Xylazine -Tranq dope - An Emerging Magnifier of the Opioid Crisis

A Deadly Combination

Xylazine is a drug used by veterinarians for decades as a sedative and pain reliever on cattle, horses and other animals.  Studies for human use more than 50 years ago were terminated because of intolerable side effects.  It has never been approved or intended for human use.  Since the early 2000’s, but with a dramatic escalation in the last 5 years, xylazine has been detected in the illicit US drug supply, most commonly combined with fentanyl.  In the most recent data, fentanyl-xylazine combinations have been identified in 48 states. In 2022, xylazine was detected in 90% of street opioid samples tested in Philadelphia.    In a 2023 report from Tennessee, the fatal overdoses of fentanyl mixed with xylazine increased 352% from 2019 to 2022.  In April, 2023, the White House Office of Drug Control Policy designated fentanyl combined with xylazine as “an emerging threat to the United States.”  The administrator of the US Drug Enforcement Administration (DEA) concluded in early 2023 that “Xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier.”

Xylazine isn’t an opioid like morphine, heroin or fentanyl and isn’t affected by the opioid reversal drug naloxone (Narcan).  Xylazine acts in the central nervous system depressing sympathetic outflow leading to sedation, analgesia and muscle relaxation. Other xylazine effects include lowered blood pressure, slowing of the heart rate, hyperglycemia and respiratory depression. Unfortunately some of these effects are additive to those seen with fentanyl overdose, increasing the risk of fatality.

 Xylazine may have been initially used as a filler in illicitly manufactured fentanyl tablets because of its low cost - a kilogram of xylazine can be purchased online from Chinese suppliers for as low as $6.  The fact that some users claim that xylazine prolongs the short-lived fentanyl high is likely another driver for the combination. 

Xylazine represents a relatively new entrant into the illicit  drug supply.  Street names for the drug include tranq dope, philly dope, sleep-cut, and horse tranquilizer.   Unlike fentanyl and other opioids which can be reversed with naloxone, there is no antidote for xylazine.  In the Tennessee study there were fatal xylazine/fentanyl overdoses despite treatment with Narcan.  Illicit fentanyl users may be unaware they are also taking xylazine.  Only recently have high sensitivity rapid test strips to detect xylazine become available.  While Narcan should be administered in all suspected opioid overdoses, when xylazine is present patients may require additional medical support including intubation and oxygen to improve breathing.  IV fluids may be required to raise blood pressure.  Clearly management of a xylazine/fentanyl overdose may be more complex than a fentanyl overdose alone.  

Xylazine causes open skin ulcerations, often progressing to deep wounds down to tendons and even bone.  These don’t only occur at injection sites and may occur with oral, intranasal or inhalational use.  These ulcers usually occur on the limbs and require careful, intensive wound care.  Unfortunately,  these very nasty wounds are a barrier for some patients who need shelter or inpatient rehabilitation.  The appearance of these skin ulcers and deep sores have earned xylazine another name - the zombie drug.

What should be done now

A Congressional Research Service report has raised the possibility of a congressional action which would categorize xylazine as a schedule II drug under the Controlled Substances Act  and subject it to regulation by the FDA.  This important first step would impose penalties for illicit manufacturing and trafficking of the drug as well as impose quotas on production and importation.  

Obviously education is paramount. The general public as well as emergency care providers needs to be aware of this dangerous emerging threat while in the throes of the fentanyl epidemic.  Medical providers need the tools - readily available rapid tests for xylazine, for example - to evaluate and treat these potentially more complex opioid overdose patients.

Dan Mazanec, MD, FACP

1/9/2024

Legalize Cannabis for Recreational Use? Not so Fast!

Currently 24 states - most recently Ohio on November 7, 2023 -and the District of Columbia have legalized recreational marijuana use.  Medical use of marijuana is now legal in 39 states and D.C..Legalization has fuels a dramatic increase in use, particularly notable among young adults.   Statistics from the National Institutes of Health (NIH) show marijuana use by adults aged 19-30 years reached an all-time high in 2021 with 43% reporting use in the past year, an increase from 34% in 2016.  Daily use rose to 11% in 2021, i.e., more than one in ten young adults uses marijuana daily. 

As cannabis use skyrockets, not surprisingly, so do cannabis-related traffic injury emergency room visits - by 223% in a recently reported Canadian study.  Similarly, hospitalizations attributable to cannabis increased 1.6 times after legalization and commercialization of cannabis in Canada, primarily for cannabis-induced psychosis. 

 Perhaps before jumping into widespread legalization of marijuana for recreational use, it would be wise to carefully explore the risks of cannabis which are often understated and overlooked.  A risk/benefit analysis, comparing the pros and cons of legalization is in order.  Unfortunately, much of the clinical research on the benefits and risks of marijuana use can be categorized as poor or insufficient quality.  Limitations include reliance on retrospective or observational data, often only with short term follow up.   Prospective, randomized comparative studies with longer term follow up are desperately needed to guide public policy with profound health and safety implications for society.

We’ll start by looking at what the available existing studies tell us about the potential benefits of the drug.

PROs/BENEFITS of Cannabis Use

•  Medical use of cannabis is well established for two rare seizure disorders -  Lennox-Gastaut Syndrome (LGS) and Davet Syndrome.  Oral cannabidiol (CBD) was effective in decreasing the number of seizures compared to placebo.  The FDA has approved Epidiolex, a purified extract of cannabidiol containing no THC for these disorders.

• HIV or cancer associated  nausea, vomiting and loss of appetite The FDA has approved nabilone (brand name Cesamet ) - a synthetic cannabinoid - for use in patients with severe nausea and vomiting during cancer chemotherapy.  Another synthetic cannabis-like drug, dronabinol (brand name Marinol) has been approved for loss of appetite in AIDS patients as well as chemotherapy-induced nausea and vomiting.

• Chronic pain   Studies evaluating cannabis in persons with pain show mixed results..  A large review of the best studies of medical cannabis for chronic neuropathic (nerve) pain concluded that the benefits of medical cannabis for the treatment of chronic pain may be outweighed by potential side effects.  For example, a recent analysis found the risk for cannabis use disorder (CUD) was greatest in chronic pain patients over 65 years of age. A recent meta-analysis of 36 randomized clinical trials of cannabinoids for pain - the gold standard in clinical medical research - found most trials showed no benefit. Topical cannabinoids are legally sold in the U.S. but are not FDA regulated and cannot be claimed to prevent, diagnose or cure any disease.  Significant concerns with these non-FDA regulated products are contamination with other potentially harmful substances and the actual content of THC or cannabinoid present. 

•  PTSD/Anxiety  Small, poor quality observational studies suggest cannabis may help with the symptoms of posttraumatic stress disorder (PTSD).  However, veterans who use cannabis more than once weekly have more depression, anxiety and suicidal ideation.  Though claims are made for marijuana for anxiety relief,  use of cannabis more than once a month has been shown to increase social anxiety disorder.

With the exception of the clinical scenarios described earlier,  the currently available evidence for benefits of medical marijuana fails to justify the exuberant claims sold to the public. We’ll turn now to the other side of the question - the hazards to individuals and society in general with more widespread use of the drug.  

CONs/RISKS of Cannabis Use

• Damage to the adolescent/young adult brain  Through adolescence until about age 24 years, the brain is actively growing, remodeling, establishing critical neurologic pathways involved in information processing, decision making and impulse control.  During this time the brain may be most vulnerable to environmental exposures including cannabis.  In fact, cannabis and cannabinoids have been shown to impact adolescent and young adult neurodevelopment at multiple points with structural changes including altered gray matter development, particularly in the hippocampus and decreased white matter myelination (where cannabis receptors are located) demonstrated on magnetic resonance imaging (MRI).   Regular young cannabis users perform poorly on tests of learning capacity, memory, delayed recall, and information processing.  Alarmingly, regular adolescent/young adult cannabis users have a 37% increase in depression, 50% increase in suicidal ideation and a 3-4 fold increase in suicide attempts compared to nonusers. Cannabis use may increase the risk for schizophrenia by 4-5 times. 

  What are the consequences of the cognitive and structural brain changes seen in adolescent/young adult cannabis users with continued use into midlife?  A  recent landmark study (2022) evaluated more than 1000 persons followed from birth to age 45 with comprehensive assessments of IQ, memory, and an extensive battery of neuropsychological tests regularly performed.  Interviews assessing substance use, including cannabis, were performed at regular intervals after age 18 to age 45.  Brain MRI was performed at age 45.  Long term cannabis users (using cannabis at least weekly at age 45 and at earlier assessments) were found to have a significant decline in IQ and performed worse on tests of learning, memory and processing speed than non users.  Of these persons, one-third started using cannabis before age 18.  Brain MRIs showed significantly smaller hippocampus volumes in long term users at age 45 compared to non users. The hippocampus is the portion of the brain which plays a key role in short and long term memory as well as spatial memory for navigation.   Notably, the hippocampus is reduced in size in persons with schizophrenia and is one of the first regions of the brain to demonstrate damage in Alzheimer’s disease.  The potential devastating implications of these findings demand urgent further investigation, specifically whether long-term cannabis users are at increased risk of dementia later in life. 

•  Complications in pregnancy  Cannabis is now the most commonly used federally illegal drug in pregnancy with a 7% incidence among pregnant women in 2017.  Some more recent data suggests the incidence in some populations is now 25-30%.  Typically pregnant women are using the drug to attempt to alleviate nausea, vomiting or stress and are unaware of the potentially devastating consequences.  THC crosses the placenta and is found in breast milk 6 days after maternal use of cannabis.   Prenatal maternal cannabis exposure is now linked to increased risk of small for gestational birth infants, preterm births, and increased need for neonatal intensive care admission.  Serious adverse childhood outcomes of prenatal cannabis use include increased risk of  autism spectrum disorders, attention deficit/hyperactivity disorders and psychotic-like experiences. Paternal cannabis use is also linked to low birth weight infants and spontaneous abortions as well as sudden infant death syndrome.  Both the American Academy of Pediatrics and the American College of Obstetrics and Gynecology strongly recommend pregnant women discontinue cannabis use during pregnancy and while breastfeeding.

• Cardiovascular Disease New data emerging from multiple studies indicates that cannabis use - recreational or medical - increases the risk of cardiovascular disease.   Cannabis increases sympathetic nervous system tone and when vaped or smoked increases carbon monoxide levels five-fold.  This may account for the association of cannabis use with serious cardiac rhythm abnormalities including atrial fibrillation and ventricular tachycardia.  Just as concerning are observational studies associating cannabis use with increased risk of hypertension, stroke, myocardial infarction (heart attack), and heart failure. A recent report of hospitalized adults over 65 with at least 2 cardiovascular risk factors found marijuana users had a significantly increased risk of a heart or brain event while hospitalized compared to the group who didn’t use cannabis. The latest findings (November, 2023) of a study of 150,000 persons followed for 4 years noted a 34% increase in risk of heart failure in daily marijuana users compared to non-users.  Daily marijuana use may increase a person’s risk of coronary artery disease by one-third compared to non-smokers.  Cannabis use should probably be considered a cardiovascular risk factor like elevated cholesterol or family history of early cardiac death.

• Cannabis Use Disorder (CUD) CUD is an addictive condition described by an inability to stop or decrease marijuana use despite social, physical, or psychological problems related to the drug.  Persons with CUD demonstrate addictive behaviors including craving the drug and experience withdrawal symptoms when attempting to stop marijuana.  They may develop tolerance - the need to use more drug to get the same high.  They may avoid important activities with friends or family in favor of using marijuana.  Persons with CUD are at increased risk of both psychotic and non-psychotic bipolar disorder and unipolar depression. The prevalence of CUD is reported as high as 21% among persons who use cannabis in states with legal recreational use.  Recreational users are at higher risk for moderate or severe CUD.  A likely factor is the increased amount of THC - the primary psychoactive component of cannabis - in currently available marijuana.

• Driving Impairment  Multiple studies have demonstrated significant effects on driving performance attributable to cannabis.  Cannabis smoking increases lane weaving, impairs reaction time, and impairs cognitive function.   Substantial driving impairment occurs with recent cannabis smoking and correlates with blood THC levels.  Not surprisingly, legalization and commercialization of cannabis is associated with a huge increase in cannabis related MVAs - 223%!  Legalization and the higher THC concentrations in today’s marijuana product are the primary culprits.

• Cannabis Hyperemesis Syndrome  (CHS)  Chronic cannabis users - at least weekly and often since adolescence - are at risk for CHS.  The symptoms of CHS are intense, persistent vomiting, often without warning up to several times per hour.  Abdominal pain and dehydration may also occur.  An episode may last up to 48 hours.  Some people with CHS find some relief of the nausea by taking hot showers or baths which they may do several times daily.  CHS is not a rare problem and accounts for about 6% of all emergency room visits for vomiting.  The only cure is to completely stop using cannabis.

• Drug Interactions  Cannabis alters the metabolism of multiple widely-used prescription drugs, including antidepressants, anti-diabetic drugs, tacrolimus (anti rejection, immunosuppressive drug), B-blockers (used for heart disease, hypertension) anticoagulants, statins and many others.  Most commonly the interaction slows clearance of the drug, increasing blood levels and risk of side effects.  Cannabis users absolutely should inform their physicians about the quantity and frequency of use.

• A Gateway Drug?  Does using cannabis cause the user to progress to the use of “harder” illicit drugs such as cocaine, heroin, or other opioids?  In the teeth of the fentanyl crisis, this is a critical question.  A Department of Justice sponsored analysis in 2018 reviewed 23 studies addressing the question and concluded the results were “mixed”  and couldn't answer the question.  The analysis noted the reviewed studies were limited and often flawed but many did find statistically significant associations between cannabis use and later use of illicit drugs.  However, no unequivocal evidence of causality was found.  Studies in mice exposed to cannabinoids have demonstrated  evidence of enhanced opioid intake later in life.  The jury is still out.  However, particularly with higher THC content of currently used cannabis, more research on this question is urgently needed.

While there are selected situations where medical use of marijuana clearly has important clinical benefit, an emerging body of better quality research demonstrates we’ve underestimated and understated the consequences of cannabis legalization.  Cannabis use poses devastating risks in pregnancy and may well be a significant factor in increasing cardiovascular disease. Perhaps the most catastrophic consequence is on the mental and cognitive health of regular users throughout their lives with enormous implications for society at both ends of the age spectrum.  Laws restricting adolescent use of alcohol or tobacco (including vaping)  haven’t been very effective and are not likely to interdict cannabis use in the youth population.  It’s time to pause the rush to legalization, provide evidence-based education to the public, remove unnecessary legal barriers to quality research, and provide the tools to the FDA to evaluate the content of over-the-counter CBD and regulate the THC content of available drug.  

Improving medication assisted treatment (MAT) of opioid use disorder (OUD): Contingency Management (CM)

The opioid epidemic continues unabated with the CDC reporting more than 81,000 drug overdose deaths in the 12 months ending May 2020, about 70% opioid-related.  Persons working in startup companies are typically among the most vulnerable demographic group with risk augmented by multiple additional stressors.  Medication assisted  treatment (MAT) is the gold standard for treatment of opioid use disorder.  A study by Bolivar, et al in the current issue of JAMA Psychiatry reports that the addition of another treatment methodology - contingency management - significantly improves treatment adherence and duration of abstinence from opioids. Contingency management (CM) is an evidence-based behavioral intervention which provides patients with a material incentive - often a cash voucher - for showing evidence of meeting a therapeutic target, i.e., objective evidence of abstinence from opioids and/or methamphetamine.   Commonly the incentive is increased at regular intervals with continued abstinence.   The study was a systematic review of more than 10,000 patients in 74 studies evaluating the efficacy of CM in treating OUD with or without concurrent psychostimulant (methamphetamine) use.  Notably, a recent report suggests that up to 30% of persons with OUD are also using a psychostimulant, usually methamphetamine.  Unfortunately, concurrent psychostimulant use doubles the dropout rate for medication assisted treatment.   Bolivar’s report found CM improved treatment outcomes in more than 70% of patients with either psychostimulant use or OUD as measured by abstinence and treatment adherence compared to MAT alone.

Bolivar, et al, suggest the evidence of efficacy for CM in OUD is so compelling that the Center for Medicaid and Medicare Health Services (CMS) should authorize the use of funds for CM treatment for OUD.  They suggest that development and credentialing of CM treatment programs should be a federal public health priority. 

Slow down! Rapid opioid taper in long term users risks overdose or mental health crisis.

New evidence just published in JAMA underlines the complexity of managing opioid use disorder (OUD) in persons taking long term higher dose opioids.  The study reviewed medical and pharmacy records of more than 110,000 patients taking stable (at least 12 months), higher dose (at least 50 mg of morphine equivalent).   Patients who underwent opioid tapering - defined as a 15% or higher reduction in dose - were noted to have a nearly 68% increase in emergency room or hospital visits for overdose events and a more than doubling of visits for mental health crises including depression, anxiety or suicide attempt. 

There are sound medical indications for opioid tapering including the growing consensus that opioids lack efficacy for chronic pain. However, this study suggests tapering should be performed slowly - perhaps by 10% every 3 months - under careful clinician guidance with frequent follow-up. Stigmatized persons with OUD attempting self-taper are probably at even higher risk for overdose or mental health crisis. Employers should maintain lines of communication and check in frequently with employees dealing with SUD.

Terrible numbers. Drug overdose deaths much worse than predicted.

The CDC just released the most recent bulletin on drug overdose deaths in the U.S. reporting a nearly 30% increase above predicted numbers for the 12 months between December 2019 and December 2020. In three states, overdose deaths exceeded predictions by more than 50%. These devastating numbers are most likely driven by the impact of the pandemic as well as the huge influx of illegal fentanyl into the country.

The Top Ten: Worst Jurisdictions and Percentage above Predicted Overdose Deaths 

1. Vermont: 57.6%

2. Kentucky: 53.7%

3. South Carolina: 51.9%

4. West Virginia: 49.3%

5. Louisiana: 47.6%

6. California: 45.9%

7. Tennessee: 44.1%

8. Nebraska: 42.9%

9. Arkansas: 41.9%

10. District of Columbia: 39.2%

As a result, states such as SC are requiring prescribers to offer a prescription for naloxone, the emergency antidote for an opioid overdose,  to patients receiving certain doses of opioids.  It’s also mandated to offer a naloxone prescription to persons prescribed both an opioid and a benzodiazepine such as Ativan, Xanax, or Valium.

For more information, check out the CDC’s data on drug overdose’s.

Medication assisted treatment (MAT) is underutilized. Here’s why.

Fewer than 20% of individuals with OUD in the U.S. receive these very effective medications. Most physicians learn very little about substance use disorders (SUD) in medical school. Even today, many practicing physicians are unaware that MAT is superior to treatment without drugs. A common misconception is that taking medications to manage the chronic illness of addiction is just replacing one addiction with another. Physicians prescribing MAT are required to obtain a special certification - the X waiver, further limiting access to this life saving treatment. The proposed “Mainstreaming Addiction Treatment Act” would eliminate the need for the X waiver and require an educational program of all providers renewing their DEA certificate (required for prescription of opioids and other controlled substances) with updated information on prevention and treatment of SUD.

Join the movement to improve drug treatment of opioid use disorder.

Here’s how.  Everyone can help reduce the stigma associated with medication management (MAT) by becoming knowledgeable about the facts.  Recognize OUD as a chronic illness which requires life long drug treatment for control, just as insulin is used to control diabetes.  Encourage your congressional representative and senators to pass federal legislation to eliminate barriers and restrictions on medical providers prescribing these medications.

Yes, medication works for opioid use disorder

In fact, effective treatment generally requires medication. The “gold standard” of treatment for this disease currently includes prescription medications such as methadone and buprenorphine More are in the pipeline. These medications improve retention in addiction treatment and OUD remission more successfully than any other treatment. A 2019 National Academies of Science, Engineering and Medicine review of the literature on treatment of OUD found that methadone or buprenorphine therapy was associated with a 50% reduction in fatal overdoses.

Get Back to the Office

The pandemic stay-at-home orders fueled an increase in opioid-related overdose fatalities. Mason, et al report in the June 22, 2021 issue of JAMA a study of opioid-related overdose deaths in Cook County, Illinois pre and post the 2020 stay-at-home order issued March 21, 2020 and lifted May 30, 2020. Weekly deaths averaged 35 per week in the 3 months pre-lockdown and rose sharply by 25% during the stay-at-home order. Fentanyl accounted for almost 80% of the deaths. It’s likely that increased social isolation as well as loss of support group services and interruption of in-person treatment were major factors in the rise. Engaging with coworkers in a supportive, destigmatized work environment is a healthier strategy.

Pulled muscle at the gym? Take Tylenol.

Acute musculoskeletal pain includes sprains and strains and accounts for more than 65 million health care visits annually. As we emerge from the pandemic and return to the gym eager to get back into shape, we’re likely to experience more of these injuries. Historically, opioids have frequently been prescribed for acute musculoskeletal pain relief. 25% of persons presenting to an emergency room with an ankle sprain receive an opioid prescription. A new guideline from the American College of Physicians and the American Academy of Family Practice specifically recommends against clinicians prescribing opioids for acute musculoskeletal pain. The guideline suggests topical nonsteroidal drugs or Tylenol as preferred choices. Strains and sprains get better with time and simple treatment. The serious adverse consequences of opioids aren’t worth the risk.

Opioid Use Disorder (OUD) starts early.

More than half of adults with a SUD report symptoms by age 18 and 80% by age 24. A recent study by Wilson, et al in JAMA examined risk factors for OUD in opioid-naive youths and young adults in a sample of almost 190,000 persons who received an initial opioid prescription. Those on the “high-risk” trajectory were older, more likely to have depression or anxiety, and to have received a prescription for a more potent opioid for a slightly longer time. The initial prescription was most often from an internist or dentist. Persons on the “high risk trajectory” had a three times greater risk of a subsequent diagnosis of OUD. Unfortunately, this study only addresses the second most common young adult source of opioids, a health care provider’s prescription. The first source is a “gift” from a friend or relative.