In August 2017, the then president of the United States, Donald Trump, declared addiction to opiates , the most powerful drugs against chronic pain, a national emergency. In that year alone, the abuse of substances such as codeine and morphine claimed the lives of more than 63,000 citizens of that country, where deaths from drug overdoses have increased sevenfold in a decade. By American initiative supported by the European Union, the search for effective therapeutic alternatives has become a priority for the scientific community, as much as it was in the 80s to find the first antiretrovirals against HIV.
The development of new molecules will benefit hundreds of millions of people: 20% of the population of developed countries suffer from chronic pain . “Those affected will have therapies as effective as opiates, but without the addiction problems that their misuse generates and without other side effects, such as constipation,” says Juan Antonio Micó, outgoing president of the Spanish Society of Pain (SED) . Although looking for alternatives is urgent, opiates are still necessary to relieve, for example, patients with advanced cancer. On the other hand, in Spain and Europe, the more restricted use of these drugs has avoided the problems of North America . “They are essential drugs if they are well prescribed and controlled, and if they are administered for a limited time,” says Micó.
The research of many scientists focuses on cannabis . The four hundred compounds in this herb interact with cellular receptors in the nervous system that regulate many organic functions, including pain. Medicinal use of the plant has been proven to reduce chronic pain, especially cancer-related pain . A study of the Ben-Gurion University of the Negev (Israel) with 2,736 people over 65 years of age showed that, after six months of treatment, 18% of the patients had stopped the opioid analgesics they were taking or had lowered the dose. Participants were asked to rate the intensity of pain they perceived before and after using cannabis: 93% indicated that it had dropped from 8 to 4 points on a scale of 0 to 10.
The most common side effects of cannabis are dizziness and dry mouth; It is worth suffering for the benefits, but the ideal would be to produce drugs with minimal sequelae. Spanish scientists have taken a great step in this line. The best known of the compounds in cannabis is delta-9-tetrahydrocannabinol, or THC. Rafael Maldonado’s team, a researcher at the Pompeu Fabra University in Barcelona, has shown thatTHC can alleviate pain without the cognitive decline associated with cannabis use. From this discovery has emerged the project to develop a drug to treat chronic pain without side effects. It would be administered orally and clinical trials in humans, once its safety has been tested in animal models, will begin next year. Maldonado clarifies that the analgesic power of cannabis is due to “the action of THC on the cannabinoid receptor type 1 or CB1. Its sequelae are based on the action it exerts on a new entity that arises when this receptor and that of a neurotransmitter, serotonin, bind ”. The molecule developed by his team breaks that second structure without touching the first, “so we can obtain the therapeutic effects and avoid cognitive deterioration.” The goal is to fill a gap in current treatments.“There is nothing effective against intermediate pain that affects some 50 million Europeans”says the researcher. This new drug could benefit thepeople with osteoarthritis or those with neuropathic pain, a common type that occurs due to an abnormal functioning of the nervous system that makes it misinterpret the stimuli. Pain after a stroke or that of cancer patients belong to this group.
The Pompeu Fabra University team has also shown in guinea pigs that the cannabis component relieves the pain of endometriosis , reduces the growth of tissue adhesions that occur outside the uterus and improves the cognitive alterations that appear in this disease, in concrete memory. This group found that mice with endometriosis treated with THC did not lose memory , unlike those that did not, suggesting that it protects. A trial at the Hospital Clínico de Barcelona already underway will test whether these promising effects are confirmed in humans.
Other upcoming advances have to do with developing alternatives to better measure the intensity of physical suffering in sedated patients or with their expressive capacity canceled. In the Pain Unit of the University Hospital of Álava they work on a system to quantify it by facial gestures. The tool is based on evidence: the human facial expression of pain is spontaneous and universal. We all make the same gestures when we feel it, such as frowning, pressing our lips or wrinkling our nose. The director of the unit, Enrique Bárez, explains that “the modification of these gestures is tabulated with an algorithm. Applying artificial intelligence , a robot compares the gestures of a face recorded in a neutral situation (without pain) with those that arise spontaneously after a painful stimulus, and gives us a numerical value of 0 to 10 “. The possibilities of tools like this are great, since they can be used remotely: “If someone has a relative at home who cannot express himself due to having suffered a stroke, he can record his face with his mobile and send it to the hospital, where the pain of the affected person ” .
Medicine relieves and often eradicates acute pain that arises, for example, after an operation, but chronic pain that persists for more than six months and encompasses both physical and psychological factors is challenging. The arsenal that specialists use to treat it according to its intensity is wide. In addition to opiates, non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen , are available for less intense or intermediate pain. Medicines called adjuvants are also used. “They are molecules destined to treat other diseases, but they have an analgesic effect. An example are anticonvulsants and antidepressants that treat neuropathic pain without the need for a person to be epileptic or suffer from depression ”, explains the president of the SED. Most drugs have been in use for decades, because drug research in this area has stagnated. Why? Dr. Micó, who is also a professor of Pharmacology at the University of Cádiz, points out that “in this specialty progress is made at the same time that it makes it known what pain occurs”, and it has been in recent years that new windows to such knowledge.
The keys to the origin of many diseases are sought in genetics. Could turning off certain genes work? One of the centers that investigates it is the University of Cambridge, in collaboration with the University College of London. Scientists have found in laboratory mice that inactivation of the FAAH gene reduces the sensation of pain in rodents . They have not studied this gene because they have: Jo Cameron, a 73-year-old Scottish woman, has a particular FAAH genotype, and lives without pain despite the joint degeneration she suffers and having undergone a painful hand operation in which she felt nothing . For people like Cameron, this condition is dangerous, because the perception of pain is an alert mechanism that warns us of the damage to the body . But for science, its study represents an opportunity.
A dozen mutations have been identified that stop the perception of pain in those who carry them , and molecules arising from these findings are already in the clinical trial phase. It is estimated that the first drugs based on gene therapy will be available in five to ten years. Sometimes the discovery of a genetic mutation in relation to a specific pain is the first step in understanding its pathophysiology. This is the case of migraine . Scientists from the Institute of Neurosciences of the University of Barcelona have described a key mechanism in the appearance of these headaches: a mutation in the TRESK gene gives rise to two dysfunctional proteins that change the electrical activity of sensory neurons (migraines are linked to a increased excitability of these cells). Will turning off this gene remedy the pain suffered by 15% of the population? It is very likely that it is part of the solution, because this neurological disorder has genetic, but also environmental and hormonal bases.
Migraine illustrates the complexity of treating chronic pain. Dr. Micó explains that the difficulty lies in the cascade mechanisms that are activated: “In a patient with cancer, the innervation of viscera, muscles or bones can be progressively or simultaneously damaged, and each of these conditions has a different pathophysiological mechanism of production of pain. The chronic suffering of this patient would be the sum of these mechanisms ”. That is why it is common for a person not to take a single drug, but several that act in different ways.
In chronic cancer pain there is damage caused by the disease. In other cases there is no such damage, but the memory of past acute pain remains. It is like the echo of a voice: there is no longer sound emission, but it is repeated. Jordi Montero, neurologist at the Pain Treatment Unit of the Mis Tres Torres Clinic in Barcelona and author of the book Permission to complain , defines it as “an error of the brain, which sees danger where there is none” . To explain it, he cites the example of a raped person: “At the time of the attack, he suffered pain caused by injuries that eventually disappeared. But you may have had chronic pain for life every time you had sex. “
This original suffering changes the so-called emotional brain, and produces a sensitization that manifests itself in any part of the body – the extremities, the pelvis, the anus … – in a thousand different ways. Some describe this pain as a cut with a knife, others as the prick of a pin, burning under the skin, an electric shock … Dr. Montero considers it an essential part of the treatment to spend time so that the patient understands the origin of his pain and the role of emotions in that memory that it generates. Remember the case of a woman who underwent surgery for a benign brain tumor, and after a few years she experienced intense pain in the scars of the operation. There was no medical reason to justify it, so the doctor tried to find out why: “I asked him, ‘What are you afraid of?’ Without hesitation, he replied: ‘For the tumor to reproduce.’ That was the reason for the pain.
Researchers have discovered several of the neural networks involved in these emotions in chronic pain, and the challenge now is to manipulate them with new techniques such as optogenetics . “If we introduce a virus into the genome, neurons can be excited or inhibited with light of different colors. If we stimulate neurons in the amygdala from the outside, we can make a rat nervous or relax, ”says Dr. Montero. Other methods such as neurostimulation have already been incorporated into clinical practice. It consists of implanting electrodes in the epidural area near the spinal cord, whose electrical stimuli modulate the pain signal and prevent it from reaching the brain.
Specialists expect a lot from research into new treatments, but insist that the full therapeutic spectrum available should be exploited.given the complexity of a pain, chronic, which is sensory and emotional. Tennis player Rafael Nadal alluded to this dual nature of the phenomenon in an interview in which he acknowledged that at a stage in his career he got tired of suffering pain and had an emotional downturn that affected his performance. Most of the patients who live with pain experience such a mental decline, because, as Dr. Micó recalls, “their quality of life can be greatly affected: they lose their memory, have anxiety, depression or both, they do not sleep, their social relationships and enter a vicious cycle. They are increasingly aware of their suffering and prostrate ”. To break this dynamic, thephysical exercise, within the possibilities of each one. In some cases it has a rehabilitative function, but its effects go further, since“Helps the body to generate substances that protect against pain”says Micó. Among them he cites theendorphins, natural opioids produced by the brain; and thenoradrenalineand theserotonin, the neurotransmitters on which antidepressants act. Toothe immune system is strengthened, and they work even if it’s a virtual activity. For example, at the Guttmann Institute in Badalona, an international reference center in neurorehabilitation, “paraplegics have augmented reality programs where they see themselves running, which improves the pain in their legs,” says Dr. Montero. In other places, these techniques are used to reduce the pain felt by people with an amputated limb: “Mirrors are used in front of which the patient moves the healthy side, but his unconscious brain sees the affected one move, and that has an effect antalgic ”.
Movement is a great ally against physical suffering. In the pain units they know it, and that is why they have rehabilitators and physiotherapists. Many of the 183 operating in Spain also have clinicians (anesthesiologists, neurologists, rheumatologists), social workers, nurses, psychologists and psychiatrists. “They are part of the biopsychosocial model with which pain is addressed today,” recalls the former president of the SED. Together with researchers looking for new ways to tackle it, they form the army that is waging the war against pain, who also have their role in covid-19. An online survey conducted by the SED among more than 250 patients in May 2020, after confinement, revealed that 60% felt worse in health due to the pain.
The pandemic has put the adaptability of the health system to the test and has generalized the use of care tools such as telemedicine. Víctor Mayoral, current president of the SED and head of the Pain Unit of the Hospital de Bellvitge, in Barcelona, recalls that in many centers they use telematic physical examinations from confinement to assess pain : “We have more and more resources, more language to interact with the patient, and that is very positive ”. Covid-19 has been devastating, but in the field of medical research and care for the sick it has brought something priceless, highlighted by the president of the SED: “There has never been such an enormous collaborative effort between researchers and clinicians from all over the world. world to try to solve a problem. It has been extraordinary because this union is here to stay ”.
