequences. “These findings suggest that a very short exposure to ECV [e-cigarette vapor] caused a rapid EPC mobilization in blood, which may indicate an impact on vascular integrity leading to future atherosclerosis [hardening of the arteries].” A heart specialist for the European Society of Cardiology was quoted in the Daily Mail as saying: “It really surprises me that so little vapour from an e-cigarette is needed to start the heart disease ball rolling. It’s worrying that one e-cigarette can trigger such a response.”

Researchers at the University of Connecticut found evidence that e-cigarettes containing a nicotine-based liquid are potentially as harmful as unfiltered cigarettes in causing DNA damage. The study’s lead author said the results surprised him. “I never expected the DNA damage from e-cigarettes to be equal to tobacco cigarettes.” He was shocked the first time he saw the result, so he diluted the samples and ran the controls again. “But the trend was still there – something in the e-cigarettes was definitely causing damage to the DNA.”

Researchers at the University of North Carolina found that not only do e-cigarettes trigger the same immune responses as regular cigarettes, they also trigger some unique reactions. E-cigarette users uniquely showed significant increases with neutrophil-extracellular-trap (NET)-related proteins in their airways. “Left unchecked neutrophils can contribute to inflammatory lung diseases, such as COPD and cystic fibrosis.” The study also found that e-cigarettes produced negative consequences known to occur in regular cigarettes such as an increase of biomarkers of oxidative stress and activation of defense mechanisms associated with lung disease. They also found an over secretion of mucus secretions that have been associated with diseases like chronic bronchitis, bronchiectasis and asthma.

Another study by Eric and Denise Kandel, “A Molecular Basis for Nicotine as a Gateway Drug” has raised concerns with e-cigarettes as “pure nicotine-delivery devices.” Their study demonstrated that nicotine acted like a gateway drug for cocaine on the brain of mice, “and this effect is likely to occur whether the exposure is from smoking tobacco, passive tobacco smoke, or e-cigarettes.”

These results provide a biologic basis and a molecular mechanism for the sequence of drug use observed in people. One drug affects the circuitry of the brain in a manner that potentiates the effects of a subsequent drug.Although the typical e-cigarette user has been described as a long-term smoker who is unable to stop smoking, the use of e-cigarettes is increasing exponentially among adolescents and young adults. Our society needs to be concerned about the effect of e-cigarettes on the brain, especially in young people, and the potential for creating a new generation of persons addicted to nicotine. The effects we found in adult mice are likely to be even stronger in adolescent animals. Priming with nicotine has been shown to lead to enhanced cocaine-induced locomotor activity and increased initial self-administration of cocaine among adolescent, but not adult, rats. Whether e-cigarettes will prove to be a gateway to the use of combustible cigarettes and illicit drugs is uncertain, but it is clearly a possibility.

Don’t be too quick to dismiss the Kandels’ nicotine-gateway theory. They were doing basic research on the effects of nicotine on specific areas of the brain. Priming with nicotine enhanced the effects of cocaine in the nucleus accumbens. “Priming with nicotine appeared to increase the rewarding properties of cocaine by further disinhibiting dopaminergic neurons in the ventral tegmental area.” They only observed the priming effect of nicotine when mice were given cocaine at the same time as nicotine. For more on Denise Kandel’s gateway hypothesis see: “Rebirth of the Gateway Hypothesis.”

01/2/18

What is the Future for Kratom?

Kratom is back in the news as the FDA issued a public health advisory related to mounting concerns regarding the risks associated with its use. The FDA Statement from Scott Gottlieb about kratom singled out its use to treat opioid withdrawal as a particular concern. Gottlieb said: “There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder.” Individuals who use kratom are playing doctor, as there are no dependable instructions for its use and there is no consultation with a healthcare professional about the product’s dangers, adverse effects or interactions with other drugs. “There’s clear data on the increasing harms associated with kratom.”

Calls to U.S. poison control centers about kratom increased 10-fold from 2010 to 2015. There are reports of 36 deaths from kratom or kratom-containing products, according to the advisory. Not surprisingly, given the opioid cocktails appearing on the streets, kratom has been reportedly laced with various opioids. “The use of kratom is also associated with serious side effects like seizures, liver damage and withdrawal symptoms.” There are no currently FDA-approved therapeutic uses of kratom.

Before it can be legally marketed for therapeutic uses in the U.S., kratom’s risks and benefits must be evaluated as part of the regulatory process for drugs that Congress has entrusted the FDA with. Moreover, Congress has also established a specific set of review protocols for scheduling decisions concerning substances like kratom. This is especially relevant given the public’s perception that it can be a safe alternative to prescription opioids.

Gottlieb pointed out that kratom is already a controlled substance in 16 countries, “including two of its native countries of origin, Thailand and Malaysia.” Australia, Sweden and Germany are among the other countries listing kratom as a controlled substance. Several states have banned kratom: Alabama, Arkansas, Indiana, Tennessee, Vermont and Wisconsin. Several others, Florida, Georgia, New York, North Carolina and Oregon have pending legislation to ban it. Gottlieb encouraged supporters to conduct the research that will help to better understand kratom’s risk and benefit profile. “In the meantime, based on the weight of the evidence, the FDA will continue to take action on these products in order to protect public health.”

In response to the FDA advisory on kratom, The American Kratom Association (AKA) has asked the FDA to “review and correct” it. It claimed the advisory was based on “discredited, incomplete, and mischaracterized scientific claims” and as a result, it should be rescinded. Medscape reported the AKA has filed a formal dispute resolution petition with the Department of Health and Human Services challenging what it claimed was the “weak scientific basis” of the FDA advisory.

For years, the FDA has published scientifically inaccurate information on the health effects of consuming kratom, directly influencing regulatory actions by the DEA [Drug Enforcement Administration], states, and various local government entities. AKA believes the FDA health advisory on kratom will lead to more state and local bans, all based on discredited, incomplete, and mischaracterized scientific claims.

The AKA disputed the FDA claim that kratom has opioid-like abuse potential, arguing it is primarily used because it is beneficial, and not as a means to get high. The organization also downplays the overdose risk with kratom, saying: “The handful of possible kratom-associated deaths in the US involved people taking multiple drugs, with apparent causes of death varying widely, quite unlike what is seen with narcotic-like opioids.” Reversing the FDA concern that unrestricted kratom use could increase the opioid crisis, the AKA claimed the ban would increase it. The AKA claimed kratom consumers are afraid they will be forced to seek out illegal opioids if kratom was banned. “It would be an outrageous and unacceptable public health outcome if the effect of the FDA assault on kratom backfires and leads to more opioid addiction and death.”

Despite the claims by the AKA, the FDA public health advisory does not seem ill advised. A CDC Morbidity and Mortality Report in 2016 described a study of U.S. poison centers between 2010 and 2015. During the study poison centers received 660 calls about reported exposure to kratom. The number of calls increased tenfold, from 26 in 2010 to 263 in 2015. See the figure below.

Among the calls, 90.2% reported ingestion of the drug. Isolated exposure, use of kratom alone, was reported by 64.8% of cases. “Among calls reporting use of kratom in combination with other substances (multiple exposures), the most commonly reported other substances were ethanol, other botanicals, benzodiazepines, narcotics, and acetaminophen.”

Medical outcomes associated with kratom exposure were reported as minor (minimal signs or symptoms, which resolved rapidly with no residual disability) for 162 (24.5%) exposures, moderate (non-life threatening, with no residual disability, but requiring some form of treatment) for 275 (41.7%) exposures, and major (life-threatening signs or symptoms, with some residual disability) for 49 (7.4%) exposures.

There was one death reported in the CDC Report, but the person had also ingested paroxetine (Paxil) and lamotrigine (Lamictal) in addition to the kratom. While the FDA advisory said it was aware of 36 deaths associated with kratom products, it did not provide further information. The August 2016 DEA announcement to schedule kratom, which was later rescinded, said the DEA was aware of 15 kratom-related deaths between 2014 and 2016; but again did not provide any further information.

An article in BioMed Research International, “Following ‘the Roots’ of Kratom” described several short term adverse effects from kratom, including nausea, constipation, sleep problems, itching, sweating, erectile dysfunction. Long-term adverse effects include: anorexia, dry mouth, darker skin and hair loss. Withdrawal symptoms can include: hostility, aggression, muscle and bone aches, jerky limb movements, anorexia and weight loss, and insomnia. Kratom could be a deadly substance when mixed with other compounds. Multiple fatalities with a kratom product known as “Krypton” have been reported. See “Following ‘the Roots’ of Kratom,” for more particulars on the reported deaths. For more information on Krypton, see “Krypton Can Kill You.”

Table 1 of the article listed several substances found mixed with kratom in fatalities, including antidepressants, a mood stabilizer and a hypnotic sleep aide: O-desmethyltramadol (a metabolite of tramadol); propylhexedrine (an analog of methampheamine); over-the-counter cold medications and benzodiazepines; venlafaxine (Effexor), diphenhydramine (Benadryl), and mirtazapine (Remeron); zopiclone (Zopiclone), citalopram (Celexa), and lamotrigine (Lamictal).

According to preclinical data and case reports published in scientific literature as well as anecdotal experiences posted online, kratom is not a safe drug. Its consumption is associated per se with drug dependency, development of withdrawal symptoms, craving, serious adverse effects, and life-threatening effects, especially in a multidrug-intoxicating scenario.

Another article in the International Journal of Legal Medicine, “The Pharmacology and Toxicology of Kratom,” said there was growing international concern for the kratom’s effects and safety due to “an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant.” The abuse potential of kratom “requires careful evaluation of its benefits and potential toxicities.”

So what is next with kratom? When the DEA reversed its decision to temporarily classify kratom as a Schedule I Controlled Substance in October of 2016, it said it would solicit public comments (which it did) and review the FDA’s “scientific and medical evaluation” of the proposed scheduling. The FDA public health advisory for kratom indicates the agency concluded there was cause for concern in keeping it unregulated. I’d guess that further action by the DEA to schedule kratom will be delayed, pending the outcome of the AKA’s suit against the FDA.

Gottlieb’s public encouragement of research into kratom’s possible use as a therapy for “a range of disorders” may suggest room for a scheduling of kratom other than as a Schedule I Controlled Substance. If kratom were to be placed even temporarily as a Schedule I controlled Substance, further research into its potential medical benefits would be difficult to conduct. Funding for kratom research is also hard to come by. Obtaining kratom of the quality needed for research is difficult as well. A researcher referred to the FDA requirements to develop a clinical trial for kratom as a “bureaucratic nightmare.” Edward Boyle, a kratom researcher, said: “Is it an effective treatment for opioid withdrawal, or is it another pathway to addiction? I don’t think anybody has a defined concept of where it actually lies on that continuum.”

See “The Secret of Kratom” and “Kratom: Part of the Problem or a Solution?” for more information on kratom.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: FDA