In an article published in the journal Antioxidants, researchers from the Hospital de la Santa Creu i Sant Pau Research Institute (IIB Sant Pau) and the Universitat Autònoma de Barcelona demonstrate in animal models that water enriched with hydrogen molecules (H2) improves the symptomatology of neuropathic pain and related emotional disturbances.

Twenty per cent of the Spanish population suffers from chronic pain, and between 7 and 10% from neuropathic pain. This condition, mostly caused by nerve damage, causes people to feel intense and constant pain. Treatments are scarce and often involve a large number of adverse effects that affect the patients’ quality of life. For this reason, the Molecular Neuropharmacology research group, coordinated by Olga Pol at the Sant Pau Biomedical Research Institute and the UAB Institute of Neurosciences, is looking for new therapeutic possibilities that can help people who suffer from it.
Now in a study published in the journal Antioxidants, they have analyzed the effects of administering to mice models of neuropathic pain water enriched with hydrogen molecules, a treatment that had already shown positive effects in neurological disorders, such as Alzheimer’s disease and depression. The results point to this strategy as a very promising candidate for the treatment of neuropathic pain and associated emotional disorders, due to its analgesic and anti-inflammatory effects, as well as its anxiolytic and antidepressant properties.

“This treatment can alleviate not only the pain caused by a nerve injury, but also the states of anxiety and depression that accompany it, which would substantially improve the patients’ quality of life. This is important because it can allow a more effective and global treatment of neuropathic pain with fewer side effects”, explains Olga Pol.
In the study, the treatment was administered to mice by injection, but in the future other routes will be tested, such as oral administration. The next steps will be to investigate how the treatment works in animal models of pain associated with chemotherapy, because many times cancer patients present neuropathic pain as a side effect of the treatment, as well as evaluating its effects on the memory and emotional deficits that these same patients can also suffer.

New substances that activate adrenalin receptors instead of opioid receptors have a similar pain-relieving effect to opiates but without the negative aspects such as respiratory depression and addiction. This is the result of research carried out by an international team of researchers led by the Chair of Pharmaceutical Chemistry at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU). Their findings, which have now been published in the renowned scientific journal Science, are a milestone in developing non-opioid pain relief.

Opiates cause addiction, new substances do not

They are a blessing for patients suffering from severe pain. Still, they also have serious side effects: Opioids, and above all morphine, can cause nausea, dizziness and constipation and often cause slowed breathing that can even result in respiratory failure. In addition, opiates are addictive – a high percentage of the drug problem in the USA is caused by pain medication, for example.

In order to tackle the unwanted medical and social effects of opioids, researchers all over the world are searching for alternative analgesics. Prof. Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry is one of these researchers. “We are focusing particularly on the molecular structures of the receptors that dock onto the pharmaceutical substances”, says Gmeiner. “It is only when we understand these on the atomic level that we can develop effective and safe active substances.” Collaborating with an international team of researchers, Prof. Gmeiner discovered an active substance in 2016 that bonds to known opioid receptors and that offers the same level of pain relief as morphine, even though it has no chemical similarity to opiates.

New approach: Adrenaline receptors instead of opioid receptors

Peter Gmeiner is currently following a lead that seems very promising: “Many non-opioid receptors are involved in pain processing, but only a small number of these alternatives have as yet been validated for use in therapies”, he explains. Gmeiner and a team of researchers from Erlangen, China, Canada and the USA have now turned their attention to a new receptor responsible for binding adrenaline – the alpha 2A adrenergic receptor. There are already some analgesics that target this receptor, such as brimonidine, clonidine and dexmedetomidine. Gmeiner: “Dexmedetomidine relieves pain, but has a strong sedative effect, which means its use is restricted to intensive care in hospital settings and is not suitable for broader patient groups.”

The research consortium aims to find a chemical compound that activates the receptor in the central nervous system without a sedative effect. In a virtual library of more than 300 million different and easily accessible molecules, the researchers looked for compounds that physically match the receptor but are not chemically related to known medication. After a series of complex virtual docking simulations, around 50 molecules were selected for synthesis and testing, and two of these fulfilled the desired criteria. They had good bonding characteristics, and activated only certain protein sub-types and, thus, a very selective set of cellular signal pathways. In contrast, dexmedetomidine responds to a significantly wider range of proteins.

Pain relief without sedation in animal models

By further optimizing the identified molecules, for which extremely high-resolution cryo-electron microscopic imaging was used, the researchers synthesised agonists that produced high concentrations in the brain. They reduced pain sensation effectively in investigations with animal models. “Various tests confirmed that docking on the receptor was responsible for the analgesic effect,” explains Gmeiner. “We are particularly pleased that none of the new compounds caused sedation, even at considerably higher doses than those required for pain relief.”

The successful separation of analgesic properties and sedation is a milestone in developing non-opioid pain medication, especially as the newly-identified agonists are comparatively easy to manufacture and administer orally to patients. However, Prof. Gmeiner has to dampen any hopes of rapid, widespread use in human medicine: “We are currently still talking about basic research. The development of medication is subject to strict controls, and in addition to significant amounts of funding, it takes a long time. However, these results still make us very optimistic.”

People who sit a lot and do not exercise often develop back pain. Credit: Markus Bernards for Goethe University Frankfurt

Lack of exercise, bad posture, overexertion, and constant stress at work or home – back pain is a widespread condition with many causes. For a not insignificant number of sufferers, the symptoms are chronic, meaning they persist for a long time or recur repeatedly. Sports and exercise therapies under instruction can bring relief. Common treatment methods include physiotherapy as well as strength and stability exercises. But how can the therapy be as successful as possible? Which approach alleviates pain most effectively? A meta-analysis by Goethe University Frankfurt, published recently in the Journal of Pain, has delivered new insights.

The starting point was data from 58 randomised controlled trials (RCTs) of over 10,000 patients worldwide with chronic low back pain. First, the data relevant to the topic were filtered out of the original manuscripts and then evaluated in groups. When evaluating these data, the researchers examined on the one hand whether and to what extent standard forms of treatment and individualised treatment differ in terms of the result. “Individualised” means that there is some type of personal coaching, where therapists specifically target the potentials and requirements of each patient and decide together with them how their therapy should look.

The study concluded that individualised treatment for chronic back pain led to a significantly increased effect compared to standard exercise therapies. The success rate in pain relief was 38 per cent higher than with standard treatment. “The higher effort required for individual treatment is worthwhile because patients benefit to the extent that is clinically important,” says Dr Johannes Fleckenstein from the Institute of Sport Sciences at Goethe University Frankfurt.

However, the study went even further. The research team in Frankfurt compared a third group of treatment methods alongside the standard and individualised ones. In this group, individualised training sessions were combined with cognitive behavioural therapy (CBT). This procedure – talk therapy – is based on the assumption that negative thoughts and behaviours surrounding pain tend to exacerbate it. Through CBT, pain patients learn to change the way they handle it. They stop being afraid to move or are taught tactics for coping with pain. This makes them realise that they are by no means helpless. But what does psychotherapeutic support through CBT contribute to the success of the treatment? Data analysis revealed the following: When an individualised approach and CBT were combined, the success rate in pain relief was an impressive 84 per cent higher than with standard treatment. The combined therapy, also called multimodal therapy, thus led to the best result.

Fleckenstein sees in the study “an urgent appeal to public health policy” to promote combined therapies in terms of patient care and remuneration. “Compared to other countries, such as the USA, we are in a relatively good position in Germany. For example, we issue fewer prescriptions for strong narcotic drugs such as opiates. But the number of unnecessary X-rays, which, by the way, can also contribute to pain chronicity, and inaccurate surgical indications, is still very high.” This is also due, according to Fleckenstein, to economic incentives, that is, the relatively high remuneration for such interventions. The situation is different for organisations working in the area of pain therapy, he says. Although these are not unprofitable, they are not a cash cow for investors either. In his view, it is important here to improve the economic conditions. After all, pain therapy saves a lot of money in the long run as far as health economics are concerned, whereas tablets and operations rarely lead to medium and long-term pain relief.