November 2016

# Fentanyl

##

Jenn Coggan,Nanotechnology Engineering Laboratory Coordinator, University of Waterloo, Waterloo ON

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Chemical name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide

Formula: C22H28N2O

Molecular Weight: 336.47052 g/mol

Structure:

Fentanyl is a synthetic, lipophilic phenylpiperidine derivative with both analgesic (painkiller) and anesthetic (causes reversible loss of consciousness) properties. Fentanyl works by binding to the body's opioid receptors, which are found in areas of the brain that control pain and emotions.1 Fentanyl selectively binds to the mu-receptor in the central nervous system (CNS), in the same way as morphine or heroin. When an opioid drug binds to these receptors, they drive up dopamine levels in the brain's reward areas, producing a state of euphoria and relaxation.1 Fentanyl's effects resemble those of heroin and include euphoria, drowsiness, sedation, addiction, respiratory depression and can lead to unconsciousness, coma and death.

Fentanyl is a 50 to 100 times more potent analgesic than morphine and 25-50 times more potent than heroin.2 It is a schedule II prescription drug, and it is typically used to treat patients with severe pain or to manage pain after surgery. It is also sometimes used to treat patients with chronic pain who are physically tolerant to other opioids.

A single intravenous dose of fentanyl has a more rapid action (5 – 6 minutes) than morphine (15 – 30 minutes) which is due to the lipophilicity of fentanyl.3 In order for the drug to move into the CNS it must be able to pass through the lipid bilayer membrane. The structure of fentanyl is more lipophilic meaning it dissolves in fat (fat friendly) while morphine is hydrophilic (water loving) and shows a relatively low lipid solubility, about 2.5% of fentanyl. This means that fentanyl can quickly enter the brain, initiating a maximal effect within 5 minutes.

Fentanyl does not occur in nature, which is why it is referred to as a synthetic drug, and was first synthesized in 1959 by Paul Janssen (1926–2003). In comparison, morphine is a naturally occurring opiate, derived from opium poppy plants, or Papaver somniferum.4 Heroin is also a synthetic drug as it is synthesized from morphine.

(1) Morphine Sturcture

(2) Heroin Structure

Many different fentanyl derivatives have been developed by pharmaceutical companies to study the analgesic and anesthetic potency effects of adding various substituents to the basic molecule.5 Small changes in the chemical structure can produce more or less potent derivatives and even enantiomers of specific derivatives can have vastly different potencies. Unfortunately, this approach has been mimicked by chemists in clandestine laboratories to produce “designer” or illicit non-pharmaceutical fentanyl (NPF) derivatives.

There has been a lot of recent news about overdose deaths resulting from fenantyl.6 So much so that death from fentanyl overdose was declared a public health crisis in Canada in September 2015, and it continues to be a major killer drug. In 2016, deaths from fatal fentanyl overdoses in British Columbia, Canada, averaged two persons per day. In April 2016, the musician Prince died from an accidental fentanyl overdose.7

The increased frequency of death by abusing fentanyl is due to the fact that opioids such as fentanyl can cause breathing to stop. The estimated lethal dose of fentanyl in humans is 2 mg. Opioid receptors that are found in the brain and control pain are also found in the areas of the brain that control breathing rate.1 The high potency of fentanyl greatly increases the risk of an overdose, especially if a person who uses drugs is unaware that a powder or pill contains fentanyl. Fentanyl sold on the street can be mixed with heroin or cocaine, which markedly amplifies its potency and potential dangers. This combination is even more dangerous than when taking the drugs alone and is a hundred times more likely to lead to overdose and death.1

Unfortunately, this is not the end of the story. Even more potent fentanyl derivatives are starting to show up as recreational drugs, such as carfentanil. This derivative is prescribed for use only as a general anesthetic for large animals, such as elephants. It is one of the most potent opioids known and can be up to 10,000 times more powerful than morphine and 100 times that of fentanyl.8

## References

(All website listed were accessed in October 2016.)

1. H. Gutstein and H. Akil, Opioid Analgesics In: Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th edition, McGraw-Hill, 2006.
2. D.A. Volpe, et al., Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regulatory Toxicology and Pharmacology, 2011, pages 385-390.
3. S. Mayes and M. Ferrone, Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for the Management of Acute Postoperative Pain, The Annals of Pharmacotherapy, 2006, pages 2178-2186.
4. www.ch.ic.ac.uk/rzepa/mim/drugs/html/morphine_ text.htm
5. Y. Higashikawa and S. Suzuki, Studies on 1-(2-phenethyl)-4-(N-propionylanilino) piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicology, 2008, pages 1-5.
6. R.S. Vardanyan and V.J. Hruby. Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications, Future Medicinal Chemistry, 2014, pages 385-412.
7. www.huffingtonpost.com/news/fentanyl-overdose/
8. www2.gov.bc.ca/assets/gov/public-safety-and-emergency-services/death-investigation/statistical/fentanyl-detected-overdose.pdf
9. www.hhs.gov/blog/2015/12/10/rates-of-drug-overdose-deaths-continue-to-rise.html
10. www.scientificamerican.com/article/why-the-pain-drug-that-killed-prince-can-be-especially-dangerous/
11. www.cbc.ca/news/canada/windsor/carfentanil-drug-1.3755325

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