Fentanyl

Clinical and neuroradiographic features of fentanyl inhalation-induced leukoencephalopathy

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Abstract

A man in his late 40s with no known past medical history was unresponsive for an unknown period of time. Crushed pills and white residue were found on a nearby table. On presentation he was obtunded and unresponsive to verbal commands but withdrawing to painful stimuli. The initial urine drug screen was negative, but a urine fentanyl screen was subsequently positive with a level of 137.3 ng/mL. MRI of the brain showed reduced diffusivity and fluid attenuated inversion recovery (FLAIR) hyperintensity symmetrically in the bilateral supratentorial white matter, cerebellum and globus pallidus. Alternative diagnoses such as infection were considered, but ultimately the history and workup led to a diagnosis of fentanyl-induced leukoencephalopathy. Three days after admission the patient became able to track, respond to voice and follow basic one-step commands. The patient does not recall the mechanism of inhalation. While there are case reports of heroin-induced leukoencephalopathy following inhaled heroin use and many routes of fentanyl, this is the first reported case of a similar phenomenon due to fentanyl inhalation.

Background

Toxic leukoencephalopathy (TLE) is an acute or chronic neurologic syndrome due to exposure to insults or toxins, resulting in damage to the cerebral white matter.1 The broader term ‘leukoencephalopathy’ refers to disorders of the white matter of the brain. The diagnosis of TLE involves clinical symptoms of white matter dysfunction that correlate with neuroradiologic white matter abnormalities. MRI is the preferred diagnostic modality as it offers better depiction of the brain parenchyma than CT. Characteristically, T2-weighted and diffusion-weighted imaging findings show diffusely increased signal intensities within the white matter.2 In patients with extensive toxin exposure, the amount of radiographic involvement is variable.

An extensive and diverse variety of signs and symptoms have been described. The most obvious clinical manifestations are neurological and behavioural changes, ranging from a mild confusion to stupor, coma and death.1

There have been numerous insults and toxins identified including chemotherapeutic agents such as carmustine and methotrexate, immunosuppressive drugs such as ciclosporin and tacrolimus, environmental toxins such as carbon monoxide, and drugs of misuse such as alcohol, cocaine and heroin.3 Glue, toluene and other volatile compounds that are inhaled have been reported to cause TLE.4–6

Prognosis and recovery generally depend on the degree of white matter injury; some patients recover fully while others may experience progressive decline.7 The mechanism of TLE is unclear but there are several proposals including endothelial injury, myelin sheath degradation or a combination of the two.1

In the context of this case with crushed pills and white residue reported, heroin-induced leukoencephalopathy also known as ‘chasing the dragon’ was considered. The inhalation of heroin vapours can lead to TLE.8 9 It is thought that the vapours lead to vacuolar degeneration of deep white matter. Numerous cases have been reported in the literature.10 This is the first case report known to document TLE secondary to fentanyl inhalation.

Case presentation

A previously healthy man in his late 40s with no significant past medical history was found unresponsive for an unknown period of time in his hotel room while attending a work conference. Unidentified crushed pills and a white residue were found on the table of his hotel room. The white powder was visible around his mouth. His only reported medications were sildenafil and vitamin D. On initial assessment his Glasgow Coma Scale was 10, he had dried vomitus around his mouth and scant red blood on his lips, but was protecting his airway. Emergency Medical Services administered naloxone without effect.

On hospital arrival, the patient was afebrile (36.7°C) with blood pressure 116/93 mmHg, heart rate 99 bpm, respiratory rate 38/min, with an oxygen saturation of 93% on a non-rebreather mask (15–20 L/min oxygen flow rate). Physical examination revealed scant dried blood on lips but no evidence of blood in the oral cavity. Pulmonary examination showed tachypnoea without signs of increased work of breathing and clear lung sounds. Neurologically, the patient’s level of consciousness was obtunded. He was non-verbal, not answering orientation questions and not following commands. Pupils were 4–5 mm bilaterally and reactive to light and there was no blink to threat bilaterally (CN II). His gaze was conjugate, oculocephalic reflex intact, and bilateral corneal reflexes intact (CN III, IV, VI). His face appeared symmetrical. He withdrew to pain in the bilateral lower extremities but not the upper extremities. He had diffusely brisk reflexes and increased tone in the bilateral upper extremities. He resisted manual manipulation of the bilateral upper extremities and briefly raised both arms antigravity. The bilateral lower extremities were withdrawn briskly to light touch. Babinski reflex was absent bilaterally as the great toes showed no movement. Sensation, coordination and gait were deferred as the patient was not following commands.

Investigations

CT head without contrast showed symmetrical hypodensities in the posterior bilateral cerebellar hemispheres, bilateral globus pallidus and questionably in the pons (figure 1), and toxic or metabolic injury were provided as the most likely diagnoses. A chest radiograph showed diffuse bilateral patchy bi-basilar ground glass opacities. Bedside point-of-care ultrasound showed no pericardial effusion, normal left ventricular function, no mitral or aortic insufficiency and the inferior vena cava was non-distended with appropriate inspiratory collapse. An ECG showed sinus tachycardia, left anterior fascicular block and prolonged QT interval (QTc 524 ms). Select admission laboratory results are shown in table 1. A respiratory viral panel (COVID-19, influenza A/B, RSV) was negative. Urine microscopy showed one white cell and two red cells with no bacteria, and a standard urine drug screen (amphetamine, barbiturates, benzodiazepines, cocaine, opiates, cannabinoids, methadone, oxycodone) was negative as were serum acetaminophen, ethanol and salicylate levels. Urine fentanyl (a separate non-facility test that returned 6 days later) was raised to 137.3 ng/mL (positive cut-off 1.0 ng/mL). No prior labs were available for baseline comparison as the patient was otherwise healthy with little prior contact with the healthcare system.

Figure 1

Figure 1

Axial CT images of the brain without intravenous contrast showing symmetrical abnormal hypodensity in the bilateral globus pallidus (small arrows) and posterior cerebellar hemispheres (hash tags) corresponding to regions of reduced diffusivity and FLAIR hyperintensity on subsequent brain MRI. Apparent hypodensity in the pons (large arrow) was suspicious for an additional site of involvement but had no correlate on subsequent MRI and proved to be an artefact. Conversely, abnormality of the bilateral centrum semiovale (asterisks) was not appreciated on the CT scan and was only evident on subsequent MRI.

Table 1

Select admission laboratory values

A routine electroencephalogram (EEG) with a duration of 25 min showed frontal intermittent rhythmic delta activity (FIRDA) and no epileptiform abnormalities (figure 2).

Figure 2

Figure 2

Frontal intermittent rhythmic delta activity (FIRDA) indicative of a moderate encephalopathy, non-specific as to aetiology. No seizures or epileptiform discharges. FIRDA is seen in toxic or metabolic encephalopathies, degenerative diseases and deep midline structural abnormalities.

MRI of the brain with and without intravenous contrast showed symmetrical confluent reduced diffusivity and FLAIR hyperintensity in the supratentorial white matter with sparing of subcortical U-fibres, symmetrically in the bilateral globus pallidus and symmetrically in the posterior cerebellar hemisphere folia, involving the cerebellar cortex and adjacent white matter. Small foci of susceptibility and post-contrast enhancement were seen in the affected portions of the cerebellar hemispheres. The cerebral cortical grey matter, internal capsules, hippocampi and brainstem were normal. Magnetic resonance angiography (MRA) of the brain was normal. Based on the MRI and MRA findings, a toxic or metabolic process remained the leading diagnostic consideration (figures 3–6).

Figure 3

Figure 3

Axial trace diffusion weighted images (top row) and corresponding apparent diffusion coefficient maps (bottom row) of the brain showing symmetrical confluent reduced diffusivity throughout the bilateral centrum semiovale (asterisks), globus pallidus (arrows) and posterior cerebellar hemispheres (hash tags).

Figure 4

Figure 4

Coronal T2 fluid attenuation inversion recovery images showing symmetrical hyperintense signal abnormality in the bilateral centrum semiovale (thick arrows), globus pallidus (asterisks) and cerebellar cortex/folia (hash tag). Note the distinct sparing of subcortical U-fibres (thin arrows).

Figure 5

Figure 5

Coronal (left) and axial (right) maximum intensity projection MR angiogram images of the brain showing normal flow-related enhancement throughout the major intracranial arteries.

Figure 6

Figure 6

Coronal T1-weighted turbo field echo images acquired prior to (A) and following intravenous contrast administration (B) show thin linear branching foci of enhancement in the affected region of the left cerebellum (arrow) with corresponding hypointensity on susceptibility-weighted imaging (C, large arrow), favoured to represent dilated veins.

A repeat routine EEG with a duration of 21 min again revealed FIRDA and no epileptiform abnormalities. After 18 days, although the history and MRI findings supported a diagnosis of fentanyl-induced leukoencephalopathy, he continued to remain bedbound, tube feed dependent, and require restraints due to poor safety. At that time he had a thrombocytosis with platelets 946 (normal 150–400 ×109/L), which had gradually risen from his initial platelet count of 252 on admission. Given his uncertain prognosis and unexplained thrombocytosis, a lumbar puncture was performed to complete a robust work-up and rule out an infectious aetiology. Cerebrospinal fluid (CSF) laboratory analysis is shown in table 2.

Table 2

Cerebral spinal fluid analysis

Differential diagnosis

In this case drug toxicity was considered the most likely diagnosis from early in the work-up. The crushed pills and residue found in the patient’s hotel room, the neurological examination and the radiology findings, when considered in aggregate, were highly suggestive of a drug toxicity. In general, toxic encephalopathy should be considered when brain imaging shows symmetric abnormalities involving the deep grey nuclei, white matter and cerebellum. However, there are numerous neurotoxins and each can present with a variety of imaging manifestations.

‘Chasing the dragon’ leukoencephalopathy can occur with inhalation of heroin smoke and has a well described symmetrical pattern of diffusion and FLAIR signal abnormalities involving the bilateral globus pallidus, cerebellum and supratentorial white matter,11 which fits closely with the imaging findings seen in our patient.

Cerebellar, Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) syndrome has been reported as a common pattern of toxic brain injury with a number of illicit drugs and shares some features with the case presented here, with the notable exception that the hippocampi were spared in our patient.12

Other toxicities including carbon monoxide and cyanide can result in bilateral globus pallidus injury. However, the symmetrical white matter and cerebellar injury seen in our case would be atypical for carbon monoxide.

Ischaemic injury can be difficult to disentangle from opiate toxicities as the two can overlap in imaging appearance and hypoxia is a frequent complication accompanying opiate-related respiratory suppression.13 It is possible that brain hypoxia may have a synergistic effect with direct toxin-mediated metabolic injury. Adult hypoxic brain injury, such as from cardiac arrest or near-drowning, will most commonly present with ischaemic (DWI) changes in both the cerebral cortical grey matter and deep grey nuclei, and possibly with a parasagittal or watershed distribution. In this patient the lack of cerebral cortical involvement and absence of a watershed pattern made isolated hypoxic brain injury unlikely.

Other vascular aetiologies (e.g., posterior reversible encephalopathy syndrome), infectious aetiologies (e.g., viral meningitis and rhombencephalitis), metabolic diseases (e.g., Leigh syndrome, pantothenate kinase-associated neurodegeneration), demyelinating disease (e.g., osmotic demyelination) and prion disease (e.g., Creutzfeldt-Jakob disease) can also result in symmetrical imaging abnormalities in the deep grey nuclei. However, these were all considered unlikely given the other features of the patient’s presentation.

Lumbar puncture with elevated protein was thought to be secondary to known CNS insult rather than a sign of a separate acute process. Raised CSF red blood cells are consistent with a traumatic tap.

Infectious aetiologies were considered given the onset of fever; however, such an acute change in cognition in the context of the patient’s history as well as the absence of laboratory abnormalities made an infectious process unlikely.

Over the course of his admission, sequelae of TLE and likely opioid withdrawal were symptomatically managed. Opioid withdrawal was a possibility given the patient’s fever, tachycardia and agitation that improved with opioids. There was no objective evidence to suggest the patient was taking other opioids prior to admission given a negative urine drug screen on admission and a lack of track marks to suggest intravenous drug use. Non-convulsive status epilepticus was considered as a potential aetiology of the patient’s symptoms given persistent encephalopathy and raised creatine kinase; however, two EEGs excluded this possibility.

Treatment

In the emergency department, given the patient’s urinary incontinence, elevated lactate and cognitive impairment, he received two doses of 2 mg lorazepam due to initial concern for seizure. He had escalating oxygen requirements requiring up to 20 L/min on a non-rebreather mask. He also received 3 L of intravenous fluid for his acute kidney injury and concern for rhabdomyolysis. Based on his chest radiograph findings, he was started on ceftriaxone and azithromycin. In the absence of ST elevations or depressions on ECG, the patient’s elevated troponins were attributed to a non-ST elevation myocardial infarction type II.

The patient was initially admitted to the medical intensive care unit for toxic metabolic encephalopathy of unclear aetiology and acute respiratory failure. In a few hours the patient was weaned to a 2 L nasal cannula and soon after to room air. He received opioids, antipsychotic medications (haloperidol, olanzapine) and benzodiazepines (lorazepam) to manage agitation, pain and suspected opioid withdrawal. A nasogastric tube was placed and tube feeds were initiated.

Supplements such as coenzyme Q10, vitamin E and vitamin C have anecdotally been shown to benefit some patients with heroin-induced spongiform leukoencephalopathy.14–19 Empirical antioxidant therapy with coenzyme Q10 was considered, but unfortunately could not be crushed to be administered through the nasogastric tube. The patient completed a course of antibiotics for a presumed aspiration pneumonia.

Outcome and follow-up

After 26 days the patient was discharged from the hospital to a skilled nursing facility. At the time of discharge the patient was oriented to self, place and general date. He was able to communicate with simple sentences and was actively participating in physical and occupational therapy. After another month of inpatient rehabilation the patient was able to perform all activities of daily life independently and was discharged to home with outpatient physical and occupational therapy. He reported that his voice sounded a little muffled and felt like he had to strain. He saw otolaryngology as an outpatient who noted a consistent dysphonia with their examination showing a right true vocal fold hypomobility and bilateral atrophy resulting in a small but persistent glottic fap. He underwent voice therapy and had subjective improvement in his voice. Otolaryngology noted improvement in the vibratory capacity of his vocal cords and improvement in his supraglottic function. He also participated in rehabilitation psychology to reduce feelings of distress. Less than a year from his hospitalisation he had returned to work full-time without accommodations. He is without neurological deficits. His expressive and receptive language functions are normal, thought process linear, and content within normal limits. Repeat imaging was not performed.

Discussion

Fentanyl and its analogues are extremely strong synthetic opioids with 50–100 times more potency than morphine.20 Fentanyl can be smoked, injected subcutaneously or intravenously, swallowed or sniffed. Overdose deaths from fentanyl outnumber deaths from other illicit substances, including methamphetamines and cocaine.21 Fentanyl typically has a short duration of action and rapid onset of effect. Importantly, fentanyl can be contaminated with emerging substances such as xylazine.22

Cases have described opioid intoxications including heroin, morphine and methadone resulting in acute TLE and delayed post-hypoxic leukoencephalopathy, distinct pathologies.23 ,24 Previous case reports have shown that opiates, mostly heroin, may lead to TLE. There have been prior reports of fentanyl-induced TLE. One report describes TLE following an overdose of fentanyl-contaminated fake oxycodone,25 while other cases involved the use of a fentanyl patch.26–28 There are also cases noted after oral ingestion of patches, intravenous or unknown routes of ingestion.29–32 Our case is the first to describe inhalational use of fentanyl causing TLE.

The pathophysiology of TLE is unclear, but several proposed mechanisms of injury to white matter exist including hypoxaemia, direct toxin damage to the myelin sheath or the capillary endothelium.1 Neuropathology has shown spongiform degeneration as evidenced by vacuolar changes. The degree of white matter vacuoles corresponds to the hyperintensities seen on DWI imaging.8 With regard to opioids, their lipophilicity, particularly fentanyl, allows for penetration of the blood–brain barrier.33 Furthermore, inhalation may be the fastest of all the routes as it has high bioavailability, bypassing first-pass metabolism by the liver.34 Based on the varied routes of access all resulting in the same pathology, this toxicity may have more to do with the drug class itself than the route of entry.

In our patient the initial urine drug screen was negative for opioids. A specialised fentanyl test was required to obtain the diagnosis. This case report is unique in that it describes inhalation of fentanyl causing damage to deep white matter and bilateral cerebellum without significant cortical involvement on MRI. EEG should be employed in TLE primarily for ruling out non-convulsive status epilepticus. Other white matter disorders such as posterior reversible encephalopathy syndrome (PRES) have a higher probability of seizures compared with TLE.35 Pathophysiological mechanisms such as white matter oedema versus demyelination or axonal injury are theorised as affecting EEGs differently but, overall, there is limited research and clinical evidence about what diagnostic and prognostic information it can provide.36 37

This case can help inform future clinicians to be watchful for other toxins that may not be initially identified on screening tests. Furthermore, this case illustrates the need for inclusion of fentanyl in routine urine drug screens for earlier identification and appropriate management.

Patient’s perspective

“Well, honestly, I don’t recall much. When I came to I saw that I was in the hospital and was being attended to. From what I can remember early on is that my recovery was miraculous. Early on it was looking like I would need 24 hour care after being discharged but I focused and worked hard in my therapy session and was determined not to leave the hospital only to be checked into a group facility for ongoing care. It’s been 6 months now and I am back at home, working and feeling strong and healthy. I have regrets often about what I did to myself, my wife, and my family. I’m grateful to all the doctors, nurses, and EMTs that saved my life and the therapists that got me back to a functioning member of society.”

Learning points

  • Toxic leukoencephalopathy (TLE) is a non-specific encephalopathy syndrome caused by a variety of toxic aetiologies resulting in damage to the cerebral white matter.
  • On MRI, symmetrical diffusion restriction in the bilateral cerebellar hemispheres, deep grey nuclei, hippocampi and supratentorial white matter should raise consideration for opioid toxicity.
  • While heroin has been the principal opiate associated with TLE, this case highlights the importance of recognising other opiates such as fentanyl as potentially causative.
  • Fentanyl is not routinely tested on all urinary drug tests; thus, providers need to be suspicious of its presence and to work with their local laboratories to have it added to the standard drug testing platforms.

Inhaling Fentanyl Could Cause Irreparable Brain Damage

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A man found unconscious in his hotel room in February 2023 became the first recorded case of brain disease caused by fentanyl inhalation.

Inhaling Fentanyl Could Cause Irreparable Brain Damage
Evidence bags containing fentanyl are displayed during a news conference at Surrey RCMP Headquarters, in Surrey, B.C., on Sept. 3, 2020.

A 47-year-old Seattle man who had been visiting Oregon on business became the first recorded case of brain disease as a result of fentanyl inhalation. Although the incident happened in February 2023, the report of toxic leukoencephalopathy (disease of white brain matter) was just published in BMJ Case Reports.

Reports Due to Heroin Inhalation, but Not Fentanyl

On Feb. 25, 2023, the man was found unresponsive in his hotel room. While he had no known previous medical issues, the man had been unconscious for an unknown period before he was found. He was discovered close to unidentified crushed pills and white residue on a nearby table.

When he arrived at the Oregon Health & Science University (OHSU) emergency department, he could not follow commands or answer questions. He could respond to pain stimuli in his legs but not his arms.

A hospital brain scan revealed that the white matter in his brain was inflamed and swollen, and his cerebellum—responsible for gait and balance—was injured.

While an initial drug screening produced negative results, a subsequent urinalysis showed a very high level of fentanyl, prompting a diagnosis of toxic leukoencephalopathy due to fentanyl inhalation.

Medical experts have previously documented cases of brain disease caused by heroin inhalation, but this is the first case involving inhalation of illicit fentanyl.

Alleged 1st-Time Use

Fentanyl is a synthetic opioid known to be 50 to 100 times more potent than morphine, according to the U.S. Centers for Disease Control and Prevention (CDC). While it can be prescribed for pain, it is often sold through illegal drug markets for its heroin-like effect. As a result, rates of overdose deaths involving synthetic opioids, including fentanyl and fentanyl analogs, increased by more than 22 percent between 2021 and 2022. The overdose death rate was nearly 22 times higher in 2021 than it was in 2013, the CDC reports.

“Opioid use, especially fentanyl, has become very stigmatized,” Dr. Chris Eden, lead author of the case study, said in a news release. “This is a case of a middle-class man, in his late 40s, with kids, who used fentanyl for the first time. It demonstrates that fentanyl can affect everyone in our society.”

Over 1 Million Fentanyl Pills Seized Near San Diego Border

Eighteen days after he was brought to the hospital, the man was still bedridden and required a feeding tube. He received multiple medications to treat urinary incontinence, kidney injury, cognitive impairment, suspected opioid withdrawal, pain and agitation, and pneumonia.

“We know very well the classic opiate side effects: respiratory depression, loss of consciousness, disorientation,” Dr. Eden said. “But we don’t classically think of it causing possibly irreversible brain damage and affecting the brain, as it did in this case.”

‘Miraculous’ Recovery

After 26 days, the man was discharged from the hospital to a rehabilitation facility, where he spent another month. He returned home with the support of an outpatient physiotherapist and occupational therapist. He fully recovered and returned to work after less than a year.

“This case involved internal medicine, neurology, neuroradiology and palliative care physicians, in addition to nurses, social workers, discharge planners, physical therapists, dieticians and pharmacists,” Dr. Eden said in the press release. “I’m proud of these multidisciplinary teams at OHSU working together to take care of complex patients, both from a medical and social perspective.”

Today, the man has no recollection of the episode but expressed gratitude for his “miraculous” recovery.

“Early on it was looking like I would need 24 hour care after being discharged, but I focused and worked hard in my therapy session and was determined not to leave the hospital only to be checked into a group facility for ongoing care,” he said in a news release. “I have regrets often about what I did to myself, my wife, and my family.”

Magnesium Sulfate vs Fentanyl: The Future of Spinal Analgesics

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A new study found that intrathecal fentanyl and magnesium sulfate can effectively enhance spinal anesthesia, offering prolonged pain relief and sensory blockade

While fentanyl led to a faster onset, both provided similar durations of analgesia. This highlights the potential of utilizing natural, safe compounds like magnesium for effective pain management while avoiding risky substances like opioids.1

A new randomized controlled trial published in the Asian Journal of Anesthesiology uncovered important implications for utilizing natural mineral compounds as adjunct medications alongside anesthesia for improved healing outcomes.2 Their findings highlight the feasibility of incorporating holistic and integrative approaches within conventional medical settings.

The Dangers of Opioids

While the opioid fentanyl is commonly used to intensify and extend spinal blocks, its use risks life-threatening side effects and tremendous addiction potential. Overdose deaths linked to prescribed and illicit fentanyl have risen over 1,600% in recent years as the drug epidemics continue to intensify across North America.3 Even minor exposure can lead to risky dependencies given fentanyl’s potency level thousands times higher than morphine.4 There is an urgent need for safer alternatives capable of meeting patient analgesic needs without fueling the ongoing crisis.  

Putting Magnesium to the Test

The study, led by Richa Richa and colleagues at the Department of Anesthesiology in India, aimed to analyze the efficacy of intrathecal magnesium sulfate versus fentanyl as an additive to spinal bupivacaine anesthesia.5 They measured impacts on the onset and duration of sensory and motor nerve blocks, along with effects on circulatory vital signs.

100 patients scheduled for elective infraumbilical surgical procedures were randomly divided into two equal groups. Under strict aseptic precautions, Group 1 received hyperbaric bupivacaine combined with 25μg fentanyl, while Group 2 was administered bupivacaine with 100mg magnesium sulfate instead.6

The results proved illuminating. While fentanyl led to more rapid nerve blockade, magnesium matched its capacities for prolonging spinal anesthesia without concerning side effects.7 As the authors conclude, non-opioid magnesium shows promise as an alternative adjuvant for improving pain relief after surgery.8

An Affordable and Sustainable Solution

Not only could this simple mineral salt transform patient outcomes through effective analgesia, but alleviating reliance on habit-forming opioids offers immense societal benefits in tackling addiction epidemics. And unlike costly medications still under patent protection, magnesium is an affordable, readily available compound whose production can be sustainably scaled.9

Integrating such natural healing modalities aligns clinical practice with principles of environmental sustainability, social responsibility, and global health equity. It highlights the vast overlooked potential around traditionally used supplements for improving wellbeing across all populations.

Compound Created That Can Reverse Effects of Potentially Deadly Drugs Like Meth and Fentanyl.

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Chemical Compound Reverses Effects of Deadly Drugs

Scientists tested a chemical compound as an antidote for methamphetamine and fentanyl with highly promising results.

Their method successfully counteracted two highly addictive drugs—fentanyl and methamphetamine—in lab experiments.

Drug overdoses in the United States have risen sharply in the last two decades. Nearly 92,000 people died from overdoses of illegal drugs and prescription opioids in 2020—more than five times the number of deaths in the year 2000—and synthetic opioids like fentanyl are one of the main culprits.

Naloxone (an injectable medicine also marketed as the nasal spray Narcan) has saved countless lives, but it only works for opioid overdoses and has other limitations. Now, in an effort to identify a more universal treatment for drug overdose, a team of University of Maryland scientists tested a chemical compound—Pillar[6]MaxQ (P6AS)—as an antidote for methamphetamine and fentanyl. Their findings, published on December 15 in the journal Chem, were highly promising.

“Opioids already have a reversal agent in naloxone, but there are a variety of non-opioid drugs of abuse—like methamphetamine, PCP, mephedrone, ecstasy (MDMA) and cocaine—that do not have a specific antidote,” said the study’s lead author Lyle Isaacs, a professor in the Department of Chemistry and Biochemistry at UMD. “That’s one of the huge opportunities for our compound.”

https://www.youtube.com/embed/ACaLaa00SOA?feature=oembed
Chemist Lyle Isaacs explains how P6AS works to reverse the effects of drugs.

In vitro and in vivo laboratory tests showed that P6AS successfully sequestered fentanyl and methamphetamine, a non-opioid stimulant, and mitigated their potentially deadly biological effects. Additional in vitro tests revealed that P6AS also binds strongly to other drugs, including PCP, ecstasy, and mephedrone, which suggests that P6AS could someday be used to counteract a wide array of drugs.

The study was conducted by Isaacs’ lab in collaboration with researchers in UMD’s Department of Cell Biology and Molecular Genetics and Department of Psychology. Although the synthesis and chemical properties of P6AS were first documented in 2020 by Isaacs and Weijian Xue, a former post-doctoral associate in the Department of Chemistry and Biochemistry, this study reports its first in vivo applications.

P6AS works as a molecular container, which means that it binds and sequesters other compounds in its central cavity.

“When we put molecules into our containers, we can turn off their biological properties and thereby reverse any effects that they might have,” Isaacs explained. “We’ve measured the interaction between our container and a variety of drugs of abuse—things like methamphetamine, fentanyl, ecstasy, PCP and others—and we find that this new container that we’ve made binds many of them very strongly.”

In vivo tests revealed that the effects of methamphetamine could be reversed by administering P6AS five minutes later, which is “still a little bit short for real-world situations,” Isaacs explained. The effects of fentanyl, however, could be reversed by administering P6AS up to 15 minutes later, which comes closer to meeting the federal guidelines for drug reversal agents.

Unlike naloxone, which stops a drug of abuse from binding to receptors in the brain, the UMD team’s molecular container targets drugs directly in the bloodstream.

“Our compound soaks up the drug in the bloodstream and, we believe, helps promote its excretion in the urine,” Isaacs said. “This is known as a pharmacokinetic process, where we’re trying to minimize the concentration of free drug that’s present in the body.”

Whether this compound helps promote a drug’s excretion from the body must be tested experimentally. If it performs in the way that researchers think it will, it could be particularly useful for overdoses of fentanyl, which is up to 50 times stronger than heroin and up to 100 times stronger than morphine. Its potency and lingering effects in the body explain why some patients continue to overdose even after receiving naloxone. Isaacs believes that the excretion of fentanyl could help prevent this phenomenon, known as renarcotization.

Isaacs said it will likely be years before the new compound is approved for human use. However, he envisions that it could be delivered as an injection, much like naloxone but potentially with broader applications. Isaacs believes it could even be used to treat overdoses of extremely powerful drugs like carfentanil, which has been linked to a string of overdose deaths in recent years.

“There are other synthetic opioids that are much stronger than fentanyl—things like carfentanil, which are difficult to reverse using naloxone,” Isaacs said. “In addition, people are getting so much fentanyl that multiple doses of naloxone are needed, so there’s room for a new and improved agent that might help in those situations.”

‘Fake Xanax’ Tied to Seizures, Coma Is Resistant to Naloxone

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Bromazolam, a street drug that has been detected with increasing frequency in the United States, has reportedly caused protracted seizures, myocardial injury, comas, and multiday intensive care stays in three individuals, new data from the US Centers for Disease Control and Prevention (CDC) showed.

The substance is one of at least a dozen designer benzodiazepines, created in the lab, but not approved for any therapeutic use. The Center for Forensic Science Research and Education (CFSRE) reported that bromazolam was first detected in 2016 in recreational drugs in Europe and subsequently appeared in the United States.

It is sold under names such as “XLI-268,” “Xanax,” “Fake Xanax,” and “Dope.” Bromazolam may be sold in tablet or powder form, or sometimes as gummies, and is often taken with fentanyl by users.

The CDC report, published in the Morbidity and Mortality Weekly Report (MMWR), described three cases of “previously healthy young adults,” two 25-year-old men and a 20-year-old woman, who took tablets believing it was alprazolam, when it was actually bromazolam and were found unresponsive.

They could not be revived with naloxone and continued to be unresponsive upon arrival at the emergency department. One of the men was hypertensive (152/100 mmHg), tachycardic (heart rate of 124 beats per minute), and hyperthermic (101.7 °F [38.7 °C]) and experienced multiple generalized seizures. He was intubated and admitted to intensive care.

The other man also had an elevated temperature (100.4 °F) and was intubated and admitted to the ICU because of unresponsiveness and multiple generalized seizures.

The woman was also intubated and nonresponsive with focal seizures. All three had elevated troponin levels and had urine tests positive for benzodiazepines.

The first man was intubated for 5 days and discharged after 11 days, while the second man was discharged on the fourth day with mild hearing difficulty.

The woman progressed to status epilepticus despite administration of multiple antiepileptic medications and was in a persistent coma. She was transferred to a second hospital after 11 days and was subsequently lost to follow-up.

Toxicology testing by the Drug Enforcement Administration confirmed the presence of bromazolam (range = 31.1-207 ng/mL), without the presence of fentanyl or any other opioid.

The CDC said that “the constellation of findings reported should prompt close involvement with public health officials and regional poison centers, given the more severe findings in these reported cases compared with those expected from routine benzodiazepine overdoses.” In addition, it noted that clinicians and first responders should “consider bromazolam in cases of patients requiring treatment for seizures, myocardial injury, or hyperthermia after illicit drug use.”

Surging Supply, Increased Warnings

In 2022, the CDC warned that the drug was surging in the United States, noting that as of mid-2022, bromazolam was identified in more than 250 toxicology cases submitted to NMS Labs, and that it had been identified in more than 190 toxicology samples tested at CFSRE.

In early 2021, only 1% of samples were positive for bromazolam. By mid-2022, 13% of samples were positive for bromazolam, and 75% of the bromazolam samples were positive for fentanyl.

The combination is sold on the street as benzo-dope.

Health authorities across the globe have been warning about the dangers of designer benzodiazepines, and bromazolam in particular. They’ve noted that the overdose reversal agent naloxone does not combat the effects of a benzodiazepine overdose.

In December 2022, the Canadian province of New Brunswick said that bromazolam had been detected in nine sudden death investigations, and that fentanyl was detected in some of those cases. The provincial government of the Northwest Territories warned in May 2023 that bromazolam had been detected in the region’s drug supply and cautioned against combining it with opioids.

The Indiana Department of Health notified the public, first responders, law enforcement, and clinicians in August 2023 that the drug was increasingly being detected in the state. In the first half of the year, 35 people who had overdosed in Indiana tested positive for bromazolam. The state did not test for the presence of bromazolam before 2023.

According to the MMWR, the law enforcement seizures in the United States of bromazolam increased from no more than three per year during 2016-2018 to 2142 in 2022 and 2913 in 2023.

Illinois has been an area of increased use. Bromazolam-involved deaths increased from 10 in 2021 to 51 in 2022, the CDC researchers reported.

Rise in Overdose Deaths Driven by Drug Combinations

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Experts are sounding the alarm that a combination of prescription and/or recreational drugs now contribute to nearly three-quarters of overdose deaths in the United States. 

Reports of the use of fentanyl along with the animal tranquilizer xylazine make preventing substance use disorder and associated overdose deaths even more complicated, experts said during a webinar sponsored by the National Institute for Health Care Management. 

“Nearly 74% of all overdose deaths linked to cocaine now involve synthetic opioids, such as fentanyl,” said Cecelia Spitznas, PhD, a senior science policy analyst in the White House Office of National Drug Control Policy. “This type of combination drug use is part of a new trend driving the overdose rate, along with a growing use of xylazine, or ‘tranq.’” 

The Basics: Fentanyl

Fentanyl is a powerful opioid painkiller that’s stronger than morphine or heroin.

The White House declared the drug combinations as an emerging threat against the United States in April. 

In terms of overdose prevention, “if you yourself use any substance or if you know anybody who uses substances, here’s a couple of things that we like to encourage people to think about,” Shawn Westfahl, overdose prevention and harm reduction coordinator at Prevention Point Philadelphia, said during the webinar. Avoid using drugs alone. “Most people who die from opioid overdose die with nobody around them. We encourage people to use the buddy system and stagger their use.”

Westfahl also suggests that people using substances “go slow, go easy, especially if they inject. They can put more in; they can’t take it out. And we encourage people to avoid mixing in other drugs with opioids.”

Medically Assisted Treatment

Although equal access is a challenge, “the most important thing that we in the United States can do at this point in time to combat the substance use disorders epidemic, and that’s increasing access to evidence-based treatment, in particular … to medically assisted treatment,” said Doug Henry, PhD, vice president of psychiatry and behavioral health at Allegheny Health Network in Pittsburgh. 

Allegheny Health launched a program in 2020, for example, to increase access in medically assisted treatment in rural and underserved areas in West Virginia. Offering remote treatment “was really groundbreaking,” Henry said, especially in regions with certain geographic and population density challenges.

Getting people engaged in medically assisted treatment, and keeping them in treatment, “is hugely, hugely important,” Henry said. “These efforts have led to a reduction in opioid-related overdoses.” 

What’s Alarming the Experts

Henry agreed that drug combinations are adding to the challenge.

“The ongoing opioid epidemic and the emerging epidemic of combined molecules into deadly poisons are leading to an increased frequency of overdoses,” he said. He is seeing spikes in both of his professional roles – at Allegheny Health, a 14-hospital network in southwestern Pennsylvania and western New York, and at Highmark Health, the third largest Blue Cross Blue Shield insurance company in the United States, serving members primarily in West Virginia, western New York, Delaware, and Pennsylvania. 

Westfahl reported that 1,413 people died from drug overdoses in 2022 in Philadelphia, up from 1,276 overdose deaths in 2021, a 10% increase. Most of the 2022 deaths, 83%, involved opioids. Fentanyl and tranq remain major challenges for the population served by Prevention Point, he said. 

“We are seeing a huge spike [in fentanyl use] consistently increasing throughout the years,” he said.

What You Should Know About Opioids

In 2010, for example, fentanyl was involved in fewer than 10% of drug overdoses. Last year, fentanyl played a role in 96% of overdose deaths. 

The national picture is not much more encouraging, Spitznas said. About 25%, or 70 million Americans, used illicit drugs in 2022, national survey data reveal. More than 17%, or nearly 49 million Americans, reported past-year substance use disorder.

Marijuana led drug use among Americans 12 years and older. An estimated 62 million Americans used marijuana in 2022. Next, two of the most common drugs used are in categories such as hallucinogens and pain reliever misuse, each involving 8.5 million Americans. Also, nearly 5 million people misused prescription tranquilizers and sedatives.

In terms of deaths, there’s been a dramatic uptick blamed on synthetic opioids and fentanyl, climbing to just under 80,000 deaths in April 2023. Spitznas said the categories are not mutually exclusive because many drugs are used in combination. In addition, “we think both the heroin figure and the fentanyl figures are dramatic undercounts” in national surveys. 

“Fentanyl is often used in to contaminate certain substances, so it’s unlikely that people really, truly know if they are using heroin or they’re using fentanyl,” she said. Fentanyl and xylazine test strips, if available, can help determine what substances are present when someone is overdosing. 

Good and Bad News on Treatment

National data also shows that only about 24% of Americans 12 years and older who are classified as needing substance use treatment receive it. A silver lining can be seen in a breakdown by age group, Spitznas said. “We’re doing a little bit better in getting 12- to 17-year-olds in treatments.”

Compared to the 25% of younger teens receiving treatment, “we’re doing really poorly in getting 18- to 25-year-olds into treatment,” she said. The figure is a little more than 16%. “And across the board, we need to get more people into treatment.”

Providing naloxone is a priority, Spitznas said. The FDA approved the first over-the-counter nasal naloxone spray in March. The agency also approved a second agent to reverse opioid overdoses called nalmefene in May.

If a person is overdosing on both fentanyl and tranq, the opioid reversal agents can treat the effects of fentanyl. But xylazine, or tranq, is not an opioid. It’s a veterinary medicine that causes prolonged sedation, and the FDA has not approved its use in humans. 

“One way to think about this is that naloxone can restore breathing. You may not have a rapid return of consciousness when there’s fentanyl and xylazine together. But as long as breathing returns, that is a good thing,” Spitznas said. “That is why we’re recommending continuing with naloxone as well as calling 911 and getting emergency services.”

Treatment for combination overdoses may not ease withdrawal symptoms. “People dependent on xylazine may experience an extreme withdrawal, even if they receive medications for opioid use disorder,” Spitznas said. There is no medication available for xylazine withdrawal, she said. 

What is Xylazine? Flesh-eating ‘zombie’ medicine fuelling overdose deaths across US

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Xylazine, or “tranq” is the new medicine in the US that is reportedly showing symptoms including skin rotting and zombifying people. Photograph:(Twitter)

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STORY HIGHLIGHTS

Here’s everything you need to know about tranq, including why it’s referred to as a flesh-eating zombie medicine, and how Canada and the United States are trying to regulate it.

A horrific new ‘zombie’ drug that has devastated cities throughout the United States has been discovered in the United Kingdom and has claimed the life of a British factory worker.

Karl Warburton, 43, died in May from the effects of xylazine coupled with other narcotics such as heroin, fentanyl, and cocaine, reported Daily Mail.

The West Midlands man died of acute aspiration pneumonitis, a disease commonly caused by breathing pollutants. However, xylazine was recorded as a contributing factor in Warburton’s death certificate.

The technically legal animal tranquilizer “tranq” is frequently used to cut cocaine, heroin, or fentanyl dependence. As it grows in popularity in the illegal drug market, contributing to an increasing number of overdose deaths, states in the United States are increasingly attempting to restrict access to it.

The substance enforcement administration and health authorities have issued cautions against using the substance. While the problem is most visible in Los Angeles, Canadian officials have also warned that tranq is making its way onto their streets.

Here’s everything you need to know about tranq, including why it’s referred to as a flesh-eating zombie medicine and how the United States is trying to regulate it.

What is Xylazine?

Xylazine is a veterinary medication that is licenced for use as a sedative in large animals. Rompun and Anased are two of its brand names. It is sometimes referred to as a “horse tranquilizer.”

It needs a veterinarian licence to buy and use, but it is rapidly appearing in Canada’s illicit drug supply, frequently without the user’s awareness. Other medicines are cut with xylazine since it is an inexpensive filler that can improve opioid potency.

What effect does tranq have on people?

In humans, xylazine has sedative properties. It alleviates pain, lowers brain activity, and has the potential to lower blood pressure, heart rate, and breathing rate.

People who use xylazine may develop open sores anywhere on their body. These wounds can result in hospitalisation, necrosis (rotting tissue), and even amputation, which is why it is referred to as a zombie drug.

The drug’s wounds look to be “eating away your flesh from the inside out,” according to nurses who spoke to Stat News.

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Overdoes are also more likely with drugs like fentanyl that have been cut with xylazine. According to Health Canada, xylazine can cause central nervous system depression, respiratory depression, bradycardia, and hypotension in humans, which are comparable to opioid withdrawal symptoms.

“When combined with opioids like fentanyl, as is frequently the case, xylazine enhances the life-threatening effect of respiratory depression (slowing or stopping breathing) caused by opioids, increasing the risk of overdose and death,” according to Los Angeles public health officials, as reported by the National Post.

Unlike fentanyl, no medication or antidote is available to reverse xylazine overdose, like naloxone does for opioids. Experts still recommend that naxolone be administered in the event of a xylazine overdose if opioids are present.

“Tranq is basically zombifying people’s bodies,” 28-year-old Sam told Sky News. “Until nine months ago, I never had wounds. Now, there are holes in my legs and feet.”

The New York City Department of Health said that 2,668 individuals in New York died in 2021 as a result of xylazine overdoses, and experts worry that the medication might exacerbate the country’s current drug pandemic.

How are US states responding?

Many states in the United States have implemented different measures to limit the spread of the substance. 

Pennsylvania has added xylazine to its list of banned substances in an effort to strengthen drug restrictions and empower police to prosecute individuals who break them.

“We are giving greater tools to law enforcement and others to properly regulate, control and contain these drugs, make arrests and hopefully prosecutions,” Democratic Gov. Josh Shapiro said at a news conference in Philadelphia.

Ohio’s Republican governor signed an executive order banning xylazine through the state’s Board of Pharmacy in March, while West Virginia’s Republican governor signed legislation making it a restricted substance.

The designations in Pennsylvania, Ohio, and West Virginia enable veterinarians to continue using the medicine to sedate animals, but they impose stricter requirements on how the drug must be handled, recorded, and kept.

“Xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier,” said Anne Milgram, DEA Administrator, who spoke to the National host. 

“DEA has seized xylazine and fentanyl mixtures in 48 of 50 States. The DEA Laboratory System is reporting that in 2022 approximately 23 per cent of fentanyl powder and seven per cent of fentanyl pills seized by the DEA contained xylazine,” she added. 

Does naloxone work on xylazine overdoses? 

Xylazine does not react to naloxone, but that doesn’t imply the opioid-reversing medicine can’t be useful if a bystander witnesses an overdose, according to specialists, because xylazine is used in combination with opioids that will react to naloxone. While xylazine has been found in fatal overdoses, it is unknown how much the sedative had a role in the person’s death because it is taken in combination with heavier opioids. 

Claire Zagorski, a chemist, paramedic and translational scientist in Austin, Texas who spoke to CBS News said that administering naloxone to someone who is not experiencing an opioid overdose would not harm them, hence it is preferable for a bystander to do so if feasible. 

What Doctors Should Know About Xylazine in Fentanyl

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Naloxone still works but additional support may be needed; wound care a challenge

A photo of a vial of xylazine for injection over a photo of small bags of white powder.

It’s been about 3 years since Joseph D’Orazio, MD, and his colleagues at Temple University Hospital in Philadelphia first noticed something different among injection drug users who came to the hospital.

Some patients who overdosed responded differently to the rescue agent naloxone (Narcan), and then there were the wounds — severe wounds that required extensive treatment, and sometimes, amputation.

That wasn’t something they’d seen before in the ongoing opioid crisis.

They learned that a veterinary sedative called xylazine was increasingly being added to fentanyl, the predominant opioid in the area, to boost its effects and extend its high.

“That’s where we’re feeling it the most, with these really severe wounds,” D’Orazio told MedPage Today. “We’ve been doing a lot more amputations over the last couple of years for really bad necrotic wounds and dysfunctional limbs and infections that go all the way down to the bone.”

Philadelphia has been flagged as the epicenter of the xylazine crisis, which is now prevalent throughout the northeast and has started to show up in cities across the U.S. The problem is popping up on regulators’ radars. In the past few months, several federal agencies, including the FDAopens in a new tab or window, the Office of National Drug Control Policyopens in a new tab or window (ONDCP), and the National Institute on Drug Abuseopens in a new tab or window have released statements about the growing problem.

“Xylazine is making the opioid crisis worse,” said Andrew Kolodny, MD, an expert in opioid policy and addiction medicine at Brandeis University in Waltham, Massachusetts. “It’s hard to imagine anything could make the opioid crisis even worse. But this really is making it worse, both in increased mortality and in people becoming addicted to xylazine as well as opioids.”

What Is Xylazine?

Xylazine was never intended for use in humans, according to Kelly Ramsey, MD, MPH, chief of medical services at the New York State Office of Addiction Services and Supports in Albany.

“It was actually studied by a pharmaceutical company in the 1960s as a potential medication for hypertension in humans, but because of the severe central nervous system sedation, it was deemed not appropriate for human use … but it was approved by the FDA as a veterinary medication,” Ramsey, a member of the American Society of Addiction Medicine board of directors who was speaking for herself, said in a phone interview. “It’s used most typically as an anesthetic and a sedative for procedures for both large and small animals.”

Xylazine is an alpha-2 agonist that would be most comparable to dexmedetomidine (Precedex), a sedative used in the intensive care unit, said Lewis Nelson, MD, a medical toxicologist and chair of emergency medicine at Rutgers New Jersey Medical School in New Brunswick. Another comparable medicine, he said, is clonidine (Catapres).

Xylazine is added to fentanyl to make its effects last longer, said Chelsea Shover, PhD, of the University of California Los Angeles, who co-authored a paper in Drug & Alcohol Dependenceopens in a new tab or window on xylazine’s spread across the U.S.

“Fentanyl is very strong, but it’s also very short-acting,” Shover told MedPage Today. “If someone has a fentanyl use disorder, they have to use frequently to stay well. That’s difficult with illicit drugs. Lots of people in that situation don’t have a lot of money … so if something shows up on the market that can extend the high, there becomes a demand for that.”

It’s not clear exactly how xylazine found its way into the street drug market, but Shover notes that ethnographic studies first called attention to the problem in Puerto Rico in the mid-2000s.

“We have a significant Puerto Rican population here in Philadelphia,” particularly in the Kensington neighborhood where xylazine use is prevalent, D’Orazio said. “But Philadelphia isn’t the only place that has people who immigrated from Puerto Rico.”

A senior Biden administration official told MedPage Today that the earliest report of xylazine was “in the early 2000s. … The rise in the U.S. where it was used as an adulterant of fentanyl started in the mid-20-teens, with a real increase in 2019.”

A joint reportopens in a new tab or window issued in December by the Drug Enforcement Administration (DEA) and the Department of Justice noted that according to findings from the DEA’s lab system between 2020 and 2021, although the xylazine problem is most prominent in the Northeast, “each of the four regions [Northeast, South, Midwest, and West] has seen an increase in identifications of xylazine. The South has the largest increase, reporting a 193% increase in xylazine instances, followed by the West with an almost 112% increase.”

What is clear is that the xylazine on the streets is not illicit. It’s pharmaceutical-grade, and it’s being diverted, doctors said.

“This isn’t clandestine production of a drug,” D’Orazio said. “This is a pharmaceutical. They’re finding empty bottles of pharmaceutical-grade xylazine at packaging areas, where dealers are bagging [drugs].”

Narcan Still Works

One of the problems with xylazine is that it brings on profound sedation that “knocks you out for a long time,” Shover said.

“If you’re out in a public place, that leaves you vulnerable to physical or sexual assault or robbery,” she said. “You’re not aware of what’s going on around you and you’re not able to protect yourself.”

Being passed out for hours could also lead to other conditions such as deep vein thrombosis or compartment syndrome, Ramsey said.

The opioid overdose reversal agent naloxone may appear to be ineffective in someone who has overdosed with both fentanyl and xylazine in their system, but it’s actually not, several sources said.

When trying to reverse these patients with naloxone, “they’ve remained really sleepy and many have been deemed Narcan-resistant, but really it’s just a polysubstance overdose since they’re on a sedative also,” D’Orazio said. “Xylazine doesn’t reverse with Narcan so they remain sedate.”

While xylazine doesn’t cause respiratory depression, he said, it causes mental status depression, which can lead to a blunted response to the hypoxia that comes with an overdose.

“It’s like you have an occluded airway,” he said. “It’s sort of the same as how a benzodiazepine overdose would look.”

For bystanders who administer naloxone, that means if breathing returns but patients aren’t awake, they should be placed on their side in the recovery position.

In hospitals, physicians will do some airway maneuvers for these patients, such as putting their head to the bed at 30 degrees, keeping their airways open, and monitoring oxygen levels via a pulse oximeter.

Only rarely do these cases require intubation and ventilation, D’Orazio said.

He also noted that xylazine has a withdrawal profile that’s different from other sedatives, like alcohol or benzodiazepines. Instead of primary effects such as increased heart rate, sweating, confusion, or seizures, xylazine withdrawal “has primarily been anxiety-associated. People are very restless and uncomfortable. They feel dysphoric, and it’s quite difficult to manage,” D’Orazio said.

“Just recognizing that there is a xylazine withdrawal syndrome is number one,” he added.

While an optimal treatment strategy for xylazine withdrawal remains to be developed, he said, he usually recommends using benzodiazepines for detoxification.

‘The Wounds Are Much More Severe’

D’Orazio said the wounds he and his colleagues are seeing with xylazine use are different from anything they’ve witnessed with injection drug use in the past.

“There’s always been the risk of an abscess or cellulitis that leads to a wound that takes some time to heal, but this is very different,” he told MedPage Today. “With xylazine, the wounds are much more severe, much deeper, and much harder to manage.”

He said his hospital has done more amputations over the last couple of years, as not all injuries can be managed with wound care therapy.

There are no data on what percentage of those who use fentanyl adulterated with xylazine develop these severe wounds, but D’Orazio said that “most patients have at least some wounds to some degree. It may not be so severe that they need to be hospitalized, but they’ve got some degree of wounds.”

However, clinicians don’t see such wounds with people who smoke or use fentanyl intranasally, he said, so it’s not clear exactly why xylazine seems to cause these wounds.

“There’s a lot of speculation that it’s cytotoxic,” D’Orazio said, noting that more research is needed, as only animal studies exist. Indeed, there are some reports that repeated use in animals causes lesions, “so it was typically recommended that if you had to sedate that animal multiple times, don’t use xylazine in a chronic fashion,” he said.

Nelson noted, however, that there’s a lot of xylazine in the drug supply in New Jersey, but that state hasn’t seen as much of a problem with severe wounds. Philadelphia may have a larger proportion of injection drug users, he said.

It’s possible that xylazine may cause wounds via its activity as a vasoconstrictor, reducing blood flow to the area, Nelson said.

Fears of unmanageable withdrawal could also play a role in wound development, D’Orazio said. Since withdrawal is harder to treat, people worry they’ll get sick, and avoid coming to the hospital, he said. Wounds may be more severe because of that delay, he noted.

One of the downstream effects of wounds is that people can’t get into inpatient rehabilitation programs, as many don’t take complex medical cases, D’Orazio said. Wounds also prevent people from getting into sober living facilities for the same reason, he said.

“It has really cut off people who are looking to achieve recovery,” he said.

Better Tracking Needed

It’s hard to tell exactly how widespread xylazine use is in the U.S., since there’s no national tracking of the compound. The DEA report notes that “a comprehensive count of xylazine-positive overdose deaths in the United States is not currently possible, as not all jurisdictions routinely conduct testing for xylazine in postmortem toxicology. Testing procedures can vary even within the same state. In addition, it is not currently included with the CDC’s reporting of national statistics on fatal overdoses. As a result, it is very likely the prevalence of xylazine is widely underestimated.”

“It’s not part of drug use surveys,” Shover said. “It’s not a variable you can pull from publicly available data, like you can for, say, cocaine or heroin.”

The CDC did not return a MedPage Today request for comment regarding xylazine monitoring. However, the agency has published two studies on xylazine in its journal Morbidity and Mortality Weekly Report in recent years.

In 2021, the agency examined dataopens in a new tab or window from the State Unintentional Drug Overdose Reporting System in 38 states and Washington, D.C. Of 45,676 overdose deaths in 2019, 1.8% were xylazine-positive and 1.2% were xylazine-involved. The authors concluded that xylazine detection in overdose deaths is likely under-reported.

In April 2022opens in a new tab or window, researchers reported that Cook County, Illinois, saw a total of 210 xylazine-associated deaths from January 2017 to October 2021, with the numbers rising throughout the study period. As with the other study, fentanyl was present in the vast majority of xylazine-involved deaths, the team found.

Ramsey said more than 90% of fentanyl samples in Philadelphia in 2021 were found to contain xylazine. Nelson said the figure stood at 30% in New Jersey a year ago, and has likely grown since. New York City recently announced that nearly 20% of opioid-involved overdose deaths also involved xylazine.

“It’s difficult to get even just like, within the last couple months, a picture of what’s happening with xylazine in the U.S.,” Shover said.

The ONDCP discussed xylazine last month at a meeting of its evolving and emerging threats committee. “It is critical to continually assess changes in the illicit drug market to guide our approach to new threats like Xylazine,” ONDCP director Rahul Gupta, MD, said in a statement emailed to MedPage Today. “This includes evaluating existing data on trends and emerging patterns of use, listening to people and experts on the ground, utilizing the Emerging Threats process outlined by Congress in the SUPPORT Act, and ensuring that our response is protecting the people of the United States.”

Fentanyl isn’t just causing overdoses. It’s making it harder to start addiction treatment

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Packets of buprenorphine stigma
Packets of buprenorphine Elise Amendola/AP

Doctors are reporting a troubling trend when it comes to fentanyl.

The powerful drug, they say, isn’t just causing overdoses — it’s also making it more difficult to begin addiction treatment. In particular, fentanyl appears more likely to cause severe withdrawal symptoms for patients put on buprenorphine, a key medication used to treat opioid use disorder.

The development adds yet another layer of crisis to the country’s drug epidemic, which killed nearly 108,000 Americans last year. Even as fentanyl sends overdose deaths soaring, it threatens to make the world’s most-prescribed addiction drug inaccessible to the increasing number of patients who need it.

“It’s the clinical challenge of my career,” said Sarah Kawasaki, an addiction doctor and psychiatry professor at Pennsylvania State University. Inductions, or the process of starting patients on buprenorphine treatment, have become “progressively more difficult” in the past five years, she said, as fentanyl has spread throughout the drug supply.

To make matters worse, Kawasaki added, buprenorphine is one of just two medications commonly prescribed to treat opioid addiction. The other, methadone, is highly regulated; patients can only access it at specialized clinics that typically require them to appear in person each day to receive a single dose.

“We have 20 different ways to treat strep throat, but two medications that work well in the treatment of opioid use disorder,” Kawasaki said. “When you eliminate one and make the other really hard to get, it is a setup for failure.”

While doctors across the U.S. and Canada, where fentanyl is also pervasive, have reported that buprenorphine inductions have become more difficult in recent years, the phenomenon is hard to measure or explain. Theories include fentanyl’s raw potency, or that it is lipophilic — it sticks to fat molecules — and remains in the body for longer than other opioids.

Buprenorphine is what’s known as a partial agonist, meaning that it binds tightly but incompletely to the same brain receptors that give a euphoric effect when opioids bind to them. But it binds to the receptor awkwardly, like a puzzle piece that doesn’t quite fit. As a result, patients with opioids already in their system can feel what’s known as “precipitated withdrawal” as the addiction medication shoves the fentanyl aside.

As a result, it’s normal for doctors to wait several hours until patients start experiencing withdrawal symptoms before they administer buprenorphine. At that point, the “bupe,” as it is known, helps to treat withdrawal symptoms like anxiety or gastrointestinal distress, as well as eliminate future opioid cravings.

With fentanyl, however, doctors are sometimes forced to wait a full day, if not longer, to make sure buprenorphine doesn’t cause severe discomfort. In some cases, even patients experiencing withdrawal because they refrained from drug use for many hours — typically ideal candidates for buprenorphine — find that their symptoms get worse, not better, once they begin using the medication. Many don’t come back for another dose, known in doctors’ parlance as a “failed induction.”

Doctors warn those failed attempts can be dangerous — not just because they risk patients returning to fentanyl use, but also because those patients might feel so miserable that they refuse to ever try buprenorphine again.

Some clinicians report that patients have become more likely to request methadone, despite its inconveniences. Kawasaki, who works at a clinic that offers both methadone and buprenorphine, said she’s had trouble enrolling patients in a clinical trial about buprenorphine induction because her patients are opting for the drug less likely to cause withdrawal symptoms.

Though the phenomenon is widespread, doctors haven’t reached a consensus about how to move forward. Nor have they received much guidance from medical societies and local health officials, leaving doctors to rely informally on word of mouth, email chains, and new scientific papers.

One recent set of recommendations from the Substance Abuse and Mental Health Services Administration did little beyond acknowledge the issue, warning that patients using fentanyl long-term and at high doses “may not be appropriate for buprenorphine.”

“There’s a patchwork of induction strategies at this point,” said David Fiellin, an addiction physician and the director of Yale University’s Program in Addiction Medicine. “In a lot of ways, we’re in an area without much science.”UPCOMING EVENT

The knowledge gap led Fiellin to issue a recent call in the Journal of Addiction Medicine for “rapid research” analyzing the relationship between the type and quantity of drugs used and difficulties beginning buprenorphine treatment.

In the meantime, however, doctors are employing strategies that vary dramatically. Some have begun administering radically larger amounts of buprenorphine in an effort to overcome withdrawal symptoms by brute force — as much as 32 milligrams, or four times a typical first dose.

Some doctors, like Kawasaki, also use common medications to treat any remaining symptoms of physical discomfort and anxiety, including antihistamines, ibuprofen, and drugs to combat nausea and gastrointestinal problems.

Others have tried the opposite approach: “microdosing” buprenorphine in increasing amounts over the course of several days, avoiding a moment where a sudden, large buprenorphine dose causes immediate withdrawal. Samantha Young, a doctor and researcher at the British Columbia Centre for Substance Use, said she sometimes prescribes shorter-acting opioids typically used for pain, like hydromorphone, to help alleviate withdrawal symptoms as patients build up to larger buprenorphine doses.

“When I teach residents and medical students about buprenorphine, I tell them it’s an art based on the science,” Young said.

Others, still, have tried the controversial approach of administering naloxone, a drug used to reverse opioid overdoses, even to patients who are not overdosing. The result is a very short period of intense withdrawal, setting the patient up for a first buprenorphine dose that alleviates discomfort instead of causing it.

Any strategy that works is promising, Fiellin said. But the fact that it’s become harder for doctors to prescribe buprenorphine is concerning in its own right. While the medication is highly effective, it’s also tightly regulated, meaning convincing doctors who aren’t addiction specialists to prescribe it has long been challenging. The newfound difficulties, he said, risk reversing recent progress.

“There was a period of 10 or 15 years where bupe initiation was not seen as a challenge, so it was much more common that nonspecialists would take on buprenorphine prescribing,” Fiellin said. “Unfortunately, we’re in a situation where now initiation is seen as a huge challenge, and I worry that’s going to set us back with respect to expanding the number of clinicians who are prescribing buprenorphine.”

Still, some physicians remain optimistic. And patients who want to begin buprenorphine treatment shouldn’t despair, they say. Ultimately, buprenorphine induction for people using fentanyl is still possible, despite its difficulties. The pervasiveness of fentanyl in the North American drug supply “does make the induction a bit more challenging,” Young said. “But just so people know: We’ve developed a lot of methods — if you want to get on bupe, and you use fentanyl, great! We can definitely do that for you, without you being in withdrawal.”

Fentanyl’s Effects on the Brain

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Summary: Fentanyl exposure produces specific EEG signatures in the brain. The findings also revealed the drug impairs people’s breathing four minutes before noticeable changes in alertness.

Source: Mass General

Fentanyl is used to supplement sedation and to relieve severe pain during and after surgery, but it’s also one of the deadliest drugs of the opioid epidemic.

In research conducted by investigators at Massachusetts General Hospital (MGH) and published in PNAS Nexus, tests of the brain’s electrical activity revealed fentanyl’s effects over time and indicated that the drug stops people’s breathing before other noticeable changes and before they lose consciousness.

In the study, electroencephalogram (EEG) tests were run for 25 patients undergoing general anesthesia for surgeries lasting 2 hours or more. The researchers discovered that certain EEG patterns were associated with respiration, sedation, and loss of consciousness.

“We found that fentanyl produces a specific EEG signature distinct from other anesthetic drugs, which could make it possible to monitor its effects to enable safer, more precise, and personalized opioid administration,” says senior author Patrick L. Purdon, PhD, the Nathaniel M. Sims Endowed Chair in Anesthesia Innovation and Bioengineering at MGH.

“For example, think of patients with COVID-19 who are sedated in the ICU or patients undergoing surgery—currently there is no way to know if opioids are working in these unconscious patients.”

This shows a brain
Fentanyl produces a specific EEG signature, which could allow clinicians to monitor its effects to enable safer, more personalized administration during and after surgery.

The EEG tests by Purdon and his colleagues also revealed that fentanyl begins to impair breathing about 4 minutes before there is any change in alertness and at 1,700-times lower drug concentrations than those that cause sedation.

“This explains why fentanyl is so deadly: it stops people’s breathing before they even realize it,” says Purdon.

The findings make it clear that no amount of fentanyl would be safe outside of a clinical setting with trained specialists. As fentanyl exposure is likely to remain a persistent risk during illicit use, the rapid respiratory depression the researchers observed supports the need for increased availability of medical observation or supervision units, naloxone, and other tools to reduce the risk of death among individuals with substance use disorder.

Additional co-authors include Gustavo A. Balanza, Kishore M. Bharadwaj, Andrew C. Mullen,
Amanda M. Beck, Erin C. Work, Francis J. McGovern, Timothy T. Houle, and Eric, T. Pierce.

Funding: This work is supported by funds from the National Institutes of Health through a National Institute on Drug Abuse grant.

Abstract

An EEG Biomarker of Fentanyl Drug Effects

Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects including respiratory depression. At present we do not have real-time clinical biomarkers of these brain effects.

We describe here the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4-8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation.

We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈ 1700-fold lower concentrations than those that produce sedation as measured by reaction time.

The EEG biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.