Opioid painkillers are virtually indispensable in everyday clinical practice – for example in postoperative care or during cancer treatment. But they have severe side effects and are also contributing to massive substance abuse, particularly in the United States. A research team at Charité – Universitätsmedizin Berlin has now taken an important step towards developing a new generation of painkillers. The scientists explain in the journal Scientific Reports* that the effect of a painkiller depends on the pH value at the source of the pain. This factor determines both the associated risks and addictive potential of an opioid molecule. With its SPARK-BIH funding program, the Berlin Institute of Health (BIH) is currently helping scientists to validate new opioid molecules that have a more favorable efficacy profile – i.e., that are able to provide strong pain relief, but are not addictive and have fewer adverse effects.
Opioids have a strong analgesic effect, but they can quickly lead to dependency. These drugs have long been handled carelessly – particularly in the United States. The number of opioid dependencies there is correspondingly high, with the country experiencing an “opioid epidemic.” In Germany, too, more and more painkillers are being prescribed that contain opioids, and are now even used for non-cancer-related chronic pain. What is needed are drugs that relieve severe pain while at the same time pose fewer risks.
Together with his team, Prof. Christoph Stein, head of Charité’s Experimental Anesthesiology Unit on Campus Benjamin Franklin, is searching for a pain-relief alternative with fewer side effects. The research group has already developed three opioid substances – known as FF6, FF3 and NFEPP – which they have tested in computer simulations with colleagues from the Zuse Institute Berlin (ZIB), an interdisciplinary research institute for applied mathematics and data-intensive high-performance computing. They have now been able to more closely observe pain-relieving effects as well as typical side effects, such as fatigue, constipation, risk of respiratory arrest and addictive potential, by using an animal model of inflammatory pain. “When compared to the standard opioid fentanyl, the results of this new substance class speak for themselves,” says Prof. Stein, who is also a member of Berlin’s Einstein Center for Neurosciences. “The closer the pKa value of the binding molecule is to the pH value of the inflamed or injured tissue, the more selective the activation of receptors. And when only opioid receptors at the source of the pain are activated, the risk of addiction or side effects is far lower. In the case of fentanyl, the pKa value is higher than the physiological pH value, and this standard opioid has also been shown to reach the brain faster.”
The scientists are pursuing the approach of eliminating inflammatory pain and postoperative pain at the site of the trauma – i.e. directly within the injured tissue. In contrast to conventional opioids, the novel substances activate opioid receptors, which are the docking sites for pain medication, solely in an acid environment and thus only act on injured tissue. This approach avoids serious side effects. “We have now investigated the interaction of opioid-binding molecules with opioid receptors at different pH values in cultivated cells to try to determine which chemical properties are necessary for the novel substances to achieve optimal effect. Some of the receptors have also been genetically modified,” explains the study’s leader, Prof. Stein. “We have come to the conclusion that the acid dissociation constant, or pKa value, of an opioid molecule determines its level of risk – i.e., side effects like addiction or respiratory arrest. Until now, the significance of pH and pKa values in the safety of opioids was completely unknown.” This is therefore a groundbreaking discovery in the field of receptor research.
The current studies claim that the fine-tuning of the pKa value and the building of certain chemical bonds with opioid receptors are crucial in the development of novel drugs. If this new generation of painkillers becomes a reality, dangerous side effects and the risk of addiction could become things of the past. “We have already been able to show in numerous clinical studies that the selective activation of peripheral opioid receptors in injured tissue – for example by a local injection of conventional opioids such as morphine – results in potent pain relief for humans. We are therefore confident that our new substance class, which can now also be administered intravenously for the first time, will be successful,” says Prof. Stein. The first clinical studies using these novel substances are expected to begin within two to three years. Meanwhile, the research group is conducting parallel work on further substances in this new generation of opioids.
*Del Vecchio G. et al. pK(a) of opioid ligands as a discriminating factor for side effects. Scientific Reports. 2019 Dec 18; 9(1):19344. DOI: 10.1038/s41598-019-55886-1.