09/5/23

Flesh Eating Tranq Dope

Image by Лечение Наркомании from Pixabay

A study published by the CDC , documented a new twist to drug overdose death rates, but it is about a non-opioid veterinary tranquilizer called xylazine. It said xylazine-related overdose deaths in 2021 were 35 times higher than the 2018 rate. The number of drug overdose deaths involving xylazine was 102 in 2018. That rose to 627 in 2019, then 1,499 in 2020 and 3,468 in 2021. Male deaths were double the rates for females over the 2018-2021 period. See the following graph from the study.

An NPR article reported the Biden administration declared illicit xylazine as an emergent threat. Rahul Gupta, the head of the White House Office of National Drug Control Policy said this was the first time a substance has been “designated as an emerging threat by any administration.” Known on the streets as tranq or tranq dope, it was first linked to overdose deaths in the North East, around Philadelphia, but has rapidly spread to Southern and Western states. The DEA reported it has seized xylazine and fentanyl mixtures in 48 of 50 states. See “Tranq Dope and Its Consequences.”

The CDC study indicated the rate of overdose deaths involving xylazine was highest in Region 3 (DC, Delaware, Maryland, Pennsylvania, Virginia and West Virginia), followed by Region 1 (Connecticut, Massachusetts, Maine, New Hampshire, Rhode Island and Vermont) and Region 2 (New Jersey and New York). Between 97.1% and 99.4% of drug overdose deaths involving xylazine also mentioned fentanyl. It has also been co-involved with cocaine, heroin and methamphetamine. See the following map from the CDC study.

Pennsylvania governor Josh Shapiro announced steps his Administration is taking to limit access to xylazine. Among the measures was a notice of intent to temporarily add xylazine to schedule III of Pennsylvania’s Controlled Substance, Drug Device and Cosmetic Act. The Acting Secretary of Health said, “Across the country and here in Pennsylvania we are seeing an alarming increase in the number of overdose deaths in which xylazine was a contributing factor.”

The FDA issued a warning about the risk of xylazine in humans to health care professionals on November 8, 2022. It said xylazine was originally approved in 1972 as a sedative and analgesic for use in veterinary medicine. Its development for use in humans was discontinued because of adverse effects. Structurally, it is similar to clonidine and causes a rapid decrease in the release of norepinephrine and dopamine in the central nervous system. The effects appear similar to that of opioids, making it difficult to distinguish between opioid toxicity and xylazine.

On March 28, 2023, the Combating Illicit Xylazine Act was introduced with bipartisan, bicameral support. The legislation will address a gap in federal law by:

Classifying its illicit use under Schedule III of the Controlled Substances Act;
Enabling the DEA to track its manufacturing to ensure it is not diverted to the illicit market;
Requiring a report on prevalence, risks, and recommendations to best regulate illicit use of xylazine;
Ensuring all salts and isomers of xylazine are covered when restricting its illicit use;
Declaring xylazine an emerging drug threat.

Unless you are a veterinarian, own large animals—or are familiar with the drug scene in places like the Kensington area of Philadelphia—you probably have not heard of xylazine before. “Xylazine—Medical and Public Health Imperatives” by Gupta et al in The New England Medical Journal said its first illicit use was reported in Puerto Rico around 2001. It began to appear intermittently in the continental U.A. between 2006 and 2018. The drug’s duration of effect is longer than fentanyl. Using them together enhances the euphoria and analgesia induced by fentanyl and seems to reduce the frequency of injections.

Xylazine is not easily detected by routine toxicology screens, and is likely under-detected and underdiagnosed. It is rapidly eliminated from the body, with a half-life of 23-50 minutes. Individuals with repeated use of xylazine can become physically dependent and experience withdrawal. “When xylazine is stopped abruptly, severe withdrawal symptoms may develop.” There are currently no FDA-approved medications to manage xylazine withdrawal. Repeated use also leads to severe, necrotic ulcerations.

Xylazine causes wounds that erupt with a scaly dead tissue called eschar; untreated, they can lead to amputation. It induces a blackout stupor for hours, rendering users vulnerable to rape and robbery. When people come to, the high from the fentanyl has long since faded and they immediately crave more.

The NYT noted that xylazine can cause wounds so severe that some result in amputation. The article said a 38-year-old tattoo artist known as the Hood Grandma rolled her wheelchair in to the exchange check-in for Prevention Point Philadelphia, a 30-year-old health services center in Kensington, the neighborhood at the ‘epicenter’ of Philadelphia’s drug trade. Her mother, sister and partner all died of overdoses. Last year her right leg had to be amputated because of an infection from tranq bore into the bone. She said, “the tranq dope literally eats your flesh.”

She unrolled a bandage from elbow to palm. Beneath patches of blackened tissue, exposed white tendons and pus, the sheared flesh was hot and red. To stave off xylazine’s excruciating withdrawal, she said, she injects tranq dope several times a day. Fearful that injecting in a fresh site could create a new wound, she reluctantly shoots into her festering forearm.

Another woman developed a dependence on pain killers prescribed after a serious car crash. She began using heroin and eventually fentanyl, chasing the cheaper and more potent high. She watched in horror as the bruises she was accustomed to “from injecting fentanyl began hardening into an armor of crusty, blackened tissue.” People told her everyone’s dope was being cut with something that caused the grisly, painful sores. She said, “I’d wake up in the morning crying because my arms were dying.”

STAT News described how Savage Sisters, a harm reduction group in Philadelphia, has increased how often it offers wound care in the community. The executive director of Savage Sisters said she has been jumping up and down for three years, trying to get attention to the danger of xylazine infiltrating heroin and fentanyl. She said, “what we’re doing is a Band-Aid on a bullet hole.”

Drug users are reluctant to seek help until their medical condition had advanced to a dangerous point. One man waited until the wound on his wrist became so swollen and painful, he couldn’t move his hand. “The hospital told him that if he hadn’t come in then, he would have lost his hand.” Another man who had his wounds cleaned and wrapped was reluctant to consider going to a hospital for more advanced care because he was worried about getting “sick” in the hospital and being unable to use when he begins to experience withdrawal.

At this time, there has been minimal study of the xylazine drug scene. “Experts and advocates are still trying to understand just how dangerous xylazine is and how it works.” While presentations with images of the gruesome wounds from necrosis or dead tissue illustrate the serious adverse health effects from xylazine, medical professionals aren’t even sure what’s causing the necrosis, the wounds. Xylazine-related wounds can be healed with proper care, but many doctors aren’t aware that’s possible. It’s also changing what recovering from an overdose looks like after being given naloxone.

Someone who overdoses on tranq dope might start to breathe again after receiving naloxone, but still be unconscious from the sedative effect of xylaxzine. Giving them another dose of naloxone still won’t wake them up. “When it was just fentanyl, it was more straightforward. . . These kinds of unholy mixtures that bring down the level of consciousness in different ways are really making the overdose response picture tricky.” Although there are protocols for easing someone off illicit opioids, there is nothing for xylazine.

Savage Sisters provides drug users with cards they can give to medical providers that say, “Test me for xylazine.” The card also gives suggestions to medical professionals for treating the symptoms of xylazine withdrawal, which include anxiety. See the graphic below, taken from the STAT article.

It seemed that after fentanyl hit the streets, the drug scene couldn’t get any worse. But then drug entrepreneurs discovered xylazine mixed with fentanyl extends the fentanyl high and is cost-effective. Sure, your arms may feel like they’re dying, like tranq dope is eating your flesh. But isn’t the high worth it?

07/19/22

The Vicious Cycle of Antidepressant Use

CDC data reported that 13.2% of adults used antidepressants in the past 30 days, and their use increased with age. A similar increase by age was apparent when antidepressant use was examined in both men and women. “In all age groups, antidepressant use was higher among women compared with men.” However, a new study suggested that antidepressant use has very little effect on patients’ health-related quality of life.

The above information on antidepressant use was taken from the CDC data brief report looking at Antidepressant Use Among Adults in the United States. Antidepressant use in the past thirty days increased among adults aged 18-39 (7.9%), then to 14.4% among adults aged 40-59, and to 19.0% among adults aged 60 and over. Disconcertingly, 20% of women between 40 and 59 almost one quarter of women 60 and over were prescribed antidepressants. Overall, antidepressant use increased from 10.6% in 2009 to 13.8% in 2018. See the following charts from the CDC data brief.

The New York Times cited these statistics in “How Much Do Antidepressants Help, Really?” It observed that clinical drug trials only follow people taking antidepressants for 8 to 12 weeks, missing the vast majority of people who take them longer. The NYT article then referenced a study published in April of 2022, “Antidepressants and health-related quality of life (HRQoL) for patients with depression.” This study compared Americans with a depression diagnosis who took antidepressants, to Americans with a depression diagnosis who did not take the medications over the course of two years.

The data came from the US National Medical Expenditures Panel Survey (MEPS). The study included all types of antidepressants—SSRIs like Prozac, SNRIs like Effexor, and older antidepressants like phenelzine. The researchers found no significant differences in the changes in quality of life reported by the two groups, suggesting “that antidepressant drugs may not improve long-term quality of life.”

A physician and epidemiologist who was not involved in the study said it was difficult to come to a conclusion on this study alone. Individuals who are prescribed antidepressants are likely more depressed than individuals who aren’t prescribed drugs. “People with more severe depression might be less likely to improve their mental quality-of-life scores over time,” for reasons that don’t correspond to the antidepressants they take. When Peter Simons reviewed the study for Mad in America, he said that critique was simply false.

The researchers used a statistical method called the difference-in-difference (D-I-D) analysis that compared each subject’s follow-up levels to their individual baseline levels for their physical and mental component summaries, (PCS and MCS). They acknowledged their study’s inability to control for the effect of the severity of depression. “However, the D-I-D analysis compare each subject’s follow-up levels to his/her individual baseline levels for the PCS and MCS and investigate the overall change for the group which should minimize the impact of this factor on the overall analysis.”

Another perceived issue with the study was that since people were taking antidepressants for an extended time, some quality-of-life improvements could have taken place before the study began following them. Omar Almohammed, a co-author of the study said it was still reasonable to expect continued increases in quality of life long after beginning an antidepressant. “If we don’t expect improvement from the continuous use of these medications, then the correct decision might be to stop the continuous use of these medications.”

But pills are often cheaper. And it can be difficult for some to access therapy because there aren’t enough providers, and mental health treatment aren’t fully covered by all insurance plans. Robert DeRubeis of the University of Pennsylvania said, “It’s not at all clear that even in the short term, pharmacological approaches, on average, are more effective than psychological ones.”

Clinical trials suggest that although antidepressants do improve depression symptoms over the first few months, their benefits are modest and are much less pronounced among people with mild depression compared with those with severe depression. (This is worrying considering that, according to one study, 73 percent of Americans prescribed antidepressants don’t even have a diagnosis of depression.) And experts are divided over whether these small benefits make a noticeable difference to people’s moods or overall functioning.

Much of this improvement is attributed to the placebo effect, rather than the medication itself. Even researchers who argue the benefits from antidepressants admit they “do not work for everybody.” And over time, they will have even less benefits. There are approximately 15.5 million Americans who have been taking antidepressants for at least five years. The longer that people take them, there will likely be increasingly smaller benefits, “in part because patients build up a tolerance to the medications.”

But there is a vicious cycle if you decide to discontinue your use of antidepressants. Too rapid of a taper can lead to antidepressant withdrawal, euphemistically called “discontinuation syndrome.” These withdrawal symptoms are sometimes seen as a depressive relapse, “proving” the need to remain on antidepressants in order to hold off a major depressive episode. They often include physical sensations such as dizziness, nausea, and “brain zaps” (an electric shock sensation in the head). In “Distinguishing relapse from antidepressant withdrawal,” Mark Horowitz and David Taylor said many withdrawal symptoms overlap with symptoms of anxiety or depressions, making it difficult to distinguish.

Their onset soon after dose reduction, the association of psychological with physical symptoms, their prompt response to reinstatement, and their typical ‘wave’ pattern of onset, peak and resolution can help distinguish withdrawal symptoms from relapse.

Giovanni Fava has researched the adverse effects of antidepressants for almost thirty years. In 1994, he said in an editorial for the journal Psychotherapy and Psychosomatics, “The field of psychopharmacology has generally neglected the issue of potential sensitization of psychiatric disease to psychotropic drug use.” In January of 2022 he released Discontinuing Antidepressant Medications, as a guide for clinicians who want to help patients withdraw from antidepressants. Fava was interviewed by James Moore about the release of his book for a Mad in America podcast.

In Discontinuing Antidepressant Medications, Fava introduced the construct of behavioral toxicity of psychotropic drugs, applying it to the field of antidepressant tapering and discontinuation. Fava said it was originally described by Alberto DiMascio and Dick Shader.

A medication that is used at the normal, average doses may become toxic to the patient and this toxicity expresses itself with phenomena such as loss of clinical effect, where the patient is doing well on antidepressant and after a while of taking medication regularly, the antidepressant no longer works. If you try to increase the dosage, it may only help for a little while. So, loss of clinical effect and hypomanic episodes—that is the medication is really working too much and brings the patient to a state of hypomania or mania which is a symptom of bipolar disorder—but also a paradoxical fact that is that the antidepressant makes you more depressed.In the book, I discuss the relationship between venlafaxine and apathy. This is an example of a paradoxical effect and resistance, the fact that these patients become resistant either to the same medication, when it’s prescribed again or to another medication. Withdrawal is part of behavioral toxicity and my view is quite different from that of other investigators in the field because as a clinician I know that all these manifestations of behavioral toxicity are related.

Fava said if you have two, or three or even four of these manifestations together, it is likely an example of behavioral toxicity. He works with the most difficult cases and explained that the longer a patient is on a medication, “The higher the toxicity that you provoke.” In other words, the antidepressant that initially was effective “has become toxic” to the patient and is causing a problem. He said it is difficult to discontinue an antidepressant if you don’t use some additional medications and psychotherapy. Discontinuing antidepressants is not something that can be applied to all patients.

So, when I discuss with a patient, I’ll say that most of the patients, 90% of the patients respond, “Please, get this medication out of my body as soon as you can.” Then, we continue with that, but a basic problem which is not only in this field but in psychiatry and in medicine today is to believe that there is a procedure we should apply to all patients, and that is clinical practice shows that it’s not possible.

Antidepressant withdrawal, discontinuation syndrome, is becoming a greater concern in American psychiatry, but it isn’t where it needs to be. In addition to Giovanni Fava, Peter Breggin has been critical of the over prescription of psychiatric medications and wrote Psychiatric Drug Withdrawal in 2013. In 2020, the Royal College of Psychiatrists published “Stopping Antidepressants,” which contains information for “anyone who wants to know more about stopping antidepressants.” In May of 2018, The All-Party Group for Prescribed Drug Dependence (in the Parliament of the U.K.) published, “Antidepressant Dependency and Withdrawal.”

The Executive Summary of that publication said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting and of short duration. Antidepressants fulfill criteria for being dependency-forming medications. Around one-third of users “report being addicted to AD [antidepressants], according to their own definition of that concept.” The increase of long-term antidepressant use along with with the misdiagnosis of withdrawal reactions warrants serious concern.

The lengthening duration of AD use (which has doubled on average in the last 10 years) has fuelled rising AD prescriptions over the same time period. The evidence suggests that such lengthening duration may be partly rooted in the underestimation of the incidence, severity and duration of AD withdrawal reactions; underestimations which may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment. It warrants serious concern that the misdiagnosis of withdrawal may be contributing to escalating long-term AD use (since drugs are being reinstated rather than withdrawn), given that long-term use is associated with increased severe side-effects, increased risk of weight gain, the impairment of patients’ autonomy and resilience (increasing their dependence on medical help), worsening outcomes for some patients, greater relapse rates, and the development of neurodegenerative diseases, such as dementia.

For more on antidepressants on this website, try: “Withdrawal or Relapse When Tapering Antidepressants?” and “Are Antidepressants Worth the Risks?”

01/11/22

The Cost of Buprenorphine-Assisted Recovery

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As I was leaving a rescue mission in Pittsburgh, I saw a homeless man curled up in a fetal position in front of the building. He was unresponsive when I called out to him, so I went back inside and told someone to call 911. While I was doing this, another staff member got Narcan and administered it to the man. When the paramedics arrived, they were eventually able to convince him to go to the emergency department of a local hospital. But he refused further treatment services there and was released.

This is a typical response of those who experience a nonfatal opioid overdose. According to Davis et al in an article published in the Annals of Emergency Medicine, opioid users resist treatment with buprenorphine even though it significantly reduces overdose mortality. In an attempt to minimize this treatment void, some EMS paramedic units are administering buprenorphine to patients almost immediately after reviving them from an opioid overdose. STAT reported back in June of 2019 that New Jersey’s health commissioner authorized paramedics to offer the drug to patients after their overdose has been reversed with naloxone.

The first-in-the-nation model has a twofold purpose, health officials said: Beyond treating the withdrawal symptoms that can result from a naloxone revival, administering buprenorphine on scene could serve as an immediate transition to longer-term treatment.

Dr. Dan Ciccarone, a professor who studies heroin use and the opioid epidemic, said while the prehospital use of buprenorphine comes out of left field, “It’s a potentially brilliant idea.” He sees this as an attempt to treat the person in as well-meaning and patient-centric way as possible. “And that means naloxone plus a softer landing with buprenorphine.” Doctors in numerous emergency departments already prescribe buprenorphine in an effort to provide relief after reversing an overdose. Extending that ability to paramedics “is a new frontier.”

As a safeguard, New Jersey’s 1,900 paramedics will need to obtain permission from the emergency physician overseeing their unit before administering buprenorphine when responding to an overdose call. The supervising physician must have a DEA waiver [and undergo training] to prescribe buprenorphine, a spokeswoman said.

We need to think beyond how we’ve traditionally treated nonfatal opioid overdoses. A CDC press release indicated in the 12-months ending in April 2021, the estimated overdose deaths from opioids increased from 56,064 in April of 2020 to 75,673. Overall drug overdoses increased 28.5% during the same period of time. An interactive web dashboard is available and can gives you predicted overdose data for individual states. The overall increase in overdoses for the United States is 28.5%.

Pennsylvania was among the states hardest hit by the opioid epidemic. In 2018, it had one of the highest death rates from drug over doses, with 65% of 2,866 fatalities involving opioids. Policy responses made to mitigate the spread of COVID-19 in Pennsylvania made the problem worse. Analysis of data from the Pennsylvania Overdose Information Network for both fatal and nonfatal overdoses revealed statistically significant increases across some of the populations most affected by opioids before the pandemic.

In “Assessing the Relationships Between COVID-19 Stay-at-Home Orders and Opioid Overdoses,” the authors said the stay-at-home order in Pennsylvania contributed to a statistically significant increase in opioid overdoses compared with preceding months. See “Unintended Consequences of COVID-19” for more on this topic. It seems this increase in opioid overdoses may have partly motivated Pittsburgh to become only the third city in the country to announce a pilot group of Emergency Medical Services (EMS) paramedics that will administer prehospital buprenorphine.

On November 22, 2021, The Office of Community Health and Safety in Pittsburgh announced paramedics had completed training to administer prehospital buprenorphine and began implementing the practice over the weekend before Thanksgiving. In September, the Pennsylvania Department of Health Bureau of EMS approved the Prehospital Buprenorphine Pilot Program for the City of Pittsburgh’s EMS. The pilot program was designed by the Bureau of EMS in partnership with the Office of Community Health and Safety.

As part of the pilot, Advanced Life Support EMS units will be able to administer buprenorphine to patients experiencing opioid withdrawal regardless if that patient decides to go to the hospital. Patients will then be able to schedule a virtual follow up with the UPMC Medical Toxicology Bridge Clinic to have a consultation with a doctor within 24 hours to get a buprenorphine prescription and be connected to other critical harm reduction resources.

Advanced Life Support EMS units will be able to administer buprenorphine to patients experiencing opioid withdrawal regardless of whether they decide to go to the hospital. Patients will then be able to schedule a virtual follow up to have a consultation with a doctor within 24 hours in order to get a buprenorphine prescription and be connected to other harm reduction resources.

The mayor of Pittsburgh, Bill Peduto, said: “The opioid epidemic has deeply affected so many cities and communities. If tools like buprenorphine exist, we need to have them in our communities and with our emergency medical personnel.” The Pittsburgh Post-Gazette reported there has been a 58% increase in overdose-related calls between October of 2020 and July of 2021—the latest month the city had data on. See the following chart showing the drug overdose calls to EMS in Pittsburgh.

Research shows that buprenorphine-assisted recovery from opioid use decreases the likelihood of recurrent overdoses and death from overdoses while increasing the likelihood of the person engaging in recovery. Dr. Jody Glance said buprenorphine helps patients more comfortably stop using opioids by alleviating their withdrawal symptoms. “Once the person is stabilized on the medication, they will not have the same level of cravings or desire to use illicit opioids.” This stabilization allows the person to engage in activities to support their ongoing recovery.

Dr Glance said some people remain on buprenorphine because they believe it is saving their life. “A lot of people find that the medication is so helpful, that coming off of it is more risky than staying on it.” She added that sometimes people stay on buprenorphine for a long time. Like other chronic, relapsing illnesses, “with opioid use, a lot of times people need a medication on a more long-term basis.” For patients who want hospital treatment, the program allows them to schedule a follow up visit with The UPMC Medical Toxicology Outpatient Clinic to continue taking the drug.

While it is an amazing, almost miraculous tool, bringing relative stability to the lives of opioid addicts, it comes with a price. Buprenorphine is itself an opioid. The DEA classifies it as a Schedule III controlled substance. It’s effectiveness in alleviating withdrawal and minimizing cravings for licit and illicit opioids is based on this pharmacological fact. And long-term use of buprenorphine perpetuates some of the same neurochemical actions found in opioid use disorder.

In her book, Never Enough, Judith Grisel introduced what she said were the three laws of psychopharmacology. They are: 1) all drugs act by changing the rate of what is already going on in the brain; 2) all drugs have side effects; and 3) the brain of someone who misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit, or by reducing the number of receptors that can receive signals. The psychopharmacological action of buprenorphine-assisted recovery on the brain continues to activate these principles.

Not only do we need to bring stability to the lives of addicts after a nonfatal overdose, we need to educate them about the potential consequences they face with long-term use of buprenorphine. Inform them of the cost they’ll pay for a buprenorphine-assisted recovery.

For more information on Judith Grisel and the significance of the three laws of psychopharmacology to addiction recovery, see “Never Enough and No Free Lunch” and “Never Enough and Adaptation.”

07/21/20

Drug Overdose Deaths: In the Shadow of COVID-19

Over the last several months news of the COVID-19 pandemic has flooded the U.S. news media. Fears of a resurgence of positive cases and deaths from the virus are the new concern as states relax social distancing guidelines. When you look at the CDC website tracking total cases and deaths due to COVID-19, a clear geographic pattern is evident. California, Illinois, Michigan, Pennsylvania, New York, New Jersey and Rhode Island all have reported 40,000 or more cases, while Alaska, Hawaii, Montana, Wyoming and Vermont have reported less than 1,000 cases. Unfortunately, worry over COVID-19 has driven concern over drug overdose deaths as a public health concern from the consciousness of most people.

The CDC also reported a pattern to its data on overdose deaths in a “National Vital Statistics Report,” that illustrated the most lethal drug by geographic region. Overall, the drug most frequently involved in overdose deaths in the U.S, was no surprise; it was fentanyl. It accounted for approximately 39% of all drug overdose deaths. When the data is grouped regionally, fentanyl was the drug most frequently involved in overdose deaths east of the Mississippi and methamphetamine was the drug most frequently involved west of the Mississippi. Region 7, consisting of Nebraska, Iowa, Missouri and Kansas broke this pattern in reporting fentanyl as the drug most frequently involved in overdose deaths. See the following map for fentanyl taken from the October 2019 edition of the “National Vital Statistics Reports.”

The top 15 drugs belonged to several drug classes: opioids (fentanyl, heroin, hydrocodone, methadone, morphine, oxycodone, and tramadol), benzodiazepines (alprazolam, clonazepam, and diazepam), stimulants (amphetamine, cocaine, and methamphetamine), an antihistamine (diphenhydramine) and an anticonvulsant (gabapentin). Nationally, 38.9% of drug overdose deaths involved fentanyl (including fentanyl metabolites, precursors, and analogs), 22.8% involved heroin, 21.3% involved cocaine, and 13.3% involved methamphetamine. Alprazolam, oxycodone, and morphine were each involved in 6.9%–9.5% of the drug overdose deaths in 2017, while methadone, hydrocodone, diphenhydramine, clonazepam, diazepam, gabapentin, amphetamine, and tramadol were each involved in less than 5.0%.

Among the opioids, fentanyl, heroin, hydrocodone (Vicodin) and oxycodone (OxyContin) have been getting the lion’s share of the overdose press. But notice that methadone, used as an opioid maintenance drug, and tramadol also made the list. Benzodiazepines like alprazolam (Xanax), clonazepam (Klonopin) and diazepam (Valium) have been a growing, and hidden misuse and overdose problem, overshadowed by opioids like heroin and fentanyl. Gabapentin (Neurontin) likely became an overdose drug because of its use as a cheap way to potentiate an opioid high.Six drugs were found among the top ten most frequently involved drugs in all 10 of the Department of Health and Human Services (HHS( public health regions: alprazolam, cocaine, fentanyl, heroin, methadone and oxycodone. See the following table listing the top fifteen drugs most frequently involved in overdose deaths.

Commenting on the CDC data in the “National Vital Statistics Report” for ABC News, Holly Hedegaard, an epidemiologist and co-author of the report, noted how the drug problem was not the same across the country. “What’s interesting is that the patterns are different across the U.S.”

Zachery Dezman, an assistant professor of emergency medicine, thought the regional variations were the end product of cultural influences. Methamphetamine use beginning in California could account for the drug’s strong regional presence. “Like all culture, it varies from region to region and is a result of history, demand, law enforcement.” Although methamphetamine can be made cheaply, using material found on most farms, it produces a large amount of toxic waste. “So methamphetamines are more often produced in rural or isolated areas where it is easier to hide from the authorities.”

Dezman’s assessment may have been true in the 1990s, but there seem to be other factors influencing the geographic divide noted above. Writing for The Fix, Seth Ferranti indicated that 90% of the methamphetamine in the U.S. comes from Mexico, primarily manufactured in super labs by drug cartels. The Mexican labs, like the TV show Breaking Bad, are making a very pure, relatively cheap meth. Local suppliers then “cut” the meth with cheaply produced fentanyl in order to sell more of it at a lower expense. Brandon Costerison, a project manager for the National Council on Alcoholism and Drug Abuse said: “It’s a lot stronger, so we’re seeing a lot more psychosis, but we’re also seeing it being tainted with fentanyl, which is leading to more deaths.”

According to the 2018 National Drug Threat Assessment, the methamphetamine sampled in the second half of 2017 averaged 96.9% pure. The price per gram of meth was $70. The purity had increased 6%, while the price decreased 13.6%. Most of the Mexican transnational criminal organizations (TCOs) or drug cartels are involved in trafficking methamphetamine, which has led to increased competition between the cartels. The authors of the 2018 National Drug Threat Assessment speculated this competition led the Mexican TCOs to try moving into new territories and experiment with novel smuggling methods, such as the use of drones, in attempts to increase their methamphetamine customer base.

Though not favored by traffickers due to their noise, short battery life, and limited payload, advances in technology may make this method more feasible. As the technology advances and addresses these shortcomings, drones may prove more attractive to smugglers, which in turn may increase their prevalence as a smuggling technique across the border.

Currently methamphetamine laboratory seizures in the U.S. are at the lowest level in 15 years and domestic production is at its lowest point since 2000. From a high of 23,703 in 2004, there were 3,036 seizures in 2017. Between 2012 and 2017, the number of seized domestic meth laboratories decreased by almost 78%. This can be attributed, at least partly, to the Combat Methamphetamine Epidemic Act (CMEA), which was signed into law on March 9, 2006 to regulate over-the-counter sales of methamphetamine precursors like ephedrine and pseudoephedrine. But it left a supply hole the Mexican cartels were happy to fill.

The number of deaths due to psychostimulants continues to increase dramatically. According to the CDC, methamphetamine drug poisoning deaths are included under the broader category of psychostimulants, which include MDMA, amphetamine and caffeine. While the value changes yearly, recently 85 to 90% of the drug poisoning deaths reported under psychostimulants mentioned methamphetamine on the death certificate. “According to the CDC, in 2016 there were 7,542 psychostimulant drug poisoning deaths in the United States, representing a 32 percent increase from 2015, and a 387 percent increase since 2005.” See the following figure from the 2018 National Drug Threat Assessment.

Despite the growth of methamphetamine use, for people who use the drug, treatment options are slim. Currently there is no FDA-approved medication for methamphetamine use disorder, but there seems to be some promising results with naltrexone. Available as a pill or an extended release injection (Vivitrol), naltrexone is used to prevent a relapse with opioid use and it suppresses the euphoria and pleasurable sensations from drinking alcohol. There have been some studies of naltrexone as a treatment for methamphetamine use disorder.

Ray et al published a double blind, placebo-controlled study of naltrexone with individuals meeting DSM criteria for methamphetamine abuse or dependence. The results indicated that naltrexone reduced the pleasurable effects of the drug as well as cravings. The lead author of the study, Lara Ray told ScienceDaily: “The results were about as good as you could hope for.” She has done several studies on the effectiveness of naltrexone for methamphetamine addiction, including one on how executive function moderated naltrexone effects on methamphetamine-induced craving.

Naltrexone significantly reduced the subjects’ craving for methamphetamine, and made them less aroused by methamphetamine: Subjects’ heart rates and pulse readings both were significantly higher when they were given the placebo than when they took Naltrexone. In addition, participants taking Naltrexone had lower heart rates and pulses when they were presented with their drug paraphernalia than those who were given placebos.

NPR published an article noting how a woman successfully used naltrexone to help her stop using methamphetamine. She had used drugs like cocaine for years, since she was a teenager. But when she tried crystal meth, she said she was hooked from the first hit. “It was an explosion of the senses. It was the biggest high I’d ever experienced.” She went from 240 pounds to 110. She also lost custody of her children. She said three to four hours after she took the first naltrexone pill, she felt better. After taking the second pill, her withdrawal symptoms lessened.

Nancy Beste, the certified addiction counselor and physician’s assistant who treated the woman, has tried naltrexone with about 16 patients who use methamphetamine. It appeared to help reduce cravings in about half of them. She also treats individuals with opioid addiction and all her patients do counseling in conjunction with medication-assisted treatment. Her treatment goal is to eventually wean them off the medications. Unlike buprenorphine and methadone, naltrexone is not a controlled substance with its own addiction potential. In my opinion, that makes it a promising medication assisted treatment (MAT) for methamphetamine.

Drug overdose deaths did not just disappear when COVID-19 arose. The CDC reported 128 people die every day from an opioid overdose. Although the number of drug overdose deaths decreased by 4% from 2017 to 2018, it was still four times higher than in 1999. Prescription-involved deaths had increased by 13.5% while heroin-involved deaths decreased by 4%. Synthetic opioid-involved deaths, excluding methadone, increased by 10%. Methamphetamine-involved deaths accounted for approximately 11% of the of the number of drug overdose deaths in 2018. The COVID-19 pandemic may have overshadowed the opioid epidemic, but it didn’t stop it.

I’ve written about all these drug classes and the potential they have for abuse. For starters, see “Through the Fentanyl Looking Glass,” “Doubling the Risk of Overdose,” and others on opioids. Also see “Global Trouble with Tramadol”, “Gabapentinoids Perpetuate Addiction” and “The Evolution of Neurontin Abuse” for more on the problems with gabapentin or tramadol. See “Are Benzos Worth It?” “It Takes Away Your Soul” and “Dancing with the Devil” on concerns with benzodiazepines. Search on the website for the drug you are interested in reading more about in other articles.

11/5/19

Ticking Time Bomb of Speedballing

What do the following celebrities have in common: John Belushi, Chris Farley, Phillip Seymour Hoffman, and River Phoenix? Their deaths were attributed to speedball use, a combination of cocaine and heroin or morphine. Speedballs may also combine other pharmaceutical opioids, benzodiazepines or barbiturates along with stimulants, as it seems was the case with the death of Phillip Seymour Hoffman. The combination of stimulant and depressant drugs suppresses the usual negative side effects of each class of drugs, which can lead to misjudging the tolerance or intake of one or both drugs. “Due to the countering effect of the cocaine, a fatally high opioid dose can be unwittingly administered without immediate incapacitation, thus providing a false sense of tolerance until it is too late.”

Combining stimulants and opiates dates back at least to Sigmund Freud, who unsuccessfully attempted to counteract a friend’s morphine addiction with cocaine. Freud later acknowledged he may have hastened his friend’s death by “trying to cast out the devil with Beelzebub.” Nevertheless, Freud continued his personal use of cocaine despite his failed attempt to counter his friend’s morphine addiction. Several scholars have debated whether or not Freud’s use of cocaine influenced his developing theories, especially their emphasis on sex. For more information on Freud and his cocaine use, see “Sigmund Freud was a Cocaine Evangelist and Addict.”

The polysubstance misuse of stimulants and opioids has not received much media attention, but in the evolving nature of the opioid crisis that may be changing. The CDC recently published the results of an investigation of drug overdose deaths with cocaine and psychostimulants in the US between 2003 and 2017. In 2017 there were 70,237 drug overdose deaths, of which nearly a third (32.9%) involved cocaine, psychostimulants or both. Nearly three quarters of cocaine-involved deaths and about one half of the psychostimulant-involved deaths involved at least one opioid. Between 2006 and 2012 there was a decrease in overall cocaine-involved death rates that seems to have paralleled a decline in cocaine supply, but they began to increase again in 2012 (See the following figures).

Drug overdoses continue to evolve along with emerging threats, changes in the drug supply, mixing of substances with or without the user’s knowledge, and polysubstance use. In addition, the availability of psychostimulants, particularly methamphetamine, appears to be increasing across most regions. In 2017, among drug products obtained by law enforcement that were submitted for laboratory testing, methamphetamine and cocaine were the most and third most frequently identified drugs, respectively. Previous studies also found that heroin and synthetic opioids (e.g., illicitly-manufactured fentanyl) have contributed to increases in stimulant-involved deaths. Current findings further support that increases in stimulant-involved deaths are part of a growing polysubstance landscape. Although synthetic opioids appear to be driving much of the increase in cocaine-involved deaths, increases in psychostimulant-involved deaths have occurred largely without opioid co-involvement; however, recent data suggest increasing synthetic opioid involvement in these deaths.

Among the 70,237 overdose deaths in 2017, 13,942 (19.8%) involved cocaine and 10,333(14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 in both drug categories across demographic categories such as sex and race. Male overdoses involving cocaine increased 31.9%. Male overdoses involving psychostimulants increased 32.4%. Female overdoses involving cocaine increased 38.9%. Female overdoses involving psychostimulants increased 35.7%.

White, non-Hispanic overdoses involving cocaine increased 35.3%. White, non-Hispanic overdoses involving psychostimulants increased 40.0%. Black, non-Hispanic overdoses involving cocaine increased 36.1%. Black, non-Hispanic overdoses involving psychostimulants increased 33.3%. Hispanic overdoses involving cocaine increased 25.0%. Hispanic overdoses involving psychostimulants increased 33.3%.

Preliminary data for 2018 suggests continuing increases in drug overdose deaths. Given the rise in deaths involving cocaine and psychostimulants “and the continuing evolution of the drug landscape,” the authors called for a rapid, multifaceted and broad approach that included both surveillance efforts and prevention and response strategies. The mixture of opioids in stimulant-involved overdoses underscored the importance of continued opioid overdose surveillance and prevention measures, including the expansion of naloxone availability. The CDC is expanding its drug overdose surveillance to include stimulants. And it is implementing evidence-based opioid prevention efforts such as improving the ability for users to access care and collaborations with public health and public safety organizations.

The increase of stimulant deaths without opioid involvement requires efforts to identify and improve access to care for persons who only use stimulants as well. The authors also suggested implementing upstream prevention efforts focusing on shared risk with both opioids and cocaine. The Fix cited comments by Hans Brieter, a psychiatry professor at Northwestern University, on how cocaine is thought of as a safer drug to use by many people today. “There’s been a lot of bad press about other drugs.” Younger people today didn’t see firsthand the 1970s dangers of cocaine, he said, so they mistakenly believe it to be the safer drug. Increased efforts towards protective factors that address substance use/misuse and improve risk reduction (“don’t use alone”) should be made as well.

The concluding sentence of the CDC Report called for collaboration between the community and public health and safety organizations, in order to understand the local drug scene and reduce its risks to users of both drugs. “Continued collaborations among public health, public safety, and community partners are critical to understanding the local illicit drug supply and reducing risk as well as linking persons to medication-assisted treatment [MAT] and risk-reduction services.” Here we may be seeing a peek under the hood at what the authors fear the most with their suggested linking to MAT, namely the increasing synthetic opioid involvement in cocaine-involved or psychostimulant overdose deaths. Remember that speedballing mixes a stimulant with a depressant. Due to the offsetting effects of the two drugs, a fatal amount of an opioid could be used without a realization of the danger until it’s too late.

10/15/19

The Ticking Time Bomb of Vaping

The clouds for the coming storm of adverse effects with e-cigarettes began to gather in the spring of 2019. Time Magazine reported the FDA was alerting Americans that vaping may be associated with seizures. Then in late May, researchers at the Stanford University School of Medicine published a study warning that the flavoring liquid of e-cigarettes may increase the risk of cardiovascular disease. After there was a report in the New England Journal of Medicine about an e-cigarette exploding in a teen’s mouth, reports of adverse effects began to fall all summer. The NEMJ said the teen had a circular puncture to the chin, extensive lacerations in his mouth, multiple disrupted lower incisors, a mandibular fracture and other injuries.

By late summer, the reports of possible cases of severe respiratory illnesses among people vaping more than doubled. Five people had died. In early September, the CDC suggested people should avoid using e-cigarettes. The NEMJ said e-cigarette products containing THC were the most commonly reported, in 84% of the study’s patients. But 17% of patients reported using only nicotine-based products, and 44% reported using both THC-based and nicotine-based products.

The findings in this report support several public health recommendations issued by the CDC. Since no single product or substance has been associated with the illness, persons should consider not using e-cigarettes while this investigation is ongoing, especially those purchased from sources other than authorized retailers (e.g., e-cigarette products with THC) and those modified in a manner not intended by the manufacturer. Adult smokers who are attempting to quit should consult with their health care provider and use proven treatments. Irrespective of these findings, e-cigarettes should never be used by youths, young adults, pregnant women, and adults who do not currently use tobacco products.

As of October 1, 2019, the CDC reported there were 1,080 lung injury cases associated with e-cigarette or vaping products from 48 states and 1 US territory. There were 18 confirmed deaths in 15 states. All patients reported a history of using e-cigarette or vaping products. Most said they had used THC-based products. Sixteen percent of patients were under 18; 21% were 18 to 20 years old. “No single product or substance has been linked to all lung injury cases. More information is needed to know whether a single product, substance, brand, or method of use is responsible for the outbreak.” See the CDC link for data on symptom onset and hospital admission with lung injury peaking in mid-August to early September.

According to NPR, the CDC’s principle deputy director, Dr. Anne Schuchat said: “We’re worried that there are plenty of risky products still out there. . . That’s one of the reasons we’ve intensified our warnings.” She said it was essentially impossible to know what is in the e-cigarette or vaping product you are getting, especially the THC-containing products. “The data we are getting does not suggest this has peaked.” She added that these are serious injuries in the lung, “and we don’t know how well people will recover from them, whether lung damage may be permanent.”

The Wall Street Journal reported experts think the symptoms are sparked by an inflammation or injury in the lungs from a chemical exposure. Researchers at the Mayo Clinic published a review of lung biopsies from 17 patients and said the injuries seemed more like the consequence of inhaling toxic chemicals rather than an oil. However, some of the earlier cases were diagnosed as lipoid pneuma, “which is a result of inhaling a fat or oil into the lungs.” Aside from the vaping link, federal officials are not sure of the exact cause of the outbreak. See the WSJ link for a short video on how it appears to be related to black market THC vapes.

The New York Times reported that as of October 4^th, there were 21 confirmed deaths in 18 states. See the following map by the New York Times for cases of vaping-related lung illness and vaping-related deaths.

Dr Howard Zucker, the New York State health commissioner, said this was a public health emergency:

It is undeniable that the vaping industry is using flavored e-cigarettes to get young people hooked on potentially dangerous and deadly products. While the court’s ruling temporarily delays our scheduled enforcement of this ban, it will not deter us from using every tool at our disposal to address this crisis.

Reflecting on his blog about the vaping illnesses and deaths, William White, the Emeritus Senior Research Consultant of Chestnut Health Systems, said new technologies that increase the efficiency of drug consumption by altering per episode and lifetime drug dosage, drug purity, or the method of drug administration may require “a fundamental rethinking of the risks associated with particular drugs.”

While the toxic effects of new drugs and new ways of using known drugs are usually identified early in their social emergence, the nightmare scenario would be a Trojan Horse that possessed few if any short term negative effects but devastating effects linked to long-term use. That is precisely the scenario that forced a radical rethinking of the effects of smoking tobacco over the past century. When toxic drug effects become quickly apparent before widespread use, mass public health damage can be minimized. In the case of tobacco smoking, short term studies would not have revealed smoking as the ticking time bomb that it is. We must be vigilant in identifying other drugs and patterns of drug consumption that may share a similar trajectory.

White’s concluding paragraph said those in the forefront of dealing with addiction have a unique opportunity to identify these threats early in their emergence. When we see them, “we can communicate what we are observing to public health and community leaders, and by so doing, arouse action to reduce the numbers of people exposed to such threats as well as get people already exposed the help they need as quickly as possible.” So, here is something new about vaping that just appeared this morning, as I was completing this article on October 8, 2019: “Vaping nicotine linked to lung cancer.”

News, Medical reported how a team of researchers at New York University School of Medicine caused mice to develop lung cancer. Yes, it is just an initial study with mice, but remember that if vaping is a relatively new way of using nicotine, research into the adverse effects of vaping is even newer. Mice studies are where researchers begin to investigate the problems. The study, “Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice” said that since given the fact that epidemiological data on the relationship between e-cigarettes (ECS) and human cancer may not be known for another ten years, the carcinogenicity of ECS was tested in mice. The researchers found that mice exposed to e-cigarettes for 54 weeks developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). “We showed that ECS exposure of mice induces lung cancer and bladder urothelial hyperplasia.” The lead author of the study, Moon-shong Tang, said to News, Medical:

Tobacco smoke is among the most dangerous environmental agents to which humans are routinely exposed, but the potential of E-cig smoke as a threat to human health is not yet fully understood. Our study results in mice were not meant to be compared to human disease, but instead argue that E-cig smoke must be more thoroughly studied before it is deemed safe or marketed that way.

Then on October 11, 2019, an article was published in Nature that reported on various studies of adverse consequences of e-cigarette use. Some researchers are focusing on general lung damage and inflammation from toxic chemicals, others are concentrating on vitamin E acetate, an oily chemical suggested as a cause of the vaping illness. One researcher cautioned against hoping for quick answers; her initial findings took three and a half years to complete. The chief medical officer of the American Lung Association said science would eventually win, “But I don’t think it’s going to be as soon as people would like.”

Other researchers are working to categorize the chemicals contained in e-cigarettes. But the thousands of products and the culture of users who readily modify e-cigarettes and their contents makes this “a tough nut to crack.” One researcher said vapers are altering everything from how hot their e-cigarettes get to what chemicals are included in vaping cartridges, including in one instance, liquid Viagra. In the meantime, the vaping illness has sickened about 1,300 US vapers and killed 26. Brandon Larsen, a pulmonary pathologist, said everything is so rapidly evolving, that “I could tell you something today and next week it could be totally wrong.”

William White is right. We must remain vigilant to recognize potential long-term adverse effects with e-cigarettes in order to minimize mass public health damage. “It takes two decades or more for a life-time smoker to develop lung cancer. If tobacco smoke-induced lung carcinogenesis is a paradigm for e-cig carcinogenicity, then it will take at least another decade to have e-cig-related human lung cancer to show up.” It seems there is emerging evidence that the trajectory of e-cigarettes is leading us down the same path as tobacco cigarettes and it seems smoking e-cigarettes is a ticking time bomb. Do we really want to wait another ten years for the conclusive evidence of epidemiological data on the relationship between e-cigarettes (ECS) and human cancer before we take action to minimize the risk?

08/3/18

Lies, Damn Lies and Autism Statistics

The Center for Disease Control and Prevention (CDC) recently published a study, “Prevalence of Autism Spectrum Disorder,” that said the overall prevalence rate for Autism Spectrum Disorder (ASD) in the US was 16.8 per 1,000 (one in 59) children who were 8 years old in 2014. Estimates of ASD increased from one in 150 children during 2000-2002 to one in 68 during 2010-2012. This means the prevalence of ASD doubled in the twelve years between 2000 and 2012; then it increased another 16% between 2012 and 2014. One autism expert said those rapid increases were not believable, and even “preposterous.”

Darold Treffert made the above comments in his article for Scientific American, “We Need to Stop Moving the Goalposts for Autism.” Dr. Treffert is an expert on savant syndrome and wrote two books on the topic. He was also a consultant for the movie Rain Man. He believes the reported increases in ASD were the result of moving the goalposts in diagnosis by diluting the condition and expanding the definition of ASD.

Problems he pointed to in the CDC study included the fact that figures included what he called “educational autism,” meaning a diagnosis made by teachers or educational specialists; and “medical autism,” a diagnosis based on review of available medical records. “There are no actual in-person evaluations.” Another issue he pointed out was the extremes of prevalence reported between states within the Autism and Developmental Disabilities Monitoring (ADDM) Network used for the CDC study. New Jersey, one of the eleven ADDM sites in the US, reported a prevalence of 2.93 percent for ASD, more than double that of Arkansas at 1.31 percent.

From my perspective as an observer of “autism” for over 60 years, I do believe there is an actual increase in the number of cases of autistic disorder, but it is not an epidemic. And it has not been an increase of 31 percent in two years here in Wisconsin, for example, or a more than 150 percent increase in the U.S. in the past decade. That is simply not believable. Instead much of that “epidemic” is a dilution of the rigor of the criteria for autism.

He noted some examples of misdiagnosis, and said the first step is to make a correct diagnosis. The broader and less precise the diagnosis becomes, the less chance of finding subgroups “among increasingly heterogeneous, diluted diagnostic groups.” He believes autism is a group of disorders, rather than a single disorder. In order to detect autism with precision Treffert said we need to start calling things by their right names. “The present method of assessing prevalence in the U.S. is not doing that well since we keep moving the goalposts.”

Treffert referred to another Scientific American article by Simon Baron-Cohen, “Is It Time to Give Up on a Single Diagnostic Label for Autism?” When reviewing the rationale for a single diagnostic label for ASD, Baron-Cohen said the term spectrum in ASD refers to the heterogeneity in autism. Although all autistic individuals share certain core features, “there are huge disparities in many areas.” This heterogeneity is part of the meaning of the term “spectrum.” He then pointed to other benefits of the ASD label:

It allows the clinician to describe the person without shoehorning them into a rigid subgroup. Its flexibility also allows for individuals who previously transitioned between different subgroups. And it reduced the risk that service providers might exclude a person because they didn’t meet the eligibility criteria based on a rigid subtype. So, the consensus among clinicians is that the addition of the word “spectrum” was helpful and long overdue. Most clinicians therefore find it useful to have the flexibility of the very broad single diagnostic label.

He then turned to the downside of a single diagnostic label. The American Psychiatric Association combined what had been Asperger Syndrome (AS) with classic autism in the DSM-5, believing the diagnosis of AS was unreliable. Hindsight suggests that wasn’t the problem. Rather, the contrast between AS and classic autism had value and “perhaps should have been retained.” He suggested using a typology of subtypes within ASD. “Under this approach, we could keep the single umbrella category called the autism spectrum and within this have type 1, type 2, etc.”

Treffert commented that the search for a reliable, consistent measure of autism prevalence occurred outside the U.S., as well. He referred to a different set of researchers in “Global Data on Autism Spectrum Disorders Prevalence” whose data for ASDs suggested the global rate was around 1.7 per 1,000 (one in 588), not the 16.8 per 1,000 (one in 59) reported by the CDC study. The authors noted in many developing countries the reported rates of ASD are significantly lower than in developed countries. “Whether this truly reflects an absolute low prevalence, deficits in diagnostic skills, maladaptation of diagnostic criteria as it relates to cultural differences in behaviour, or under sampling are issues that continue to be discussed.” Treffert added there is also an inconsistency between how the DSM-5 and the World Health Organization’s International Classification of Diseases (ICD) define ASD.

Allen Frances, the chair for the DSM-IV, added another perspective into the autism “epidemic” in his book, Saving Normal. He said before the DSM-IV, the diagnosis of autism was extremely rare. But the DSM-IV broadened the concept of autism by introducing Asperger’s disorder. And prevalence rates are extremely sensitive to any change in how a psychiatric disorder is defined. “The twentyfold increase in just twenty years occurred because diagnostic habits had changed radically, not because kids were suddenly becoming more autistic.”

As chair of the DSM-IV Task Force, I deserve blame for not having anticipated the rush to overdiagnose Asperger’s. It would have been useful in advance to predict the changes in diagnostic rates and to explain their causes. We should have proactively taken steps to educate the public and the media about what the labels mean and what they don’t mean—that kids hadn’t changed, just the way they were being diagnosed. It’s a lot easier to trigger a fad then end one.

The prevalence of autism surely came from improved surveillance and identification by doctors, teachers, families and patients. Some of the increase was also because of the introduction of Asperger’s disorder, “a new diagnosis that greatly broadened the concept of autism.” But Frances estimated that about half of the increase was due to the service opening provided—“children get the diagnosis incorrectly because it is the ticket to more attention in the school system and more intense mental health treatment.”

It would be better if school decisions were not so closely coupled to a psychiatric diagnosis that was developed originally only for clinical, not for educational, purposes. Many of the mislabeled kids do get special attention; they just don’t need the extra added stigma that comes with an incorrect diagnosis of autism.

Frances also pointed out another issue leading to the drastically high prevalence rate found by the CDC study: epidemiological miscount. He said every so often we hear about the climbing rates of some psychiatric disorder, which in this case is autism. These rates are generated by a psychiatric epidemiologist, “using a method that is inherently flawed and systematically biased in the direction of overreporting.” Epidemiological studies, like that conducted by the Autism and Developmental Disabilities Monitoring (ADDM) Network, rely on lay interviewers with no clinical experience and no ability to determine whether symptoms are clinically meaningful or not. “They make their diagnoses of psychiatric disorders based upon symptoms counts alone with no consideration of whether the symptoms are severe or enduring enough to really warrant diagnosis or treatment.”

The ADDM study, as Treffert pointed out, had no in-person interviews. The ADDM staff reviewed records and abstracted information from “comprehensive evaluations” that were completed in the local communities. A child was considered to meet the case definition for ASD,

If he or she displays behaviors, as described on one or more comprehensive evaluations completed by community-based professional providers, consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autistic disorder; pervasive developmental disorder–not otherwise specified (PDD-NOS, including atypical autism); or Asperger disorder.

Allen Frances noted where this always results in greatly inflated rates. Psychiatric symptoms in mild form are widely distributed in the general population. From time to time almost everyone will experience isolated or mild symptoms of a psychiatric disorder. “But isolated or mild symptoms alone do not define psychiatric disorder—they must cohere over time in a specified way and also cause significant distress or impairment.” Epidemiological studies, Frances said, regularly disregard these factors. “They mistakenly diagnose as psychiatric disorder symptoms that are mild, transient, and lacking in clinical significance.”

Results generated in this rough-and-ready way are no more than an upper limit on the prevalence of any given mental disorder. They should never be taken at face value as a true reflection of the real extent of illness in the community. Unfortunately, the exaggerated rates are always reported without proper caveat and are accepted as if they are an accurate reflection of the real prevalence of psychiatric disorder. Disraeli exaggerated only a tad when he said: “There are three kinds of lies: lies, damned lies, and statistics.”

05/29/18

Doublespeak in the Opioid Crisis, Part 1

How did we get to the place where overdose deaths from opioids were five times higher in 2016 than 1999? On average, 115 Americans die every day from an opioid overdose. An estimated 66% of all the drug overdose deaths in 2016 involved an opioid. From 1999 to 2016, more than 630,000 people died from a drug overdose. And there is evidence that a 1980 one-paragraph letter published in the New England Medical Journal was used to get us there.

The above statistics were from a CDC page on opioid overdose called, “Understanding the Epidemic.” The article showed a graphic representation of three waves in the rise in opioid overdose deaths. The first wave began in the 1990s with increase of overdose deaths from prescription opioids. “The second wave began in 2010, with rapid increases in overdose deaths involving heroin.” The third wave began in 2013 and is associated with illicitly manufactured fentanyl.

The letter was co-written by Dr. Hershel Jick, a drug specialist at Boston Medical Center. A Boston Globe article reported that Dr. Jick said his letter only referred to hospital patients getting opioids for a short period of time, not long-term outpatient use. He said: “I’m essentially mortified that that letter to the editor was used as an excuse to do what these drug companies did.” In his book, Pain Killer, Barry Meier noted years after the publication of his 1980 letter Dr. Jick said that he and his coauthor submitted their statistics about opioid use as a letter “because they were not robust enough to merit a study.” He added that nothing could be concluded about the long-term use of opioids from his study.

A team of Canadian researchers demonstrated the connection between Jick’s letter and the opioid epidemic. Their analysis of this connection was published in an editor’s note for the New England Medical Journal: “A 1980 Letter on the Risk of Opioid Addiction.” The original 1980 letter is in an appendix for the June 2017 editor’s note by Juurlink et al. in the NEMJ. It is quoted here in its entirety:

Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well-documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine [Demerol] in two patients, Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.

Dr. David Juurlink, who led the analysis, was quoted by the Boston Globe as saying: “It’s difficult to overstate the role of this letter. . . . It was the key bit of literature that helped the opiate manufacturers convince front-line doctors that addiction is not a concern.” The NEMJ said its readers should be aware Jick’s letter was heavily and uncritically cited as evidence addiction was rare with opioid therapy. “People have used the letter to suggest that you’re not going to get addicted to opioids if you get them in a hospital setting. We know that not to be true.”

Here’s what Juurlink and his colleagues did. They identified 608 citations of the 1980 letter “and noted a sizable increase after the introduction of OxyContin (a long-acting formulation of oxycodone) in 1995.” Of the articles citing the 1980 letter, 80.8% (491) cited it as “evidence that addiction was rare in patients treated with opioids.” Additionally, 80.8% (491) of the 608 articles did not point out the patients who were described by Jick in his letter were hospitalized at the time they received the prescription. Affirmational citations of the article began to decrease after 2002. See the NEMJ article for a chart illustrating this.

Now let’s look at this trend from another perspective. The Joint Commission (formerly The Joint Commission on the Accreditation of Healthcare Organizations or JCAHO) published a document titled: “The Joint Commission’s Pain Standards: Origins and Evolution.” In 1990 the President of the American Pain Society wrote an editorial criticizing the lack of improvement in pain assessment and treatment since 1970. He said the failure was because patients didn’t tell their doctors and nurses about their pain, nurses weren’t able to adjust doses, and doctors were reluctant to use opioids. Pain, he said, was often invisible. “Pain relief has been nobody’s job.”

In addition to his recommendations to help “make pain visible,” he emphasized the received wisdom of the day that “therapeutic use of opiate analgesics rarely results in addiction.” This wisdom “was based on only a single publication that lacked detail on how the study was done.” That “study” was the one done by Dr. Hershel Jick and the citation was his 1980 article in the NEMJ. The next year the American Pain Society released quality of assurance standards for the relief of both acute pain and cancer pain. The recommendations followed the previous recommendations of its President. The Joint Commission followed suit and announced new standards for health care organizations to improve pain management in 2000.

Recall that the CDC marked the beginning of the first wave of overdose deaths as beginning in 1999. In “Understanding the Epidemic” a CDC chart tracked the number of drug overdose deaths since 1999. It noted the initial wave of overdose deaths was due to increased prescribing of opioids (natural and semi-synthetic opioids) beginning in the 1990s; with the second wave of heroin beginning in 2010; and synthetic opioids coming as the third wave in 2016. Below is a CDC data brief apparently used to compile the CDC’s three-wave chart.

The Joint Commission standards were lauded by pain management specialists and called “A rare and important opportunity for widespread and sustainable improvement in how pain is managed in the United States.” However, some raised concerns that the new standards would encourage the inappropriate use of opioids. Total opioid prescriptions had been steadily increasing in the U.S. since 1991, which the Joint Commission attributed to the efforts of advocacy work by pain experts. From 1997 the acceleration for opioid prescribing seems to have become more rapid. “Some of this acceleration in the rate of increase in opioid prescribing may have been due to the 1995 approval of the new sustained-release opioid OxyContin.”

The FDA had approved labeling for OxyContin which said that iatrogenic addiction was “very rare” and that the delayed absorption from the sustained-release formulation in OxyContin “reduced the abuse liability of the drug.” These claims were used by Purdue Pharmaceuticals in marketing campaigns to physicians and in more than 40 national pain-management and speaker training conferences; all expense paid ones, that is. In 2001 the FDA required Purdue to remove these unsubstantiated claims form the OxyContin labeling. But the damage was done. “However, the concept that iatrogenic addiction was rare and that long-acting opioids were less addictive had been greatly reinforced and widely repeated, and studies refuting these claims were not publish until several years later.”

So a one-paragraph 1980 letter became a kind of doublespeak, misused by Purdue Pharmaceuticals and others to change popular and medical thinking about pain management. And the first wave of the opioid epidemic was the result.

Updated with additional information on Dr. Jick’s 1980 letter on 6/8/2018

03/27/18

Kratom Regulation is Coming

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?”

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.

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