In 25 years, four waves of “epidemics” of deaths due to opioids have occurred in the United States. Depending on the period, they are linked to the overdose of misused medications, heroin or even fentanyl (and derivatives) alone or combined with new synthetic opioids and stimulants. A public health issue that goes beyond the United States alone.
At the origin of a crisis that has been raging for approximately 25 years in North America, opioids have become a major cause of toxic overdose deaths in North America as well as in the European Union (EU).
The deaths of several world celebrities, including the singer Prince, have drawn the attention of the general public to a devastating epidemic which is now even the source of a decline in life expectancy in the United States, according to a study by the Institute for Computational Medicine from Johns Hopkins University. More than 800,000 Americans have died since 1999 from opioid use.
Opioids with powerful pain-relieving effects
By “opioid”, we designate any substance, natural or synthetic, that can interact with a family of specific receptors called opioid receptors, expressed on the surface of certain neurons and widely distributed in the brain. Opioids therefore have the main property of being powerful analgesics.
The human body produces its own opioid compounds (dynorphins, enkephalins, endorphins and nociceptins). However, in cases of severe pain, for example after trauma, surgery or metastatic cancer, the effect of these endogenous opioids may prove insufficient to alleviate the painful sensation. It then becomes useful – if not essential – to take an exogenous compound with an opioid action, in order to avoid suffering.
From morphine, a natural opioid, to synthetic products
For millennia, the juice of the opium poppy, containing natural opioids such as morphine or codeine, has been used as a panacea, notably by the Sumerian and Egyptian civilizations. In the 19th centurye century, the active molecules were extracted, purified then prescribed to painful patients.
Subsequently, numerous molecules with a structure similar to that of morphine (henceforth called “opiates”) such as heroin or completely synthetic with a structure different from that of morphine (henceforth called “opioids”) such as tramadol, methadone or fentanyl were produced in the laboratory.
Mortal risks in case of misuse
Some have retained medical indications and are manufactured and sold by the pharmaceutical industry: these are prescription analgesic opioids. Others have become illicit products, the sale and use of which are prohibited by international conventions. This is the case of heroin which, it must be remembered, had been manufactured and marketed in the 19the century as a “heroic” medicine.
Unfortunately, all opiates and opioids can be consumed as part of a use disorder, sometimes as recreational products and mostly in connection with the development of an addiction. They can therefore be responsible for a major risk of death. It is this phenomenon that is at the origin of the fatal overdose crisis in North America.
The consumption of opioids causes significant adverse effects (constipation, nausea, drowsiness, urinary retention, etc.) which may be acceptable when suffering from cancer or the consequences of trauma or a surgical intervention. This consumption is, however, not without vital risks, particularly in the event of abuse or misuse.
The misuse of opioids prescribed as medications, like illicit opioids used as drugs, exposes one to a risk of sudden respiratory arrest (specialists speak of neuro-respiratory depression), which depends on the dose consumed.
At the origin of the crisis: a falsely reassuring publication
For almost a quarter of a century, a serious epidemic of deaths secondary to opioid overdoses has raged in North America, and particularly in the United States. In this country, three successive waves of deaths have been described since 1999, linked respectively to opioids prescribed as medications (1999-2010), heroin (2011-2015), and fentanyl (2016-2020). We are now talking about a fourth wave linked to the combination of fentanyl and illicit stimulants (2020-2024).
Several concomitant phenomena contributed to the occurrence of this crisis. The increase in the use of opioid analgesics at the start of the 21st centurye century in the United States was initially the result of excessive and inadequate medical prescriptions favored by erroneous university and post-graduate education of doctors.
Indeed, the broad prescription of these medications was wrongly made reassuring following the publication of an article in the medical journal New England Journal of Medicine explaining the absence of risk of developing dependence in the event of long-term use of an opioid analgesic. It was in fact an observational study published in the form of a letter to the editor, involving a small number of patients, without demonstration value or external validation.
Aggressive marketing and out-of-control prescriptions
This article was then referenced hundreds of times in the medical literature to support this false theory, without additional evidence. Inadequate prescriptions for opioid painkillers then skyrocketed, fueled by aggressive and abusive marketing by one company, Purdue Pharma, which promoted its oxycodone product to doctors, pharmacists and patients. This company is now out of business and its managers accused of having caused the death of half a million people.
The absence of strict control of medical prescriptions by health authorities was then added as a contributing factor, allowing this phenomenon to develop until 2010, before a decision to withdraw oxycodone from the market by the Purdue Pharma laboratory. not be taken.
This drug had then become the main cause of death from opioid overdose in the United States, the tablets being often pillaged then snorted or injected intravenously by patients who had become addicted following their prescription of long-term opioid analgesic.
Thus, at this period, the prescription of an opioid to a member of one’s own family and, in fact, the availability in the home of this type of product, had become the main risk factor for the occurrence of an overdose, in any no one who has ever received an opioid prescription.
With fentanyl and its derivatives, an acceleration of the crisis
Subsequently and after the withdrawal of Purdue Pharma’s oxycodone from the market and its replacement by a non-pillable delayed release formulation, addicted patients successively turned to the consumption of heroin (produced and brought from Afghanistan) then fentanyl (produced at lower cost in synthesis laboratories mainly in Mexico, from raw materials imported from China or India).
Powerful structural analogues of fentanyl, initially synthesized as possible drug candidates by the pharmaceutical industry, then became the main opioid sources of deaths and the accelerating death crisis in the United States. Despite a rapid decline in the use of prescription opioids starting in 2010, overdose deaths continued to increase and an acceleration was even observed until 2024.
Thus, in 2023, approximately 90,000 deaths were attributed to opioid overdoses in the United States, and more than 85% of them to fentanyl and its derivatives. In 2022, approximately 50 million adulterated pills and 4.5 tons of fentanyl powder were seized by U.S. customs authorities, totaling 388 million lethal doses. Enough to kill the entire American population.
From now on, recreational consumption and new synthetic molecules
Today, the recreational consumption of fentanyl and its derivatives, in combination with stimulating drugs (cocaine and amphetamines) represents the spearhead of the epidemic, among younger users and in an essentially festive context.
You should know that fentanyl is 300 times more powerful than morphine and one of its derivatives, carfentanyl, is 10,000 times more powerful than morphine… therefore very toxic.
Various factors have thus contributed to the almost exponential and irremediable progression of the epidemic between 2020 and 2024, including in particular:
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the emergence of new very powerful synthetic molecules including fentanyl derivatives but also other types of opioids such as nitazenes,
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the development of compounds with a high risk of dependence and rapid acquisition of tolerance,
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the combined use of multiple drugs, such as stimulant drugs but also xylazine (“zombie drug”).
Individual vulnerability factors, genetic or non-genetic, also explain the increased risk of death among certain consumers. Finally, the way of life in modern Western society has been questioned by favoring the consumption of increasingly dangerous drugs.
In case of overdose: typical signs for a rapid diagnosis
Neurorespiratory depression following an opioid overdose results in a patient with a typical syndrome associating:
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a coma with myorelaxation, that is to say low muscle tone (hypotonia) and abolition of the tendon reflexes,
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extreme, bilateral contraction of the pupils (tight miosis)
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a slowing of the respiratory rate to less than 12/min (bradypnea).
This table is easily identifiable, which allows rapid clinical diagnosis and immediate treatment in the event of an overdose, without the need for additional analyses. If neurorespiratory depression continues, respiratory arrest occurs, followed quickly by cardiac arrest.
Various additive mechanisms have been proposed to explain the increased risk of sudden death with fentanyl derivatives and in particular the appearance of rigidity of the diaphragm muscle (the “wooden chest wall syndrome”).
Therapeutic treatment is also relatively simple. Naloxone is the only clinically available antidote.
Read more: Do you know about naloxone, a powerful antidote for opioid overdoses?
Treatments and avenues of research to limit deaths
A final word to emphasize the importance of strategies to reduce the risk of death from opioid overdose. They are based on the wide use of substitution treatments (in France, methadone and high-dose buprenorphine) and the provision in the community of naloxone known as “take home”, usable by any person, even without medical knowledge, who reportedly witnessed a possible overdose in a known opioid user found unconscious.
Finally, the development of new analgesics and new formulations of opioids devoid of neuro-respiratory toxicity seems promising, but still in the preclinical development phase with uncertain deadlines.
In conclusion, opioid overdoses represent a continuing global public health problem. But hope appeared a few weeks ago with, for the first time in 25 years, a drop in the number of deaths from opioid overdoses in the United States. A 25e anniversary certainly sad… but now, with the hope of a possible resolution of the crisis in sight.
