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19 - 12 - 2016

Opiorphin to replace morphine: our questions to Dr. C.Rougeot

A new study carried out by French researchers validated in rats a new molecule, opiorphin, with a stabilized from with painkilling properties close to those of morphine, without the side effects. Co-author of the study, Dr. Catherine Rougeot tells us more about this breakthrough. 

 In the November issue of the Journal Anesthesiology, a new study by French researchers (Gustave Roussy Institute, Pasteur Institute, Inserm, Paris-Sud University, APHP) confirmed the efficacy and safety of a natural painkiller, opiorphin, and its stabilized form. These two substances have the advantage of having analgesic effects, just like morphine does, but without its side effects. Researcher at the Pasteur Institute, co-author of this study and discoverer of opiorphin, Dr. Catherine Rougeot answered our questions.  What are the major disadvantages of morphine? C.R.: “Although morphine is an extremely powerful, maybe even the most powerful, painkiller, it still has major side effects. Because of its mechanisms of action, it acts on many tissues and organs, for example, by inducing severe constipation after a single administration. Simply because it acts on the intestinal mucosa: it prevents peristalsis, ie the set of intestinal muscle contractions. Moreover, it induces a tolerance, that is to say that it is necessary to gradually increase the dosage to have the same effect. There is also a dependence after repeated administration. And, in addition, morphine can cause potentially fatal respiratory distress.” Why did you look for another molecule?   C.R. : “I didn’t look for a painkiller. I was doing basic research and came across a molecule that had this analgesic property. In general, the pharmaceutical industries are looking for new molecules… They take morphine, modify it, transform it to make it more effective and with fewer side effects, etc. Hence the birth of many new products, but which ultimately have the same mechanism of action as morphine. It’s only a little different !” What is opiorphin, where did it come from and how was it discovered ?  C.R. : « I discovered this new molecule in 2006, well it is at that time that the publication concerning this new molecule was published (in the PNAS journal, ed). First, I discovered the functional homolog of human opiorphin in the rat, using a genomic approach. That is to say, a new gene was discovered, which we did not know anything, in terms of product resulting from this gene and its function. All my work, has been to identify the products form this gene and identify the function of these products. It took me a few years. I discovered that the rat has an endogenous painkiller (emanating from the organism, ed), sialorphine, which is as powerful as morphine. This is the product of the gene discovered.Then, my second approach was to tell myself: “Why wouldn’t such a molecule exist in humans ?” I did some research using a more biochemical approach, using human cells. I was looking to isolate a product in humans that had the same properties as the rat sialorphin. But this isn’t obvious because we started from nothing. This is what fundamental research is like. It is extremely long and difficult. This is how I came across opiorphin, a painkiller molecule that humans possess in small quantity in their body. I isolated it from human saliva, because it was practical, and it was found in the rat saliva , but it is found across the whole body. It is secreted in many tissues but always at a low level at a natural scale. Hence the benefit of producing it and injecting it at higher doses, so that it actually becomes a painkiller.”  What are the benefits of opiorphin ? Does it have a mechanism of action different from that of morphine?  C.R. : “ Opiorphin, at effective doses, or even at doses 5 times that, doesn’t cause any respiratory distress. Opiorphin is a painkiller with a mechanism of action completely different from that of morphine. Morphine will act on the entire body, including the pathways not affected by pain. Opiorphin has a mechanism of action restricted to pathways stimulated by stress, such as painful stress. Opiorphin will only act on the pathways involved in the regulation of painful transmission. It is a system of regulation of pain transmission, of painful messengers. Let’s say that its mechanism of action makes it more specific, in terms of targets.The problem is that morphine act on all opioid receptors, and we have them in all our body. Opiorphin has an indirect effect: it works by protecting natural painkilling molecules, that are just as effective as morphine. It protects our natural painkillers from destruction and increases their effectiveness.” The study mentions a stabilized form of opiorphine called STR-324. Can you tell us more?  C.R. : “ STR-324 is a natural molecule, also identified in 2006. It is a natural derivative of opiorphin. In organisms, opiorphin is capable of naturally transforming itself into this second molecule. It was named by the industry that will be continuing the work. The chemical stability of a molecule is very important for the pharmaceutical industries to make a drug. Opiorphin has no chemical stability, but its STR-324 form has a very high chemical stability. It is this form that will be priviledged by the industry in the clinical trials to come.”      The study was conducted in rats. Why did you use this animal model ? C.R. : “I want to note that we first used human cell models to test the toxicity, efficacy and activity of the molecule. It is obvious that if the molecule is toxic in human cell models, we shouldn’t go any further. To the extent that there was no toxicity, we continued in an animal model. This is the mandatory procedure for marketing a new molecule.The rat is an easy to breed mammal in the laboratory. It is an extremely well-known animal from the behavioural point of view, and standard models for the study of pain-relieving properties are well known in rats. Cells are good, but it is not an entire organism, so it does not model all the side effects that one might have. It is necessary to test in animals to measure toxicity. But I want to point out that it is very important that the animals are in good conditions, otherwise the results are false, biased.”  How is pain induced and measured and how is the pain–relieving effect observed in this model? How is the absence of adverse effects measured?  C.R. : “There are three main types of pain: thermal pain, mechanical pain and chronic pain. For example, for thermal pain, a small laser beam is used, transmitted by an automated device, which will touch the animal on the tail, and then the reflex is measured. For the mechanical pain, it is filaments, which are supported by the animal’s leg, and the withdrawal reflex of the leg is measured. This withdrawal period gives us an indication of pain and the effect of the painkiller. The longer the reflex time, the more powerful the painkiller. These are extremely standardized models.For undesirable effects, the number of faeces (or droppings) is measured. We observe, for example 85% less faeces emitted when morphine is administered relative to opiorphin. Same for intolerance: opiorphin is administered for 8 days, every day, is it would be in a person with chronic pain. The efficacy of the product is measured after 8 days, and we usually observe that morphine is no longer effective using the starting dose, whereas opiorphin has the same efficacy.  For what types of pain do you hope this candidate-drug will work ? C.R. : “ Currently, we are establishing in the animal, the profile for the application of opiorphin, to identify the types of pain opiorphin could help in terms of management of the pain. Post-operative pain is the first pain for which the effectiveness of opiorphin has been proven. It is an important event because even a caesarean, a frequent operation, can lead to chronic pain, especially around the scar. We will now test the molecule for other types of pain, especially in the context of neuropathic pain (of nervous origin, ed). It is pain for which morphine is no longer effective over time.” What are the next steps before a possible commercialization? C.R. : “We are currently at the end of the preclinical phase. It is now the manufacturer that is financing everything and who will be organizing the clinical trials in humans. The first human trials should begin late 2017.There are four clinical phases. Phase I consists of an analysis of the toxicity in humans, in a healthy individual. Phase II is an efficacy test conducted on healthy volunteers, with pain modelization in humans by mechanical pressure, for example, or by a small hot or cold element. Again, these are highly standardized models. Phase III is performed on pathological cases, that is, on patients with pain.” NB: It is at the end of Phase III that an application for the authorization to place the medicinal product on the market may be requested. Phase IV is the post-marketing phase that monitors the efficacy and safety of the new drug.          Interviewed Hélène Bour For more information : manufacturer in charge of the clinical trials :