Today's analgesics can treat virtually any kind of pain, from the commonplace aching tooth to the excruciating sensations that accompany cancer. The question today is not so much how to get rid of pain as how much the patient and prescriber are willing to pay for it. The more powerful the drug, the more dangerous the side effects.
I will tell you how pharmacologists plan to end the opioid crisis by «taming» dangerous analgesics, and whether it is possible to get rid of pain without using drugs at all.
Why do we need new painkillers?
For most people, direct familiarity with analgesics is limited to over-the-counter medications, such as headache pills. Not everyone would choose such drugs carefully: sometimes we borrow painkillers from acquaintances or ask at the pharmacy for «something for the head», and the remedies still work. So why invest huge sums in the development of more and more painkillers?
One of the reasons the whole world is talking about the need for new analgesics is the American opioid crisis. It began to gain momentum in the 1990s, and has now reached the scale of «an emergency the country has never faced before» (as Donald Trump described the situation in 2017).
I will tell you how pharmacologists plan to end the opioid crisis by «taming» dangerous analgesics, and whether it is possible to get rid of pain without using drugs at all.
Why do we need new painkillers?
For most people, direct familiarity with analgesics is limited to over-the-counter medications, such as headache pills. Not everyone would choose such drugs carefully: sometimes we borrow painkillers from acquaintances or ask at the pharmacy for «something for the head», and the remedies still work. So why invest huge sums in the development of more and more painkillers?
One of the reasons the whole world is talking about the need for new analgesics is the American opioid crisis. It began to gain momentum in the 1990s, and has now reached the scale of «an emergency the country has never faced before» (as Donald Trump described the situation in 2017).
Tens of thousands of Americans die each year from overdoses: according to estimates of the National Center for Health Statistics, in 2016 drugs caused the death of almost 64,000 U.S. citizens, in 2017 they were the victims of at least 70,000 residents, and in 2021 this figure rose sharply to 106,000 U.S. citizens. At this point, the latest statistics for a few months of 2023 already put overdose deaths at about 60,000 (with 6 more months to go) and the figure is on a rapid upward trend).
Scientists at the University of Pittsburgh recently found that the number of overdose deaths in the United States is growing exponentially: the number of deaths doubles about every nine years. As the scientists expected, the most dangerous substances were various opioids.
Synthetic opioids, with the exception of methadone, topped the list of killer drugs. Heroin came in second place in terms of deaths. The third position went to prescription opioids - that is, painkillers used in medicine.
These drugs have many side effects, the most dangerous of which is respiratory problems, which are most often the cause of death.
Many experts believe that in the United States, such drugs are often prescribed in cases where it would be possible to do without a prescription drug. However, the doctors who make these decisions cannot be accused of unprofessionalism - sometimes they simply have no other choice.
Many common insurance plans allow certain types of pain to be treated only with pills, even though other methods would be more effective for the particular patient, such as physical therapy. If the patient can't afford to pay for the procedures or wait a long time for insurance approval, the doctor has to choose the lesser evil: a prescription for analgesics.
Scientists at the University of Pittsburgh recently found that the number of overdose deaths in the United States is growing exponentially: the number of deaths doubles about every nine years. As the scientists expected, the most dangerous substances were various opioids.
Synthetic opioids, with the exception of methadone, topped the list of killer drugs. Heroin came in second place in terms of deaths. The third position went to prescription opioids - that is, painkillers used in medicine.
These drugs have many side effects, the most dangerous of which is respiratory problems, which are most often the cause of death.
Many experts believe that in the United States, such drugs are often prescribed in cases where it would be possible to do without a prescription drug. However, the doctors who make these decisions cannot be accused of unprofessionalism - sometimes they simply have no other choice.
Many common insurance plans allow certain types of pain to be treated only with pills, even though other methods would be more effective for the particular patient, such as physical therapy. If the patient can't afford to pay for the procedures or wait a long time for insurance approval, the doctor has to choose the lesser evil: a prescription for analgesics.
Another reason is the advertising of «serious» drugs on television: the U.S. remains one of the few countries in the world where it is allowed. Either way, the opioid crisis is a reality, and new solutions to the problem are needed «yesterday».
In other countries around the world, there are opposite problems with painkillers. Both obtaining and prescribing the right medication is very difficult: the procedure requires a lot of paperwork, and doctors are often afraid of criminal liability for even minor errors in handling opioid analgesics - for example, for accidentally losing an ampoule of the drug.
The body versus pain: opioid receptors
How do opioid analgesics work? To begin with, let's remember that our body has its own well-established mechanisms for coping with pain — these are called the antinociceptive system.
To protect itself from possible pain shock, the body secretes various compounds, including endogenous opioid peptides: the famous endorphins and the lesser-known enkephalins. These substances bind to opioid receptors and trigger the processes of pre- and postsynaptic inhibition, «calming down» the nerve fibers that transmit pain signals.
The same receptors are also manipulated by plant or synthetic opioids. The analgesic properties of opium poppy derivatives were known long before the discovery of endorphins and enkephalins: in fact, that is why the receptors involved in pain regulation got their name.
In other countries around the world, there are opposite problems with painkillers. Both obtaining and prescribing the right medication is very difficult: the procedure requires a lot of paperwork, and doctors are often afraid of criminal liability for even minor errors in handling opioid analgesics - for example, for accidentally losing an ampoule of the drug.
The body versus pain: opioid receptors
How do opioid analgesics work? To begin with, let's remember that our body has its own well-established mechanisms for coping with pain — these are called the antinociceptive system.
To protect itself from possible pain shock, the body secretes various compounds, including endogenous opioid peptides: the famous endorphins and the lesser-known enkephalins. These substances bind to opioid receptors and trigger the processes of pre- and postsynaptic inhibition, «calming down» the nerve fibers that transmit pain signals.
The same receptors are also manipulated by plant or synthetic opioids. The analgesic properties of opium poppy derivatives were known long before the discovery of endorphins and enkephalins: in fact, that is why the receptors involved in pain regulation got their name.
Today at least four types of opioid receptors are distinguished: μ- (mu), δ- (delta), κ- (kappa) and nociceptin receptors. The first three types are included in pain suppression. Various opioids can bind to all types, but it is the μ-opioid receptors that are most often the focus of pharmacologists attention: it is these receptors that, for example, are «hit» by morphine.
Alas, the receptors of this system not only relieve the body from unpleasant sensations - they are involved in the processes that cause euphoria and physical dependence on the substance.
Opioid-based medications are very effective and can tame the worst pain, but they come at a high price, given the risk of addiction, choking and other side effects.
Alas, the receptors of this system not only relieve the body from unpleasant sensations - they are involved in the processes that cause euphoria and physical dependence on the substance.
Opioid-based medications are very effective and can tame the worst pain, but they come at a high price, given the risk of addiction, choking and other side effects.
How to «tame» the drug: Opioids without addiction
Most scientists agree that opioids can be extremely dangerous, but there is no way to do without them, at least not in the next few years. For some patients, the pain is so unbearable that other remedies simply don't work.
That is why researchers working on new analgesics most often try to «tame» opioids in different ways. Their goal is to remove the components of substances that can cause addiction and other side effects, leaving only the analgesic components.
Such drugs, like modern narcotic analgesics, target the opioid receptors of our cells, most often those belonging to the μ group. It includes three subtypes of receptors: one of them provides pain relief, the second depresses breathing, affects the contractions of the walls of the gastrointestinal tract and causes euphoria and, in the long term, addiction; the function of the third is still unclear.
Most scientists agree that opioids can be extremely dangerous, but there is no way to do without them, at least not in the next few years. For some patients, the pain is so unbearable that other remedies simply don't work.
That is why researchers working on new analgesics most often try to «tame» opioids in different ways. Their goal is to remove the components of substances that can cause addiction and other side effects, leaving only the analgesic components.
Such drugs, like modern narcotic analgesics, target the opioid receptors of our cells, most often those belonging to the μ group. It includes three subtypes of receptors: one of them provides pain relief, the second depresses breathing, affects the contractions of the walls of the gastrointestinal tract and causes euphoria and, in the long term, addiction; the function of the third is still unclear.
The μ-opioid receptors, like the others, do their job by interacting with G-proteins. These proteins are involved in the transmission of signals affecting the speed and activity of various processes in the cell, acting as an intermediary between the cell membrane receptors and the proteins causing the final cellular response.
In 2016, the journal Nature published a description of a new low-molecular-weight opioid that causes almost no serious side effects. The creators of the drug took advantage of one of the features of G-protein operation: its activity is regulated by proteins belonging to a small family of arrestins, in particular β-arrestins.
Earlier studies have shown that they are the ones that determine whether μ-receptor side effects will manifest, including respiratory depression, the most common cause of overdose death.
So, scientists were looking for a substance that could activate the G-protein signaling pathway without «waking up» the vigilant β-arrestins. It would have been easier to find Cinderella in a crystal slipper: more than three million molecules were tested for the role of a new painkiller - we needed the one that could interact most effectively with the three-dimensional structure of the receptor. The PZM21 molecule won; it maximally activated the G-protein pathway and minimally activated the pathway associated with β-arrestins.
The substance was refined and tested on mice. Not only did PZM21 last longer than an equivalent dose of morphine: it did not make the rodents suffocate and did not make them want to come back for a second dose.
Whether doctors will ever be able to use analgesics based on PZM21 is still unknown: the compound must first undergo a series of clinical studies that will show whether it is safe for humans.
The substance was refined and tested on mice. Not only did PZM21 last longer than an equivalent dose of morphine: it did not make the rodents suffocate and did not make them want to come back for a second dose.
Whether doctors will ever be able to use analgesics based on PZM21 is still unknown: the compound must first undergo a series of clinical studies that will show whether it is safe for humans.
Painkillers that suppress addiction
Another type of analgesic, which could potentially replace modern opioids, has recently been successfully tested on rhesus macaques. The compound AT-121 works simultaneously with two opioid receptors, μ and the nociceptin receptor (NOP).
The potential drug has a double effect: it not only relieves pain, but also weakens addictive processes.
NOP controls many processes: together with other receptors it regulates pain and anxiety, participates in cardiovascular and kidney function, and provides motor activity.
In addition, it is linked to the reward system: these structures of the nervous system help to reinforce the behavior that the body «considers» useful for itself. A few years ago, scientists discovered that because of this feature, the NOP receptor may play a role in the mechanisms that cause chemical dependence on drugs.
Another type of analgesic, which could potentially replace modern opioids, has recently been successfully tested on rhesus macaques. The compound AT-121 works simultaneously with two opioid receptors, μ and the nociceptin receptor (NOP).
The potential drug has a double effect: it not only relieves pain, but also weakens addictive processes.
NOP controls many processes: together with other receptors it regulates pain and anxiety, participates in cardiovascular and kidney function, and provides motor activity.
In addition, it is linked to the reward system: these structures of the nervous system help to reinforce the behavior that the body «considers» useful for itself. A few years ago, scientists discovered that because of this feature, the NOP receptor may play a role in the mechanisms that cause chemical dependence on drugs.
Compound AT-121 was found in a library of substances capable of binding to NOP, and then refined so that it effectively interacted with both it and the μ-receptor.
Tests on monkeys showed that AT-121 relieved pain no worse than morphine, and the new substance required dozens of times less to achieve the result compared to morphine. In addition, the new drug did not interfere with the animals' breathing.
Dependence did not develop in the macaques: when the monkeys were allowed to take the drug in any quantity by pushing a button, they did not abuse the painkiller. Moreover, when AT-121 was given to macaques already hooked on the semi-synthetic opioid oxycodone, the new drug reduced the degree of dependence.
The new compound could prove to be a promising new drug if it manages to pass a series of clinical trials. Scientists will have to check whether AT-121 does not harm structures of the body not related to the perception of pain.
At the same time, the creators of the drug are looking for other substances that can bind to μ- and NOP-receptors: perhaps among them there will be an even more effective painkiller.
Tests on monkeys showed that AT-121 relieved pain no worse than morphine, and the new substance required dozens of times less to achieve the result compared to morphine. In addition, the new drug did not interfere with the animals' breathing.
Dependence did not develop in the macaques: when the monkeys were allowed to take the drug in any quantity by pushing a button, they did not abuse the painkiller. Moreover, when AT-121 was given to macaques already hooked on the semi-synthetic opioid oxycodone, the new drug reduced the degree of dependence.
The new compound could prove to be a promising new drug if it manages to pass a series of clinical trials. Scientists will have to check whether AT-121 does not harm structures of the body not related to the perception of pain.
At the same time, the creators of the drug are looking for other substances that can bind to μ- and NOP-receptors: perhaps among them there will be an even more effective painkiller.
Right on target: local anesthesia
Another way to make opioids safer is to make them act locally, minimally affecting healthy body tissues. One such method was developed in 2017 by German scientists. Their drug is designed for strong local analgesia in surgeries or injuries.
Inflamed tissues are known to create a more acidic environment than healthy tissues. This shift in acid-base balance - or acidosis - increases the activation of opioid receptors, causing G-proteins to transmit signals to the cell more efficiently.
Acidosis also helps the protonation of opioids-that is, the attachment of «donor» protons to the substance: this process allows the drugs to bind better to the receptors.
German researchers decided to create an opioid that would work only with receptors located in acidic inflamed areas.
Another way to make opioids safer is to make them act locally, minimally affecting healthy body tissues. One such method was developed in 2017 by German scientists. Their drug is designed for strong local analgesia in surgeries or injuries.
Inflamed tissues are known to create a more acidic environment than healthy tissues. This shift in acid-base balance - or acidosis - increases the activation of opioid receptors, causing G-proteins to transmit signals to the cell more efficiently.
Acidosis also helps the protonation of opioids-that is, the attachment of «donor» protons to the substance: this process allows the drugs to bind better to the receptors.
German researchers decided to create an opioid that would work only with receptors located in acidic inflamed areas.
This approach will help avoid many side effects. For example, it will prevent the drug from affecting gastrointestinal cell receptors and protect patients from constipation, a common consequence of taking opioid analgesics.
The new drug was obtained by modifying fentanyl, a popular synthetic opioid painkiller. Some of its hydrogen atoms were replaced with fluorine, which «attracts» protons.
A compound called NFEPP was tested on lab rats with various injuries and acute and chronic inflammation. The drug worked just as effectively as regular fentanyl, but it had far fewer side effects.
Rats given unrestricted access to NFEPP were not hooked on painkillers and did not suffer from choking or constipation. Additional experiments showed that the new drug is really active only in damaged tissues and does not affect healthy ones.
All of the drugs described are now being tested on animals, and it will be a while before they are tested on humans. New painkillers need to be tested on a variety of parameters so that these drugs will actually benefit rather than cause new problems.
The new drug was obtained by modifying fentanyl, a popular synthetic opioid painkiller. Some of its hydrogen atoms were replaced with fluorine, which «attracts» protons.
A compound called NFEPP was tested on lab rats with various injuries and acute and chronic inflammation. The drug worked just as effectively as regular fentanyl, but it had far fewer side effects.
Rats given unrestricted access to NFEPP were not hooked on painkillers and did not suffer from choking or constipation. Additional experiments showed that the new drug is really active only in damaged tissues and does not affect healthy ones.
All of the drugs described are now being tested on animals, and it will be a while before they are tested on humans. New painkillers need to be tested on a variety of parameters so that these drugs will actually benefit rather than cause new problems.
Tricking your brain: alternative methods
Another approach the researchers suggest for dealing with the opioid crisis is, in some cases, to do away with medication altogether.
Patients do not have to endure unpleasant sensations: the authors of such methods try to lessen the subjective feeling of pain by making the person distracted from it. Strange as it may seem, these methods work. They cannot relieve the unbearable «cancer» pain, but they can ease the life of, for example, surgical patients.
An unexpected but pleasant way to recover from surgery is music.
A meta-analysis of more than 80 studies has shown that music therapy before an intervention reduces the subjective assessment of pain intensity that occurs after the procedure. Both live concerts in hospital wards and recordings of favorite songs work this way.
Patients rated their pain on a visual analog scale: they were asked to place their feelings between «no pain at al» and «maximum unbearable pain» on a ten centimeter line. Those who listened to music before, during or after surgery, on average, placed their score one centimeter closer to the no pain point.
Another approach the researchers suggest for dealing with the opioid crisis is, in some cases, to do away with medication altogether.
Patients do not have to endure unpleasant sensations: the authors of such methods try to lessen the subjective feeling of pain by making the person distracted from it. Strange as it may seem, these methods work. They cannot relieve the unbearable «cancer» pain, but they can ease the life of, for example, surgical patients.
An unexpected but pleasant way to recover from surgery is music.
A meta-analysis of more than 80 studies has shown that music therapy before an intervention reduces the subjective assessment of pain intensity that occurs after the procedure. Both live concerts in hospital wards and recordings of favorite songs work this way.
Patients rated their pain on a visual analog scale: they were asked to place their feelings between «no pain at al» and «maximum unbearable pain» on a ten centimeter line. Those who listened to music before, during or after surgery, on average, placed their score one centimeter closer to the no pain point.
Scientists believe it's about music's ability to calm a person and reduce anxiety.
Another «entertaining» method of analgesia without medication is the use of virtual reality. Studies show that immersion into the VR world works just as well as traditional medications even for acute pain. Back in the late 1990s, virtual reality began to be used in the treatment of burns.
Specially designed games and VR tours help patients endure extreme discomfort while a specialist treats a wound or administers physical therapy.
Another «entertaining» method of analgesia without medication is the use of virtual reality. Studies show that immersion into the VR world works just as well as traditional medications even for acute pain. Back in the late 1990s, virtual reality began to be used in the treatment of burns.
Specially designed games and VR tours help patients endure extreme discomfort while a specialist treats a wound or administers physical therapy.
One of the most famous VR games created for burn unit patients lives up to its name: Snow World. The player travels through painted snow-covered landscapes and uses light head movements to throw virtual snowballs at penguins, snowmen, and mammoths.
The technique has been in use for more than 20 years, and patients have noted that during the procedure combined with the game, the pain seems less severe.
Another VR game helps people with chronic pain. The plot of the «Cool!» app is much like Snow World: while walking through a virtual park with a lot of distracting details, you have to throw shimmering soap bubbles at the target.
A 2016 study showed that the game was able to reduce the symptoms of chronic pain in all thirty participants of the experiment.
The technique has been in use for more than 20 years, and patients have noted that during the procedure combined with the game, the pain seems less severe.
Another VR game helps people with chronic pain. The plot of the «Cool!» app is much like Snow World: while walking through a virtual park with a lot of distracting details, you have to throw shimmering soap bubbles at the target.
A 2016 study showed that the game was able to reduce the symptoms of chronic pain in all thirty participants of the experiment.
Of course, none of the new methods of pain relief will be a panacea: a drug may not pass clinical trials, and a non-drug method may be completely useless for some patients.
Does it sound hopeless? Not at all.
It is this unpredictability of experimental analgesics that makes scientists look for more and more new remedies - which means that more and more people suffering from pain get hope of finding a suitable cure.
Does it sound hopeless? Not at all.
It is this unpredictability of experimental analgesics that makes scientists look for more and more new remedies - which means that more and more people suffering from pain get hope of finding a suitable cure.