Fentanyl exposure produces specific EEG signatures in the brain

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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.”

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.


Fentanyl (which can also be spelled fentanil) is a potent synthetic opioid similar to morphine but produces analgesia to a greater extent. This robust pharmacologic agent is typically 50 to 100 times more potent than morphine. A dose of only 100 micrograms can produce equivalent analgesia to approximately 10 mg of morphine. However, fentanyl exhibits vastly different properties and pharmacokinetics. Clinically, its most frequent use is as a sedative in intubated patients and in severe cases of pain in patients with renal failure due to its primarily hepatic elimination.[1]

At times, clinicians may also use fentanyl to treat chronic pain patients who have developed tolerance to opiates. When used as a sedative, it is most commonly administered as a drip, owing to its versatility in titration scenarios.[2] It may often require large doses when used as a sedative in patients with mechanical ventilation requirements. As pre-medication for procedures, namely those anticipated to cause discomfort, fentanyl is also an option perioperatively. Lastly, fentanyl use can extend to the treatment of epilepsy. That is, in combination with certain neuroleptic medications as part of therapeutic neuroleptanalgesia.[3]

Indications for fentanyl are as follows:

Preoperative analgesia
Anesthesia adjunct
Regional anesthesia adjunct
General anesthesia
Postoperative pain control
Moderate to severe acute pain (off-label)
Fentanyl was first produced in 1960 and approved for use in the USA in 1968.[4]

Fentanyl is also a drug subject to diversion for misuse. Fentanyl can be added to heroin for increased potency or be distributed under the guise of highly potent heroin. When users think they are purchasing heroin and instead actually receive fentanyl, it can often result in overdose deaths.[5] According to the CDC, many of these overdose deaths result from illegally manufactured fentanyl.

Mechanism of Action
Fentanyl is similar to other opioid drugs. Fentanyl molecules target a subclass of opioid receptor systems in the body, many of which are localized in the brain within specialized neuroanatomical structures, particularly involving the control of emotions, pain, and speaking to the point of its infamous addictive properties, reward. Biochemically, it is a Mu-selective opioid agonist. However, it has the capability to activate other opioid system receptors such as the delta and potentially the kappa-receptors. Consequently, the activation of these receptors, particularly the Mu-receptors, produces analgesia. Also, the neurotransmitter dopamine (Da) is increased in the reward areas of the brain, which elicits the stereotypical exhilaration and relaxation effects, and is typically associated with the addiction to the drug.[6]

Fentanyl is hepatically metabolized via the CYP450 enzyme system, specifically CYP3A4. The drug has a half-life of 3 to 7 hours. Excretion is 75% in the urine and 9% in feces.

reference link : https://www.ncbi.nlm.nih.gov/books/NBK459275/


Original Research: Open access.
An EEG Biomarker of Fentanyl Drug Effects” by Patrick L. Purdon et al. PNAS Nexus

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