Nestor Pinacho
In 1960, the Belgian scientist Paul Janssen successfully synthesized a drug that had some advantages over morphine and appeared to have fewer of its adverse effects. Starting the following year, it began to be used in operating rooms, in various doses, all of which were very low. It wasn't until 1968 when this substance, called fentanyl, started to be used in the United States and subsequently in many countries.
Currently, its non-medical use has become a serious public health problem in the United States and Canada. In 2022, approximately 110,000 people died from overdoses in the United States, according to preliminary data from the Centers for Disease Control and Prevention (CDC), and a significant portion of these deaths, according to experts, are associated with the crisis caused by the increase in fentanyl consumption in the country.
In the midst of this serious problem, Dr. Silvia Cruz Martín del Campo, a scientist from the Department of Pharmacobiology at the Centro de Investigación y de Estudios Avanzados (Cinvestav), South Branch, conducts studies on the pharmacological interactions of various drugs of abuse, including fentanyl. These studies, along with a group of specialists, have led to significant discoveries about the effects of these substances when consumed.
Dr. Cruz Martín del Campo has studied the analgesic effect of combining fentanyl with morphine, as well as combining it with xylazine. However, one of the most interesting results of the research has been the damage caused by the consumption of this drug to neurons that contain serotonin, a substance whose deficiency is associated with depression.
"After a certain number of administrations of fentanyl, tolerance develops, albeit more slowly than with morphine, and it can lead to cell death in certain regions of the brain. We have observed that the neurons most susceptible to damage from fentanyl are those that handle serotonin, which are concentrated in the raphe nucleus. We then correlated what happens in animals that we know have received a dosage of fentanyl sufficient to produce this selective cell damage, how it manifests in behavior, and we saw that it results in depression," she explained.
Fentanyl is not directly derived from the poppy plant or opium; being synthetic, it is easier to produce, cheaper, simpler to store and transport, and more profitable.
The National Commission against Addictions states that fentanyl is currently "a substance widely used as a drug. Due to its analgesic effects, it is used in patients with chronic and disruptive pain, as well as an anesthetic in surgical procedures."
Dr. Cruz Martín del Campo explained that this substance is a synthetic opioid, meaning it is not directly derived from the poppy plant or opium but can be produced directly in a laboratory, making it easy to produce and much cheaper. She clarified that, in reality, fentanyl is the base molecule, so it would be more accurate to talk about fentanyls resulting from small modifications to it.
As Dr. Daniel Reyes Mendoza, a professor in the Department of Physiology at the Escuela Nacional de Ciencias Biológicas (ENCB), points out, both morphine and fentanyl are controlled substances "precisely because they can lead to addiction due to the sensations of well-being, euphoria, and the pain relief effect they produce."
In most cases, fentanyl is mixed with other drugs, even without the user's knowledge.
Fentanyl was found to be a way to produce the same effects as other types of drugs at a lower cost, so it was first acquired and subsequently synthesized.
From a pharmacological perspective, the fact that fentanyl is potent does not mean it is very strong or has a greater effect than other opioids. Instead, it produces a result very similar to that of heroin but with a concentration 50 to 100 times lower, according to Dr. Cruz Martín del Campo.
It is important to note that fentanyl - whose chemical name is N-(1-(2-phenylethyl)-4-piperidinyl-N-phenylpropanamide - is rarely sold in isolation. In most cases, it is mixed with other drugs, even without the final user's knowledge.
"In the case of the United States, the consumption of fentanyl has increased exponentially over the last 15 years, although in the last five or ten years, people who were not addicted to fentanyl or were consuming other drugs are ingesting it without knowing it, as criminals adulterate these drugs with fentanyl, leading to an increase in deaths," Dr. Reyes Mendoza noted.
The human body has receptors for endogenous opioids, such as endorphins, which are released after injuries or blows to mitigate pain. They are also secreted during pleasurable situations, like laughing, eating tasty food, or exercising.
"Endogenous opioids act on endogenous receptors, but these receptors do not distinguish between exogenous opioids like fentanyl. We have receptors in many parts of the body; when exogenous opioids enter the body, they occupy these receptors. The difference between heroin and fentanyl, on one hand, and endorphins, on the other, is not only structural but also in the time they take to exert their effects. Our endogenous opioids are released when needed, in the right amounts, circulate for a few minutes, and then disappear. In contrast, other substances, the exogenous ones, are received when the body doesn't require them, in much higher amounts, and their effects last for hours, so the body has to adapt," Dr. Cruz Martín del Campo emphasized.
For these reasons, fentanyl is so addictive. Initially, the initial effects are highly desirable for those who try it, but the undesirable consequences later on are greater, and withdrawal syndrome becomes intense and unpleasant, leading the person to consume more to alleviate these effects.
Preoperative analgesia, postoperative pain, sedation in intubated patients, severe pain cases, in patients with renal failure, and epilepsy treatment.
The detoxification process, she warned, is extremely complicated due to the physical adaptations resulting from prolonged use. The treatment commonly involves prescribing certain substances, with methadone in low doses being the most common. Methadone can gradually mitigate withdrawal symptoms by keeping the endogenous opioid receptors occupied. Sometimes, individuals dependent on opioids may need to consume substances like methadone for the rest of their lives.
Dr. Cruz Martín del Campo's research, along with her colleagues, focuses on the pharmacological interactions of fentanyl with other substances and their effects when administered repeatedly in rodents. She commented that the results are used to be alert to signs that could be indicative of a similar process in people who consume these types of substances.
The doctor emphasized that what particularly caught their attention was the use of fentanyl because the damage occurred after 7 or 14 administrations, meaning not extremely chronic use. The destruction of serotonin-containing neurons is highly relevant, as serotonin regulates anxiety and enhances pleasant moods like relaxation, satisfaction, and self-esteem. That's why it is colloquially known as the "happiness hormone."
Currently, Dr. Cruz Martín del Campo is studying the effects of chronic fentanyl use on the hippocampus, the area that handles neurons related to learning processes.
"We are also looking at not so much the direct deaths but neuroinflammation; the inflammation process taken to the extreme is what causes the death of these serotonin neurons, but different cells have different amounts of intracellular proteins that can favor or not favor neuroinflammation," she emphasized.
In March 2023, the United States approved the over-the-counter sale of naloxone, a medication that binds to the body's opioid receptors and prevents, for example, greater effects from fentanyl if it has been consumed, in addition to reversing the damage if it is already in the body.
Overdoses, Dr. Cruz noted, cause death due to respiratory depression, which occurs due to the inhibition of a part of the central nervous system known as the brainstem, where the receptors responsible for causing respiratory depression are located. By administering naloxone, it reaches this binding site, competes with the effective ones, displaces them, and restores breathing. Naloxone is the life-saving antidote and can be administered through different methods, with the most recent being a nasal spray.
"One of the adverse effects of morphine and fentanyl is that they depress the respiratory centers, meaning that if you overdose, you could die because you can no longer breathe. If you see a person who has consumed fentanyl and is experiencing an overdose, they start turning cyanotic, meaning their lips turn blue, and that is because they are no longer breathing," Dr. Reyes Mendoza explained.
Naloxone is difficult to obtain, and typically, when heroin addicts experience an overdose, they inject a concentrated saltwater solution in an attempt to reverse its effects. Therefore, Dr. Cruz Martín del Campo calls for naloxone to be available in Mexico without a prescription to act in case of an overdose.
Both Dr. Cruz Martín del Campo and Dr. Reyes Mendoza agree that attention must be paid to the fentanyl situation in our country. While there may not be as many users as in other countries, fentanyl is present in Mexico, and the number of overdoses is increasing. Naloxone is needed to reverse these overdoses, and forensic tests are needed to determine if fentanyl was consumed because as long as it is not measured, we will continue to claim that there are no deaths due to fentanyl overdoses when, in reality, there are, and the users are well aware of it," Dr. Cruz Martín del Campo concluded.
Selección Gaceta Politécnica #166. (September 30th, 2023). IPN Imagen Institucional: Read the full magazine in Spanish here
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