Kurzgesagt – In a Nutshell
Kurzgesagt – In a Nutshell
Embedded Files
Sources – Fentanyl
Sources – Fentanyl
We thank the following experts for their input and critical reading:
Christian Lüscher
Professor and MD of Basic Neuroscience, University of Geneva
Tse Yang Lim
Postdoctoral Research Fellow in Epidemiology, Harvard T.H. Chan School of Public Health
Dealing with substance abuse is a difficult task. Thankfully, you’re never alone in the task. Whether you want to confront your addiction, help out a friend or family member, or simply ask professionals sensitive questions in confidence, there are helplines, health centers and other resources available:
USA:
SAMHSA substance abuse hotline:
https://www.samhsa.gov/about/contact
US Department of Health and Human Services (HHS) opioid crisis helpline:
https://www.hhs.gov/opioids/index.html
Find a Health Center map:
https://findahealthcenter.hrsa.gov/
NARCAN (Naloxone) guide:
https://www.health.ny.gov/publications/12028.pdf
UK:
Local drug and alcohol support:
https://www.talktofrank.com/get-help/find-support-near-you
Support for your, or someone else’s drug use:
Details on naloxone kits and instructions on how to obtain/use them:
https://www.viaorg.uk/information/naloxone/
Germany:
Addiction help hotline for you or someone else:
https://www.guttempler.de/nottelefon/
A directory of all drug and addiction counselling centres:
https://www.dhs.de/service/suchthilfeverzeichnis
France:
CSAPA Center for assistance of substance abusers and their entourage:
https://intervenir-addictions.fr/orienter/vers-qui-orienter/csapa/
Anonymous free helpline for substance abuse:
https://www.jeunes.gouv.fr/drogues-info-service-vos-cotes-7j7-de-8h-2h-418
Italy:
National drug abuse and counseling helpline:
https://www.iss.it/numeri-verdi/-/asset_publisher/LXvuDqwiaG9G/content/il-telefono-verde-droga
Accredited communities and facilities for handling drug abuse care and recovery:
—After giving birth, pain gets toned down and the mother is showered in happy hormones so she can bond with the newborn child. During an intense hunt, the hunter forgets how it is physically exhausting and leads to minor injuries. Both are technically not great experiences but necessary to be repeated for our survival. And nature invented a powerful mechanism that does both: The mighty opioid receptor.
Opioid receptors are widely expressed in the central and peripheral nervous system – even present in gastrointestinal tract and immune cells. They are involved in many different different mechanisms in our bodies.
There are different types which have different natural ligands. In both examples above are about β-endorphin, which are one of the natural ligands for the mu-receptor, where also fentanyl binds to. But of course in both examples, there are other hormones and mechanisms involved.
#Herman TF, Cascella M, Muzio MR. Mu Receptors.
https://www.ncbi.nlm.nih.gov/books/NBK551554/
Quote: “The mu (μ) receptors are a class involved in neuromodulating different physiological functions. These receptors primarily affect nociception but also stress, temperature, respiration, endocrine activity, gastrointestinal activity, memory, mood, and motivation. Because these receptors bind opioids, they are also commonly referred to as mu-opioid receptors (MORs). However, opioid receptors are a large family of receptors that also includes delta (δ)-opioid receptors (DORs), kappa (κ)-opioid receptors (KORs), and nociceptin receptors (NORs), also referred to as opioid-receptor-like receptor 1 (ORL1), which appear to have a role in the development of tolerance to mu-opioid agonists used as analgesics.
[...]
Endogenous opioids are the natural ligands of opioid receptors that play a role in neurotransmission, pain modulation, and other homeostatic and functional pathways of the brain and peripherally. Beta-endorphin serves primarily as an agonist for MORs and minorly for DORs. This peptide is derived from the larger proopiomelanocortin (POMC) peptide and is secreted by the arcuate nucleus of the hypothalamus (via the anterior lobe of the pituitary gland) during stress and exercise.”
#Sobczak, Ł.; Goryński, K. Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse. Molecules. 2020.
Walter MH, Abele H, Plappert CF. The Role of Oxytocin and the Effect of Stress During Childbirth: Neurobiological Basics and Implications for Mother and Child. Front Endocrinol (Lausanne). 2021
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.742236/full
Quote: “Anxiety has been shown to prolong the time to give birth and this is correlated to low blood plasma concentrations of oxytocin in women (75). Additionally, Thomas et al. (76) found a positive relationship between the length of parturition and the concentration of β-endorphin, an endogenous opioid that is released during time of stress. It is being discussed if the prolongation of parturition under stress is caused by an opioid-dependent reduction of oxytocin release, as this was shown in rats (77).
This is achieved by two means: first, opioids inhibit the neurosecretory terminals in the neurohypophysis via binding to κ-opioid receptors (78) and, second, by reducing the pulse rate of oxytocinergic neurons of the PVN via binding to μ-opioid receptors (79). Support for these proposed mechanisms comes from further studies in rodents in which it was shown that oxytocin infusions and the administration of the opioid antagonist naloxone can mitigate the prolongation of parturition caused by disturbing the dam (77). The inhibition and regulation of oxytocin secretion through the effects of opioids serves to control the contractions during childbirth and to prevent uterine tachysystole. After birth, the number of opioid receptors and the concentration of β-endorphin in the hypothalamus is reduced. This builds the basis upon which the extremely high postpartum oxytocin concentrations are achieved (79). From these findings it is likely to conclude that stress, which is caused by disturbance of the mother during childbirth, leads to an increase in the opioid-mediated inhibition of oxytocin secretion and thereby to a reduction in uterine contractions that will have a negative effect on the progress of labor.”
—It is like a keyhole that sits on the neurons that control pain and pleasure. If activated it reduces pain and how much you care about pain – and it creates pleasure and good feelings. The details are complex and not relevant for this story – what you need to know is that any molecule that can fit into an opioid receptor like a key, is called an opioid.
Opioids cause pain-relief and euphoria acting on different parts within the nervous system.
They relieve pain when they act in the synapses between neurons that carry pain signals and neurons in the spinal cord. They dim the pain signal by binding to opioids receptors on both these neurons, which results in a lessened pain sensation.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids/#12.1
Quote: “How do opioids affect pain signals? Recall that opioid receptors can be both presynaptic and post-synaptic. Presynaptic opioid receptors are located on the axon terminals of the Aδ and C fibers. The axons of these first-order afferent neurons synapse in the dorsal horn of the spinal cord and release glutamate and Substance P when an action potential or pain signal arrives. Activation of postsynaptic glutamate- and Substance P-sensitive receptors on the second-order afferent neuron recreate the pain signal in the ascending pathway. Endorphins can activate presynaptic opioid receptors to reduce or inhibit the release of glutamate and Substance P, which diminishes pain transmission. Endorphins can also activate postsynaptic opioid receptors to decrease the strength of the depolarization initiated by glutamate and Substance P. The combined effect of presynaptic and postsynaptic opioid receptor activation is to diminish the pain signal headed for the brain.
When the original pain stimulus is so intense that activation of the endogenous opioid system is insufficient to mitigate the pain, exogenous opioid drugs may be administered to the patient to control the pain. Exogenous opioids will similarly activate presynaptic and postsynaptic opioid receptors to moderate the pain signal.”
On top of that, opioids bind to neurons in parts of the brain that regulate alertness to induce sedation and reduce how much you care about the pain:
#An, Andy Yi (“Medicurio”) (2019): “Opioid Drugs (Part 2)”
https://medicurio.ca/2022/09/14/opioid-drugs-part-2/
Quote: “The locus ceruleus is located in the brainstem and its function is to keep us awake and alert or make us feel stressed. It also is involved in activating the sympathetic nervous system, our “fight or flight” response, which when activated causes sweating, pupil dilation, and increased heart and breathing rate. The locus ceruleus has opioid receptors, so when opioids bind to neurons in the locus ceruleus, they shut them down to cause common side-effects of opioid use such as drowsiness, sedation, dry skin, pinpoint pupils, and slowed heart and breathing rate.”
Opioids also produce euphoria by binding to and deactivating neurons in the brain that block dopamine release, resulting in more dopamine flowing into the reward centers of the brain.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids/#12.1
Quote: “In Chapter 11, we saw how ethanol causes neuronal release of beta-endorphin (β-EP) to activate mu opioid receptors (MOR) on a GABA interneuron. The opioid receptors are inhibitory and will reduce the release of GABA from the interneuron. Freed from GABA inhibition, the VTA neuron releases dopamine to activate its receptors in the nucleus accumbens (NAc). The mechanism is very similar to how opioids act upon the reward center except that morphine directly activates the opioid receptors rather than releasing an endorphin. Activation of mu opioid receptors (MOR) on GABA interneurons in the ventral tegmental area (VTA) and decreases the tonic GABA inhibition of the dopamine neuron. The disinhibited VTA neuron thus increases its release of dopamine in the nucleus accumbens:
[...]
Because opioid receptors are found throughout the nervous system, opioids cause other effects aside from pain relief. In the CNS, effects include sedation and euphoria. Opioids can interact with other CNS depressant drugs to produce a synergistic degree of depression.”
In a broader sense, opioids can be many things: agonists, antagonists, partial antagonists, and a mix of those options. Antagonists like Naloxone block opioid receptors and do not activate them, which is why they can be considered separate from agonists like morphine. While talking about the negative effects of opioids in this video, we are excluding opioid antagonists like Naloxone, which does not have the negative effects we describe and is a crucial medication to reverse the effects of opioid overdose.
#NIDA: "Naloxone Drug Facts"
https://nida.nih.gov/publications/drugfacts/naloxone
Though we are not discussing them in our video for the sake of simplicity, some molecules bind to opioid receptors but are not considered opioids, because they do not derive from or mimic any substance found in the opium poppy. An example is Salvinorin A, a psychoactive substance found in salvia.
#Orton, Edward; Liu, Renyu (2014): "Salvinorin A: A Mini Review of Physical and Chemical Properties Affecting Its Translation from Research to Clinical Applications in Humans", Translational perioperative and pain medicine, vol. 1, 1, 9-11
https://pmc.ncbi.nlm.nih.gov/articles/PMC4208627/
—Opioids are extremely powerful, so when your body uses natural opioids like endorphins when you laugh, it releases only a tiny amount, exactly where they are needed. So the effects are mild and localized.
Natural or “endogenous” opioids like endorphins, the ones made by your body, are released locally and act only in specific sites, while opioids that you take –-“exogenous” opioids— act on all cells in the central nervous system (CNS) they can bind to.
#Le Roy, Chloé, et al. (2011): “Endogenous Opioids Released During Non-Nociceptive Environmental Stress Induce Latent Pain Sensitization Via a NMDA-Dependent Process”, The Journal of Pain, vol. 12, 10, 1069-1079
https://www.sciencedirect.com/science/article/pii/S152659001100592X
Quote: “Endogenous opioids [are] expected to act only at opioid receptors activated at specific synapses recruited by natural effectors as environmental stress and not at all opioid receptors in the CNS, as the case with exogenous opioids.”
—And now we are getting to drugs. Humans found opioids in nature, like Morphine, and were quite taken by them. They got refined into a whole family of drugs used in hospitals and to relieve patients that are in immense pain. Codeine, Oxycontin, Vicodin. And of course Heroin and the worst of all: Fentanyl.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids/#12.1
Quote: “Opioids can be classified into three different types. Natural opioids are opium alkaloids that have a phenanthrene nucleus found in the opium poppy plant (Papaver somniferum). They are also referred to as opiates. The three most important opiates are thebaine, morphine, and codeine. [...]
The drugs that are synthesized from natural opioids are called semisynthetic opioids and have similar chemical structures to opiates. Perhaps the most notable semisynthetic opioid is heroin, also called diacetylmorphine or diamorphine, the generic name in the United Kingdom. The names of most semisynthetic opioids will reflect which substance they are most chemically related to. The names hydromorphone (Dilaudid®) and oxymorphone (Opana®) are reminiscent of morphine, while hydrocodone (Vicodin®) and oxycodone (Percocet®, OxyContin®) are more similar to codeine.
Finally, synthetic opioids are synthesized independently within a lab instead of being based on naturally occurring opiates. These do not share the phenanthrene nucleus of opiates or semisynthetic opioids but can, nonetheless, couple to the opioid receptor and produce similar pharmacological effects. Synthetic opioids include methadone, fentanyl, meperidine, and tramadol. See the table below for a summary of the different types.”
—Heroin rushes through your entire body and flips every opioid receptor it finds. A rapid cascade of things happen everywhere, all at once. A symphony of intense sensations.
Natural or “endogenous” opioids like endorphins, the ones made by your body, are released locally and act only in specific sites, while opioids that you take —-“exogenous” opioids— act on all cells in the central nervous system (CNS) they can bind to.
#Le Roy, Chloé, et al. (2011): “Endogenous Opioids Released During Non-Nociceptive Environmental Stress Induce Latent Pain Sensitization Via a NMDA-Dependent Process”, The Journal of Pain, vol. 12, 10, 1069-1079
https://www.sciencedirect.com/science/article/pii/S152659001100592X
Quote: “Endogenous opioids [are] expected to act only at opioid receptors activated at specific synapses recruited by natural effectors as environmental stress and not at all opioid receptors in the CNS, as the case with exogenous opioids.”
—Every cell regulating pleasure is now high. Without their control floodgates of happy hormones open and fill you up top to bottom with pure bliss.
Opioids like heroin produce euphoria by binding to and deactivating GABA interneurons. These neurons are responsible for blocking dopamine release so, when opioids deactivate them, more dopamine flows into the reward centers of the brain. Dopamine is a neurotransmitter and hormone sometimes called a “happy hormone” because its release in the reward centers of the brain is linked to feelings of happiness and pleasure.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids/#12.1
Quote: “In Chapter 11, we saw how ethanol causes neuronal release of beta-endorphin (β-EP) to activate mu opioid receptors (MOR) on a GABA interneuron. The opioid receptors are inhibitory and will reduce the release of GABA from the interneuron. Freed from GABA inhibition, the VTA neuron releases dopamine to activate its receptors in the nucleus accumbens (NAc). The mechanism is very similar to how opioids act upon the reward center except that morphine directly activates the opioid receptors rather than releasing an endorphin. Activation of mu opioid receptors (MOR) on GABA interneurons in the ventral tegmental area (VTA) and decreases the tonic GABA inhibition of the dopamine neuron. The disinhibited VTA neuron thus increases its release of dopamine in the nucleus accumbens:
[...]
Because opioid receptors are found throughout the nervous system, opioids cause other effects aside from pain relief. In the CNS, effects include sedation and euphoria. Opioids can interact with other CNS depressant drugs to produce a synergistic degree of depression.”
#Cleveland Clinic: “Dopamine” (retrieved 2024)
https://my.clevelandclinic.org/health/articles/22581-dopamine
—Wherever you felt pain before, from wounds or aching joints or menstrual cramps, or loneliness or self loathing – it is gone now. You are simply unable to feel pain or care about it anymore.
Opioids like heroin relieve pain when they act in the synapses between neurons that carry pain signals and neurons in the spinal cord. They dim the pain signal by binding to opioids receptors on both these neurons, which results in a lessened pain sensation.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids/#12.1
Quote: “How do opioids affect pain signals? Recall that opioid receptors can be both presynaptic and post-synaptic. Presynaptic opioid receptors are located on the axon terminals of the Aδ and C fibers. The axons of these first-order afferent neurons synapse in the dorsal horn of the spinal cord and release glutamate and Substance P when an action potential or pain signal arrives. Activation of postsynaptic glutamate- and Substance P-sensitive receptors on the second-order afferent neuron recreate the pain signal in the ascending pathway. Endorphins can activate presynaptic opioid receptors to reduce or inhibit the release of glutamate and Substance P, which diminishes pain transmission. Endorphins can also activate postsynaptic opioid receptors to decrease the strength of the depolarization initiated by glutamate and Substance P. The combined effect of presynaptic and postsynaptic opioid receptor activation is to diminish the pain signal headed for the brain.
When the original pain stimulus is so intense that activation of the endogenous opioid system is insufficient to mitigate the pain, exogenous opioid drugs may be administered to the patient to control the pain. Exogenous opioids will similarly activate presynaptic and postsynaptic opioid receptors to moderate the pain signal.”
They can also decrease feelings of loneliness by binding to receptors that mediate rewarding social relationships:
#Løseth, Guro; Eikemo, Marie; Leknes, Siri (2024): “Opioid Regulation of Social Homeostasis: Connecting Loneliness to Addiction”, Biological Psychiatry
https://www.sciencedirect.com/science/article/pii/S0006322324017621
Quote: “According to the Brain Opioid Theory of Social Attachment , formation and maintenance of social bonds is promoted by endogenous opioid signalling causing positive emotions in response to positive social interaction. On the other hand, social deprivation is proposed to reduce opioid tone and produce aversive withdrawal-like symptoms. Accordingly, opioid drugs could grant temporary relief and mask the need for social connection by binding to the receptors that underpin social motivation, potentially ‘hijacking’ the system to promote drug seeking instead of social attachment.”
There is also some evidence that endogenous opioids contribute to self-esteem, so exogenous opioids could ease feelings of self-hatred:
#Tchalova, Kristina (2023): “Shifting the sociometer: opioid receptor blockade lowers self-esteem”, Social Cognitive and Affective Neuroscience, 18, 1
https://academic.oup.com/scan/article/18/1/nsad017/7085663
Quote: “We investigated whether endogenous opioids may serve as the biological correlate of the sociometer. We administered 50 mg naltrexone (an opioid receptor antagonist) and placebo in a counterbalanced order to 26 male and female participants on two occasions ∼1 week apart. Participants reported lower levels of self-esteem—particularly self-liking—on the naltrexone (vs placebo) day.”
On top of that, opioids bind to neurons in parts of the brain that regulate alertness to induce sedation and reduce how much you care about the pain:
#An, Andy Yi (“Medicurio”) (2019): “Opioid Drugs (Part 2)”
https://medicurio.ca/2022/09/14/opioid-drugs-part-2/
Quote: “The locus ceruleus is located in the brainstem and its function is to keep us awake and alert or make us feel stressed. It also is involved in activating the sympathetic nervous system, our “fight or flight” response, which when activated causes sweating, pupil dilation, and increased heart and breathing rate. The locus ceruleus has opioid receptors, so when opioids bind to neurons in the locus ceruleus, they shut them down to cause common side-effects of opioid use such as drowsiness, sedation, dry skin, pinpoint pupils, and slowed heart and breathing rate.”
—Your brain’s alert system is put to sleep. Like dimming the lights in a cozy room, you now feel at ease. Warm. Serene. Any stress you had melts away and what keeps you on edge dissolves into a dreamlike haze.
#An, Andy Yi (“Medicurio”) (2019): “Opioid Drugs (Part 2)”
https://medicurio.ca/2022/09/14/opioid-drugs-part-2/
Quote: “The locus ceruleus is located in the brainstem and its function is to keep us awake and alert or make us feel stressed. It also is involved in activating the sympathetic nervous system, our “fight or flight” response, which when activated causes sweating, pupil dilation, and increased heart and breathing rate. The locus ceruleus has opioid receptors, so when opioids bind to neurons in the locus ceruleus, they shut them down to cause common side-effects of opioid use such as drowsiness, sedation, dry skin, pinpoint pupils, and slowed heart and breathing rate.”
—This peace even spreads to your essential organs, slowing your breath, soothing and slowing your intestines. Your chest rises and falls like the gentle waves of a quiet shore.
The side effects of many opioids are similar, especially the effect on breathing.
#Nysora: “Opioids: Pharmacodynamics” (retrieved 2024)
https://www.nysora.com/anesthesia/opioids/
Quote: “In most respects, the μ-agonist opioids can be considered pharmacodynamic equals with important pharmacokinetic differences; that is, both the therapeutic and adverse effects are essentially the same. Their efficacy as analgesics and their propensity to produce ventilatory depression are indistinguishable from each other. Pharmacodynamic differences do exist with nonopioid receptor mechanisms such as histamine release.”
Opioids can slow down breathing or even stop it.
#Nysora: “Opioids: Pharmacodynamics” (retrieved 2024)
https://www.nysora.com/anesthesia/opioids/
Quote: “Depression of ventilation is the primary adverse effect associated with μ-agonist drugs. When the airway is secured and ventilation is controlled intraoperatively, opioid-induced depression of ventilation is of little consequence. However, opioid-induced respiratory depression in the postoperative period can lead to brain injury and death.
μ-Agonists alter the ventilatory response to arterial carbon dioxide concentrations at the ventilatory control center in the medulla. The depression of ventilation is mediated by the μ-receptor; μ-receptor knock-out mice do not exhibit respiratory depression from morphine.(14)
In unmedicated humans, increases in arterial carbon dioxide partial pressure markedly increase minute volume (Fig.5). Under the influence of opioid analgesics, the curve is flattened and shifted to the right for a given carbon dioxide partial pressure and reflecting that the minute volume is smaller.(15) More importantly, the “hockey stick” shape of the normal curve is lost; that is, there may be a partial pressure of carbon dioxide below which the patient will not breathe (i.e., the “apneic threshold”) in the presence of opioids.
Fig.5 Opioid-induced ventilatory depression study methodology. The method characterizes the relationship between Paco2 and minute volume. The curve labeled “Normal” represents the expected response of minute volume to rising Paco2 levels in an awake human. Note the dramatic increase in minute volume as CO2 tension rises. The curve labeled “Opioid” represents the blunted response of minute volume to rising CO2 levels following administration of an opioid. Note that the slope of the curve decreases and the curve no longer has a “hockey stick” shape; this means that at physiologic Paco2 levels, the patient receiving sufficient opioid may be apneic or severely hypoventilatory. (Adapted from Gross JB. When you breathe IN you inspire, when you DON’T breathe, you . . . expire: new insights regarding opioid-induced ventila-tory depression. Anesthesiology. 2003;99:767-770, used with permission.)”
Opioids make digestive muscles contract and become rigid, slowing down bowel movements, which can lead to constipation:
#Nysora: “Opioids: Pharmacodynamics” (retrieved 2024)
https://www.nysora.com/anesthesia/opioids/
Quote: “Opioids have important effects on gastrointestinal physiology. Opioid receptors are located throughout the enteric plexus of the bowel. Stimulation of these receptors by opioids causes tonic contraction of gastrointestinal smooth muscle, thereby decreasing coordinated, peristaltic contractions. Clinically, this contraction results in delayed gastric emptying and presumably larger gastric volumes in patients receiving opioid therapy preoperatively. Postoperatively, patients can develop opioid-induced ileus that can potentially delay the resumption of proper nutrition and discharge from the hospital. An extension of this acute problem is the chronic constipation associated with long-term opioid therapy.”
—Your brain's reward center is completely fried and can’t comprehend what happened. If what you just did felt this good, it has to be amazing for your survival and you should do it again.
#Koob, George F. (2019): “Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement”, Biological Psychiatry , vol. 87, 1, 44-53 https://www.sciencedirect.com/science/article/abs/pii/S0006322319314350
Quote: “Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system.”
#Volkow, Nora D.; et al. (2019): “Prevention and Treatment of Opioid Misuse and Addiction: A Review”, JAMA Psychiatry, vol. 76, 2, 208-216
Quote: “Addiction to opioids (or other drugs) involves molecular processes associated with learning, which help consolidate automatic behaviors in response to the drug and the stimuli associated with the drug; this is referred to as conditioning. People can become conditioned to opioids because of their rewarding effects or because of their relief of pain, withdrawal symptoms, or dysphoria. With repeated exposures, conditioning is strengthened, energizing the desire and motivation to consume the drug.”
—Once you’ve taken opioids a few times, your brain has had enough. The cells controlling pain and pleasure are constantly high and drowsy. So it boosts them and makes them hyperactive.
Opioid tolerance involves mechanisms at all scales, from opioid receptors to the nervous system as a whole:
#Christie, Macdonald J. (2008): ”Cellular neuroadaptations to chronic opioids:tolerance, withdrawal and addiction”, vol. 154, 2, 384–396
https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1038/bjp.2008.100
Quote: “A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the m-opioid receptor itself, cellular tolerance and withdrawal in opioid-sensitive neurons, systems tolerance and withdrawal in opioid-sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks [...]
tolerance results from adaptive mechanisms at the level of the drug target (MOPr), as well as at the cellular, synaptic and network levels, where adaptations due to homeostatic mechanisms tend to restore normal function in spite of the continued perturbations produced by opioid agonists.”
– This happens very fast, sometimes after a few days of use. You have developed an opioid tolerance, toning down all the nice effects you are doing the drugs to achieve. To feel like before, you’ll need way higher doses
It is generally recognized that opioids take just a few doses to produce tolerance.
#University of Utah Genetic Science Learning Center: “Opioids and the Physiology of Tolerance” (retrieved 2024)
https://learn.genetics.utah.edu/content/addiction/tolerance/
Quote: “When someone takes a drug for the first time, they experience its full effect. But if they keep taking it, their body adjusts. It takes more of the drug to produce the same effect.
This is known as tolerance. With opioids, tolerance can build after just two to three doses.”
#DrugRehab.com: ”Can You Become Addicted to Heroin the First Time You Try It?” (retrieved 2024)
https://www.drugrehab.com/addiction/drugs/heroin/heroin-addiction-first-try/
Quote: “Most first-time heroin users start by snorting or smoking the drug. After the first hit, they experience a warm, euphoric feeling that causes their pain and worries to melt away. Some heroin users say it’s the most pleasurable feeling they have ever experienced.
The drive to use heroin a second time is usually psychological. People don’t become addicted immediately, but they may be inclined to try the drug again to relive its pleasurable effects.
But as people use heroin more often, they begin to build a tolerance to the drug. The drug’s effects lessen over time, and people need to take larger and more frequent doses to achieve the same rush. Many people become dependent on heroin while attempting to counteract their rising tolerance.”
Many factors, including the mode of administration and the dose also play a role in how quickly a person can develop tolerance to the drug. There are no large-scale studies in humans on how long it takes to develop tolerance, especially to the euphoric effect, but studies on animals and small cohorts of humans seem to indicate that tolerance appears within days or weeks, and definitely within a month.
#Christie, Macdonald J. (2008): ”Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction”, vol. 154, 2, 384–396
https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1038/bjp.2008.100
Quote: “In experimental animals and isolated cells, ‘acute’ tolerance can be observed rapidly (seconds to minutes) during the course of a single episode of opioid intoxication (Williams et al., 2001). This type of tolerance may be more closely related to processes of rapid m-opioid receptor (MOPr) desensitization and internalization that should be distinguished from the more substantial tolerance that emerges after days to weeks of opioid administration.”
#Chu, Larry F.; et al. (2012): “Analgesic tolerance without demonstrable opioid-induced hyperalgesia: A double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain”, Pain, vol. 153, 8, 1583-1592
https://journals.lww.com/pain/abstract/2012/08000/analgesic_tolerance_without_demonstrable.11.aspx
Quote: “After 1 month of oral morphine therapy, chronic low-back pain patients developed tolerance but not opioid-induced hyperalgesia.”
#Chu, Larry F.; Clark, David J.; Angst, Martin S. (2006): “Opioid Tolerance and Hyperalgesia in Chronic Pain Patients After One Month of Oral Morphine Therapy: A Preliminary Prospective Study”, The Journal of Pain, vol. 7, 1, 43 - 48
https://www.jpain.org/article/S1526-5900(05)00826-6/fulltext
Quote: “Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.”
In the case of pediatric patients and continuous infusions, tolerance to the analgesic effects of opioids can develop within 26 hours.
#Ibach, Bethany W.; et al. (2017): “Characterization of Tolerance in Children during
Fentanyl Continuous Infusions”, Journal of pediatric intensive care, vol. 6, 2, 83–90
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6260275&blobtype=pdf
Quote: “Tolerance is a complication of fentanyl continuous infusions (CINs) in critically ill children, but the incidence and time of onset are lacking. The primary objective was to identify the incidence of tolerance. Secondary objectives were to determine the onset time and compare risk factors between children with tolerance versus no tolerance and between children with early (< 24 hours) versus late tolerance. [...] A total of 59 CINs were included. Tolerance occurred in 46 CINs (78%), with median time to tolerance of 26 hours (range: 1–160 hours).”
—It all starts with a creeping unease. Instead of being euphoric and happy, nothing feels good anymore. Your coffee is tasteless. Your favorite song lame. Your loved ones distant. Anxiety kicks in. A storm of negative emotions shatters your sea of calm. Serenity is replaced by angst, like something terrible is imminent. Your worries, insecurities and all the fears you suppressed aren’t just back, but amplified into an existential crisis. You feel a restlessness so unbearable that you can’t sit still. Your heart is beating too fast. You shiver. Sweat. Hyperventilate.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids
Quote: “As is typical, withdrawal symptoms are the inverse of drug effects. The most notable symptom is hyperalgesia or increased pain sensitivity. This is caused by the pain system compensating for the inhibitory effects of opioids. With chronic use, this can result in opioid-induced hyperalgesia, where opioid pain medications increase pain instead of providing relief.
Withdrawal symptoms also include dilated pupils, sweating, nausea and vomiting, diarrhea, aches and pains, low blood pressure and heart rate, insomnia, anxiety, hyperactivity, and depression.”
#MSD Manual Consumer Version: “Opioids” (retrieved 2024)
Quote: “Each opioid is eliminated from the body at a different rate, which alters how quickly withdrawal progresses and stops. Withdrawal symptoms are worse in people who have used large doses for a long time:
At first, people feel anxious and crave the drug.
Breathing becomes rapid, usually accompanied by yawning, perspiration, watery eyes, a runny nose, dilated pupils, and stomach cramps.
Later, people may become hyperactive and agitated and have a heightened sense of alertness.
Heart rate and blood pressure increase.
Other withdrawal symptoms include
Gooseflesh
Tremors
Muscle twitching
Fever and chills
Aching muscles
Loss of appetite
Nausea and vomiting
Diarrhea”
—Your pain circuits are now oversensitive, so your bones and muscles ache and hurt for no reason. Old wounds, physical and mental torture you. You have belly cramps and diarrhea. You feel nausea and have to vomit. You’re too agitated to rest. A war inside your body that you can’t escape.
#Washington State University (2022): “Drugs and Behavior”, Chapter 12: Opioids
https://opentext.wsu.edu/biopsychological-effects-alcohol-drugs/chapter/chapter-12-opioids
Quote: “As is typical, withdrawal symptoms are the inverse of drug effects. The most notable symptom is hyperalgesia or increased pain sensitivity. This is caused by the pain system compensating for the inhibitory effects of opioids. With chronic use, this can result in opioid-induced hyperalgesia, where opioid pain medications increase pain instead of providing relief.
Withdrawal symptoms also include dilated pupils, sweating, nausea and vomiting, diarrhea, aches and pains, low blood pressure and heart rate, insomnia, anxiety, hyperactivity, and depression.”
#MSD Manual Consumer Version: “Opioids” (retrieved 2024)
Quote: “Each opioid is eliminated from the body at a different rate, which alters how quickly withdrawal progresses and stops. Withdrawal symptoms are worse in people who have used large doses for a long time:
At first, people feel anxious and crave the drug.
Breathing becomes rapid, usually accompanied by yawning, perspiration, watery eyes, a runny nose, dilated pupils, and stomach cramps.
Later, people may become hyperactive and agitated and have a heightened sense of alertness.
Heart rate and blood pressure increase.
Other withdrawal symptoms include
Gooseflesh
Tremors
Muscle twitching
Fever and chills
Aching muscles
Loss of appetite
Nausea and vomiting
Diarrhea”
—And of course there is the craving screaming for you to make it stop. Your mind and body begs for a hit. You can be in this horrible state for up to two weeks. Or make it stop right away.
#American Addiction Centers (2024): “Opioid Withdrawal Symptoms, Timeline, and Detox Treatment”
https://americanaddictioncenters.org/opioids/withdrawal-detox
Quote: “Heroin and short-acting opioid withdrawal symptoms can typically be seen within the first 8-12 hours after last used, peak within 1-3 days and continue up to 7 days. Short-acting opioids, such as morphine and immediate-release formulations of the medications oxycodone, hydrocodone, and fentanyl, will result in withdrawal symptoms within the first 8-24 hours after the last use, and withdrawal symptoms can continue up to 10 days. Long-acting opioids, such as methadone and extended- or controlled-release formulations of the medications morphine, oxycodone, hydrocodone, and fentanyl will result in the first withdrawal symptoms appearing up to 36 hours after last use and can continue up to 14 days or more.”
#Drug and Alcohol Services South Australia (2023): “Heroin withdrawal”
Quote: “Although heroin withdrawal is unpleasant, it is not life threatening unless there is serious underlying disease. Withdrawal symptoms generally start within 6-24 hours of last use and last about 5-7 days with a peak at 48-72 hours. The main physical symptoms subside but sleep disturbance and mood changes can persist for weeks, and the desire to use again for much longer. Hallucinations and seizures are not typical features of heroin withdrawal and should alert you to other causes or disorders.”
#MSD Manual Professional Version: “Opioid Toxicity and Withdrawal” (retrieved 2024)
Quote: “The opioid withdrawal syndrome usually includes symptoms and signs of central nervous system hyperactivity. Onset and duration of the syndrome depend on the specific drug and its half-life. Symptoms may appear as early as 4 hours after the last dose of heroin, peak within 48 to 72 hours, and subside after about a week. Anxiety and a craving for the drug are followed by increased resting respiratory rate (> 16 breaths/minute), usually with diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps. Later, piloerection (gooseflesh), tremors, muscle twitching, tachycardia, hypertension, fever and chills, anorexia, nausea, vomiting, and diarrhea may develop.
Opioid withdrawal does not cause fever, seizures, or altered mental status. Although it may be distressingly symptomatic, opioid withdrawal is not fatal.
The withdrawal syndrome in people who were taking methadone (which has a long half-life) develops more slowly and may be less acutely severe than heroin withdrawal, although users may describe it as worse. Even after the withdrawal syndrome remits, lethargy, malaise, anxiety, and disturbed sleep may persist up to several months. Drug craving may persist for years.”
—Ok so why not just take heroin forever and feel amazing always? The fun thing is that it doesn’t work this way – you get tolerant to the nice effects, like euphoria, faster than the bad ones, like dangerously slow breathing. So it turns from touching the love center of the universe to mostly drowsy numbness and relief from withdrawal.
Opioid consumption leads to decreasing returns in mood, eventually sinking users in a state of dysphoria.
#Kesten, Joanna M.; et al. (2022): ”Changes in the development of opioid tolerance on re-exposure among people who use heroin: A qualitative study”, PLoS ONE, 17, 6
Quote: "Tolerance development A schematic showing the amplitude of response evoked by a repeated dose of heroin. (A) In the development of pharmacological tolerance, opioid receptors become progressively less responsive and this results in a reduced response amplitude with no change in baseline. (B) In psychological tolerance there is no change in the amplitude of the response evoked by the drug injection but between injections mood is depressed when the effect of the drug wears off. As the baseline mood falls progressively with drug use then the peak height of the drug effect is also lowered. Adapted from reference 11. (C) If both pharmacological and psychological tolerance are produced then not only does the baseline mood fall between drug doses but the amplitude of the response evoked by the drug injection will also decrease."
— Fentanyl is around 50 times more potent than heroin – but this doesn’t mean 50 times more amazing, quite the opposite.
The feeling of euphoria people get from fentanyl is less pronounced than with heroin:
#European Union Drugs Agency: “Fentanyl drug profile” (retrieved 2024)
https://www.euda.europa.eu/publications/drug-profiles/fentanyl_en
Quote: “Fentanyl is a narcotic analgesic acting predominately at the µ-opiate receptor. Apart from analgesia, the fentanyls as a group produce drowsiness and euphoria, the latter being less pronounced than with heroin and morphine.”
Fentanyl is not particularly well-liked when compared with other opioids, especially heroin:
#Comer, Sandra D. (2008): “Abuse Liability of Prescription Opioids Compared to Heroin in Morphine-Maintained Heroin Abusers”, Neuropsychopharmacology, vol. 33, 5, 1179–1191
https://www.nature.com/articles/1301479.pdf
It is, however, much more potent when comparing dose equivalence:
#Mauger, Sophie; Fraser, Ronald; Gill, Kathryn (2014): ”Utilizing buprenorphine–naloxone to treat illicit and prescription-opioid dependence”, Neuropsychiatric Disease and Treatment, vol. 10, 587–598
—Fentanyl is extremely good at crossing the blood-brain barrier, the firewall that protects your brain from harmful substances. It enters your brain so easily that you get from 0 to extremely high almost instantly. But just as fast as it enters your brain, it leaves again. Its effects are very short. A heroin high can last six hours, one from fentanyl can fade in minutes.
#Koyyalagunta, Dhanalakshmi (2007): “Pain Management”
https://www.sciencedirect.com/topics/neuroscience/fentanyl
Quote: “Fentanyl is a highly lipid-soluble opioid and crosses the blood-brain barrier rapidly. The plasma level equilibrates with the CSF levels within 5 minutes. It has a rapid onset of action (30 seconds) and a short duration of action owing to redistribution to fat and skeletal muscle.”
#Duhart Clarke, Sarah E.; Kral, Alex H., Zibbell, Jon E. (2022): “Consuming illicit opioids during a drug overdose epidemic: Illicit fentanyls, drug discernment, and the radical transformation of the illicit opioid market”, vol. 99, 103467
https://www.sciencedirect.com/science/article/pii/S0955395921003728
Quote: “Heroin was generally described as producing long stretches of bodily euphoria lasting between four-to-eight hours. Study participants insisted that the high from fentanyl subsided more quickly than heroin, lasting only minutes in some cases.“
#Vahedi, Hojat S. M.; et al. (2019): “Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury”,World journal of emergency medicine, 10,1, 27–32.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6264977/
Quote: “Fentanyl has been used in anesthesiology since 1960. Different routes of administration make fentanyl a good choice in emergency situations. Its onset of action is less than 60 seconds with a half-life of 90 minutes and duration of action near 30–60 minutes. Its peak effect is 2–5 minutes.”
—But it comes with all the withdrawal symptoms.
The severity of withdrawal symptoms depends on many factors, including the habitual dose.
#MSD Manual Consumer Version: “Opioids” (retrieved 2024)
Quote: “Each opioid is eliminated from the body at a different rate, which alters how quickly withdrawal progresses and stops. Withdrawal symptoms are worse in people who have used large doses for a long time:
Since fentanyl is much more potent than heroin, the equivalent heroin dose is very large, and the withdrawal symptoms tend to be more severe.
There is also testimonial evidence to the same in survivors of both types of withdrawal syndromes:
#Gryczynski, Jan; et al. (2019): “Fentanyl exposure and preferences among individuals starting treatment for opioid use disorder”, Drug and Alcohol Dependence, vol. 204, 107515
https://www.sciencedirect.com/science/article/abs/pii/S0376871619302741?via%3Dihub
Quote: “Participants thought fentanyl withdrawal had faster onset (53.5%), greater severity (74.8%), and longer duration (62.0%) than heroin withdrawal.”
—As a bonus, because Fentanyl acts so quickly on your brain, it fries your reward center even more, making it even more addictive than heroin.
We thank our expert Christian Lüscher for confirming that fentanyl has higher addictiveness potential than heroin.
The greater addictiveness can be explained in part by higher potency
#DrugRehab.com: “Fentanyl vs. Heroin” (retrieved 2024)
https://www.drugrehab.com/addiction/drugs/heroin/heroin-vs-fentanyl/
Quote: “Heroin and fentanyl cause dependence, tolerance and addiction in the same way. The brain adapts to repeated exposure to any opioid by becoming dependent on the chemical to function normally. All opioids manipulate the pleasure and reward systems in the brain, increasing the chance of addiction. However, stronger opioids usually cause dependence and addiction more quickly than weaker opioids.”
Another partial explanation for the higher addictiveness of fentanyl is its quick action, which may lead to more frequent use.
—And since you only need so little of it, it is super easy to overdose and die by accident. It is the deadliest illegal drug in US history by far. Between 2013 and 2023, it killed about 400,000 Americans.
Extremely small amounts of fentanyl represent a serious risk to life:
#National Center for Drug Abuse Statistics: “Fentanyl Abuse Statistics” (retrieved 2024)
For scale, the following image shows 2 mg of fentanyl, a lethal dose for most people:
#National Institute of Standards and Technology: “Faux Fentanyl Lethal Dose 005” (retrieved 2024)
It is responsible for more cumulative overdose deaths than heroin, cocaine or methamphetamines since the moment we started keeping records:
#National Institute on Drug Abuse (2024): “Drug Overdose Deaths: Facts and Figures”
https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
More deaths are attributed to it than to alcohol poisoning in the same period:
#Centers for Disease and Control and Prevention: ”CDC WONDER” (data extracted 2024)
Categories of “Multiple causes of death (Final)” when available and otherwise “Multiple causes of death (Provisional)”. The ICD code taken to represent deaths by fentanyl overdose has been T40.4 or “Poisoning by, adverse effect of and underdosing of other synthetic narcotics”, which includes mainly fentanyl and its analogs. The ICD code taken to represent alcohol poisoning is T51 or “Toxic effect of alcohol”. Since 1999, around 200,000 deaths can be attributed to alcohol poisoning, more than 400,000 could be attributed to fentanyl.
These effects take into account only acute poisoning or overdose, and not long-term effects of continued drug and alcohol use.
We can also compare which the number of deaths partially attributed to “T40.4 or “Poisoning by, adverse effect of and underdosing of other synthetic narcotics” in the “Multiple causes of death” database with the total of overdose deaths per year since 1968, using the “Underlying Causes of Death” database from the CDC. Please note that these are not direct comparisons, since the causes of death classification changed in 1978 and then again in 1998, and that the “Multiple Causes of Death” database allows for multiple causes for the death of the same person. The comparison is however illustrative. Since 2020, the death rate of fentanyl (in multiple causes) is more than half of the death rate of all drugs (underlying cause), and the death rate is much higher than that of any year before the spread of illicit fentanyl use.
#Centers for Disease and Control and Prevention: ”CDC WONDER” Compressed Mortality, 1968-1978 Results: E850-E859 (Accidental poisoning by drugs and medicaments) (data extracted 2024)
https://wonder.cdc.gov/controller/saved/D74/D420F846
#Centers for Disease and Control and Prevention: ”CDC WONDER” Compressed Mortality, 1979-1998 Results: E850-E859 (Accidental poisoning by drugs and medicaments) (data extracted 2024)
https://wonder.cdc.gov/controller/saved/D74/D420F846
By the same source, fentanyl killed 400,000 people from 2013 to 2023:
#Centers for Disease and Control and Prevention: ”CDC WONDER” (data extracted 2024)
Categories of “Multiple causes of death (Final)” when available and otherwise “Multiple causes of death (Provisional)”. The ICD code taken to represent deaths by fentanyl overdose has been T40.4 or “Poisoning by, adverse effect of and underdosing of other synthetic narcotics”, which includes mainly fentanyl and its analogs.
On a graph:
—Fentanyl is a drug dealer’s dream. One truck load could supply the entire US for one year. It is cheap and convenient to make and easy to smuggle. Heroin needs plants and fields and way more space.
#Kilmer, Beau; et al. (2019): “How much illegally manufactured fentanyl could the U.S. be consuming?”, The American journal of drug and alcohol abuse, vol. 48, 4, 397–402.
https://pubmed.ncbi.nlm.nih.gov/35867407/
Quote: “This article provides guidance through two thought experiments that provide a hypothetical upper bound on U.S. consumption. The first considers a scenario in which IMF [(illegally manufactured fentanyl)] replaces heroin in all illegal opioid markets. The second starts with the number of individuals with an opioid use disorder and considers what total consumption would be if IMF was the only opioid they consumed. Both calculations suggest it is unlikely that the annual consumption of IMF in 2021 could have been more than single digit pure metric tons. For comparison, the most recent best estimates of the amount of cocaine and heroin consumed in the U.S. are 145 and 47 pure metric tons, respectively.”
#United Nations Office on Drugs and Crime (2023): “Contemporary Issues on Drugs: The Synthetic drug phenomenon”
https://www.unodc.org/res/WDR-2023/WDR23_Booklet_2.pdf
Quote: “Fentanyl is perhaps 25 to 50 times more potent than heroin.55 This translates into reduced legal risk and, therefore, costs, as traffickers can more easily conceal smaller quantities of pure fentanyl in place of larger volumes of heroin. [...]
Fentanyl’s high potency relative to heroin means that smuggling even small quantities of low purity through a variety of means is sufficient to meet demand. The advantages of a higher-potency product suggest that trafficking organizations can spread the risk of interdiction over a large number of single pedestrians or vehicles. This could make many synthetic drugs resilient to interdiction, translating into reduced retail prices. As evidence of this, the purity-adjusted low level wholesale price of illegally manufactured fentanyl powder in the United States fell by more than 50 per cent between 2016 and 2021.”
Synthetic drugs like fentanyl offer a variety of advantages to dealers in comparison with naturally occurring drugs, such as heroin, including the fact that the production process does not require cultivating crops on large land areas.
#United Nations Office on Drugs and Crime (2023): “Contemporary Issues on Drugs: The Synthetic drug phenomenon”
—So garbage Fentanyl just took over the Heroin supply. It might have seemed great for heroin addicts at first. And then its trap snapped close. While some people may seek out fentanyl specifically, several studies have found that most opioid users try to avoid it.
#State Health Access Data Assistance Center: “The Opioid Epidemic in the United States” (retrieved 2024)
https://www.shadac.org/opioid-epidemic-united-states
Quote: “Heroin rose in popularity as individuals who were addicted to prescription opioids suddenly found themselves cut off from a substance on which they had become chemically dependent and sought out a substitute. Seeking to exploit a growing market for illicitly trafficked opioids, drug traffickers eventually turned instead to fentanyl as it is easier to produce in large quantities than heroin, has a higher potency, and is easier and cheaper to smuggle than its counterpart. Resultantly, death rates from heroin began to recede, while those from fentanyl have only continued to surge.”
#State Health Access Data Assistance Center (2023): The Opioid Crisis in the Pandemic Era”
Quote: “Overdose deaths from fentanyl began to climb around 2013, just two years after the CDC made its opioid epidemic declaration. At first there was little market for fentanyl in the illicit drug trade. Instead of being sold as fentanyl, it was often used as an additive to boost the potency of heroin or even sold inaccurately as heroin. Additionally, it was often, and still continues to be, used as an ingredient in counterfeit opioid painkillers—fake OxyContin or similar pills that substitute cheaper, abundant fentanyl for the semi-synthetic opioids found in most prescription opioid painkillers. But within a few years, fentanyl was sufficiently well-known and demanded enough by customers that it no longer had to masquerade as other substances, although it still often does.”
Even within opioid users, fentanyl is not particularly sought after:
#Blanco, Carlos; et al. (2020): “America’s opioid crisis: the need for an integrated public health approach”, Translational Psychiatry, vol. 10, 167
https://www.nature.com/articles/s41398-020-0847-1
Quote: “For example, many people who use illicit opioids are exposed to fentanyl, though most do not report a desire for fentanyl”
The accompanying map shows states with significant drug overdose mortality as it has progressed from 2005 to 2022. Like we have seen above, during this time overdose deaths have been dominated by deaths due to fentanyl overdose.
#Centers for Disease and Control and Prevention: ”Drug Overdose Mortality by State” (retrieved 2024)
https://www.cdc.gov/nchs/pressroom/sosmap/drug_poisoning_mortality/drug_poisoning.htm
—Even worse, a lot of people who die from Fentanyl, don’t take it willingly.
#Han, Ying; et al. (2019): “The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies”, Translational Psychiatry, vol. 9, 282
https://www.nature.com/articles/s41398-019-0625-0
Quote: “Many people who have survived fentanyl overdose appear to be unaware that they ever took the drug. Surveys from 17 harm reduction sites in British Columbia, Canada, revealed that the prevalence of fentanyl use was 29% (70/242; based on urine drug screen), 73% of whom report that they did not knowingly use fentanyl. Urine drug screens in methadone-maintained patients in Wayne County, Michigan, showed that 38% of 368 unique patients tested positive for fentanyl, and 67.3% of 113 patients reported that they did not know anyone who sought to obtain fentanyl in a subsequent anonymous survey.”
—Dealers want people to come back and choose their product over their competitors’. And by adding a tiny trace of Fentanyl to ANY drug, they can make it more addictive. Even if people don’t realize they took an opioid, they will feel its effects. So dealers started to lace all kinds of drugs with fentanyl, turning the entire US drug market into a minefield, where any trip can be your last. Because way too often, they put a bit too much in their mixes.
#Adams and Broomfield District Attorney Office: “Fentanyl Fact Sheet” (retrieved 2024)
https://adamsbroomfieldda.org/Fentanyl-Fact-Sheet
Quote: “Fentanyl is much cheaper to make than other opioids. It is also easier to smuggle because small amounts are very powerful. It is a lot easier to smuggle in a baggie of Fentanyl powder than kilogram bricks of other drugs for the same profit margin. In addition, it is highly addictive making individuals wanting/needing to buy more as they chase their first high.”
#United States Drug Enforcement Administration: “Facts About Fentanyl” (retrieved 2024)
https://www.dea.gov/resources/facts-about-fentanyl
Quote: “42% of pills tested for fentanyl contained at least 2 mg of fentanyl, considered a potentially lethal dose.”
#United States Drug Enforcement Administration: “DEA Laboratory Testing Reveals that 6 out of 10 Fentanyl-Laced Fake Prescription Pills Now Contain a Potentially Lethal Dose of Fentanyl” (retrieved 2024)
Quote: “The DEA Laboratory has found that, of the fentanyl-laced fake prescription pills analyzed in 2022, six out of ten now contain a potentially lethal dose of fentanyl. This is an increase from DEA’s previous announcement in 2021 that four out of ten fentanyl-laced fake prescription pills were found to contain a potentially lethal dose.”
—In 2022 the combination with pills – often counterfeit oxycodone and benzodiazepines – accounted for about 20% of all fentanyl deaths. In 2023 the US authorities seized 115 million pills with fentanyl. 70% contained a lethal dose.
In 2022, there was around 75,000 deaths caused by fentanyl overdose as calculated from:
#Centers for Disease and Control and Prevention: ”CDC WONDER” (data extracted 2024)
https://wonder.cdc.gov/
The ICD code taken to represent deaths by fentanyl overdose has been T40.4 or “Poisoning by, adverse effect of and underdosing of other synthetic narcotics”, which includes mainly fentanyl and its analogs.
Estimating the number of deaths in 2022 by overdose on combinations of fentanyl together with antidepressants (~2,000), benzodiazepines (~6,000) and prescription opioids (~8,000) form graphs here
#National Institute on Drug Abuse (2024): “Drug Overdose Deaths: Facts and Figures”
https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
Gives an approximate percentage of overdose deaths in combination with pills of:
(2,000 + 6,000 + 8,000) / 75,000 = 21%
#Palamar, Joseph J.; et al. (2024): “National and regional trends in fentanyl seizures in the United States, 2017–2023”, International Journal of Drug Policy, 104417
https://www.sciencedirect.com/science/article/abs/pii/S0955395924001026?via%3Dihub
Quote: “The percentage of seizures in pill form in the US increased from 10.3 % in 2017 to 49.0 % in 2023 (adjusted annual percentage change [AAPC]=25.2, 95 % CI: 17.6, 33.2), with 115.6 million individual pills seized in 2023.”
#United States Drug Enforcement Administration (2024): “DEA Fentanyl Seizures in 2024”
Quote: “The latest DEA laboratory testing indicates 5 out of 10 pills tested in 2024 contain a potentially deadly dose of fentanyl. This is down from 7 out of ten pills in 2023 and 6 out of ten pills in 2022.”
—About half of Fentanyl overdoses came where you expect it the least, from stimulants like cocaine and meth.
In 2022, there was around 75,000 deaths caused by fentanyl overdose as calculated from:
#Centers for Disease and Control and Prevention: ”CDC WONDER” (data extracted 2024)
https://wonder.cdc.gov/
The ICD code taken to represent deaths by fentanyl overdose has been T40.4 or “Poisoning by, adverse effect of and underdosing of other synthetic narcotics”, which includes mainly fentanyl and its analogs.
Estimating the number of deaths in 2022 by overdose on combinations of fentanyl together with stimulants (~38,000) form the graph here:
#National Institute on Drug Abuse (2024): “Drug Overdose Deaths: Facts and Figures”
https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
Gives an approximate percentage of overdose deaths in combination with pills of:
38,000 / 75,000 = 51%
—if you’ve never tried opioids, you can overdose very easily.
Extremely small amounts of fentanyl represent a serious risk to life:
#National Center for Drug Abuse Statistics: “Fentanyl Abuse Statistics” (retrieved 2024)
https://drugabusestatistics.org/fentanyl-abuse-statistics/
For scale, the following image shows 2 mg of fentanyl, a lethal dose for most people:
#National Institute of Standards and Technology: “Faux Fentanyl Lethal Dose 005” (retrieved 2024)
People who have developed a tolerance to opioids might be able to survive bigger doses, but if you stop taking opioids for a while, or you take less or less potent opioids, your tolerance also decreases. Tolerance can also be affected by other factors including illness, stress, or new or different environments.
#NYC Health Department (2020): ”Drug Tolerance and Risk of Overdose” (retrieved 2024)
https://www.nyc.gov/assets/doh/downloads/pdf/covid/covid-19-drug-tolerance-overdose.pdf
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