Science & Society17 September 2018free access New therapies to relieve pain The search for more efficient and safer alternatives to opioid pain killers Philip Hunter Freelance journalist [email protected] London, UK Search for more papers by this author Philip Hunter Freelance journalist [email protected] London, UK Search for more papers by this author Author Information Philip Hunter1 1London, UK EMBO Rep (2018)19:e46925https://doi.org/10.15252/embr.201846925 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Opioids are a largely efficient medication for relieving severe pain and are prescribed for a wide variety of indications including metastatic cancer, arthritis, neuropathy or post-surgical pain. These drugs target opioid receptors to produce effects similar to morphine and include moderately strong painkillers such as oxycodone and hydrocodone (Vicodin), and strong drugs like fentanyl, which resembles opium-derived morphine and heroin. The great efficiency of opioids in treating severe pain has also been the major drawback for longer-term use given their addictive power. This does not matter for short-term use, for instance to ease post-operative pain, or terminal cancer when the primary requirement is to relieve suffering. Yet, the addictive side effect has become a huge societal problem; in addition, opioids do not work against all types of chronic pain, including some of the most severe cases such as cancer-induced bone pain or some cases of neuropathy resulting from nerve damage. These problems have spurred efforts to develop new drugs for treating pain with some success in developing derivatives with reduced side effects. The other major avenue of research is the identification of relevant pain pathways or protein binding sites including those involved in the placebo effect. The opioid addiction crisis Their efficiency has spurred physicians to prescribe opioids too readily, while drug companies have heavily advertised their effects and understated the side effects to boost usage. This three-way collusion between patients, doctors and pharmaceutical companies has stoked the ongoing epidemic of opioid addiction that has afflicted the USA and Canada in particular, but also other developed countries in Europe and Asia. Apart from exacting a heavy social toll through loss of motivation or loss of jobs, impact on relationships, crime and so on, opioid addiction has dangerous physiological effects, notably on the respiratory system, which causes most of the overdose deaths. In the USA, opioid abuse has become the worst drug crisis in US history: in 2015, more than 33,000 people died from overdoses, leaving thousands of children in foster care. In 2016, opioids still caused three in five drug overdose deaths with 40% of those resulting from authorized prescriptions (https://www.cdc.gov/drugoverdose/data/index.html). The economic costs are equally staggering: the White House estimated in November 2017 that in 2015 alone, the costs of the opioid epidemic, including health care and criminal justice spending along with lost productivity, added up to US$504 billion (https://www.cnbc.com/2017/11/20/the-true-cost-of-opioid-epidemic-tops-500-billion-white-house-says.html). The same year, US President Donald Trump declared opioid abuse a national public health emergency. The great efficiency of opioids in treating severe pain has also been the major drawback for longer-term use given their addictive power. While the epidemic dates back to 1999 when addiction levels began to rise, there are some signs of improvement. The latest report from the IQVIA Institute for Human Data Science 1 found that the volume of prescription opioid dosage defined as Morphine Milligram Equivalents (MMEs) declined by 12% in 2017, the largest annual drop in more than 25 years of measurement (https://www.iqvia.com/institute/reports/medicine-use-and-spending-in-the-us-review-of-2017-outlook-to-2022). The study suggested that the volume had increased annually since 1992, peaking in 2011 when a series of regulatory and legislative restrictions combined with tighter prescribing guidelines and greater reimbursement controls kicked in. Opioid volume prescriptions have declined by 4% per year since then. In particular, high doses of more than 90 MMEs per day, which correlate with the greatest risk of dependency and overdose, declined by 16.1% for the same year. But this decline in usage has yet to be reflected in death rates; in 2016, the last year for which reliable data are available, death from overdoses increased by 21%, from 53,600 to 64,000. It became the leading cause of death for men under 50 years old, bringing down their life expectancy from 76.3 to 76.1 years while women's life expectancy remained stable at 81.1 years. The US Food and Drugs Administration (FDA) continued their activities to counteract the addiction crisis, with its commissioner Scott Gottlieb recently issuing a statement announcing various new steps to “aggressively confront the epidemic of addiction, while advancing policies to help make sure that patients with pain have access to appropriate, evidence-based care”. Gottlieb highlighted the FDA's recently revised actions that require opioid drug manufacturers to make training available to prescribers. This includes information on acute and chronic pain management, safe use of opioids or other treatments, along with material on addiction medicine and opioid use disorders. “For the first time, we're requiring training to be offered on non-opioid alternatives for the treatment of pain and extending this educational material to other health care professionals who participate in the treatment and monitoring of pain, such as pharmacists and nurses, in addition to prescribers”, Gottlieb wrote (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm612779.htm). In the USA, opioid abuse has become the worst drug crisis in US history: in 2015, more than 33,000 people died from overdoses, leaving thousands of children in foster care. The underlying message is that opioid prescription should be confined to acute pain and short durations, with only a few exceptions such as treatment of metastatic cancer pain. While this is fuelling interest in new drugs, these will take some time to reach the clinic. Fortunately, there is plenty of scope for optimizing the use of existing therapies, commented Marcel Durieux from the University of Virginia, USA, who focuses on teaching anaesthesiology in developing countries of Africa. “I don't think there are new drug classes close to clinical implementation, but we still have a long way to go in optimally using the existing non-opioids and other techniques such as nerve blocks and physical therapy, as well as defining the best combinations in various settings”, he said. “Both the two main entryways into opioid use, primary care and surgery, could reduce use significantly by decreasing or eliminating opioids, and data are pretty clear that with some exceptions we can achieve similar pain control using other drugs”. Such drugs include non-steroidal anti-inflammatory analgesics such as ibuprofen and aspirin often used for treating patients with chronic disease accompanied by pain and inflammation. There is also paracetamol, which is similar in efficacy to aspirin but with little anti-inflammatory activity. It is less irritating to the stomach and generally preferred to aspirin, particularly in the elderly. Avoiding the addiction side effect However, the medical need for stronger opioids is considerable and so is the effort to develop replacement drugs that match or even exceed opioids' pain-relieving power with more specificity. One approach tries to modify opioid drugs themselves to make them act only at sites of inflammation, based on two key aspects. First, tissue damage and the associated inflammation make the surrounding tissue more acidic. Second, all opioids' action on their receptors varies with pH. A predominantly German team from Free University in Berlin, Germany, used these aspects to design an opioid that is only effective at the reduced pH levels of damaged tissues 1. “Conventional opioid drugs and natural opioids bind to ubiquitous opioid receptors in all tissues, including the brain, gut and peripheral neurons, both at normal and low acidic pH values”, said Christoph Stein, lead author on the study. “Our compound selectively activates pathological, as opposed to physiological, conformations of opioid receptors in injured tissues. Therefore, side effects mediated by normosensitive (off-target) receptors in non-injured tissues, such as the brain and intestinal wall, are precluded. Because deleterious side effects, such as respiratory arrest, are precluded, our compounds could be applied in all cases of pain caused by tissue injury and inflammation, for example postoperative, arthritis, neuropathy and cancer”. In this study and a recent follow-up 2, the authors claim that the new drug exerts pain relief as strong as conventional opioids without the side effects. … the medical need for stronger opioids is considerable and so is the effort to develop replacement drugs that match or even exceed opioids' pain-relieving power… The work is a significant step forward for treating pain associated with inflammation, commented Gavril Pasternak, Laboratory Head of Molecular Pharmacology and Chemistry Program at the Memorial Sloan Kettering Cancer Centre in the USA. “By modulating potency with pH, it will have a greater efficacy in areas of inflammation”, he said. “This is an extremely important concept since it implies that avoiding the CNS (Central Nervous System), which also would avoid many centrally mediated side effects and addiction, can be utilized to treat pain”. Pasternak cautioned though that this approach would be unlikely to work so well against pain not caused by inflammation, given that not all nociceptive inputs to the central or peripheral nervous system are associated with inflammation. “Similarly, it is not clear whether peripherally acting drugs will be sufficient for very severe pain”, Pasternak added. “Both of these questions will require clinical trials. However, I consider this a truly innovative approach that is deserving of moving into the clinic. While it may not address all types of pains and may not supplant all opioid use, it has great potential for providing a novel and safer approach towards pain management”. Pasternak's own laboratory has taken a different approach to reduce the risk of respiratory arrest and addiction by focusing on just one opioid receptor geared most strongly towards pain relief or analgesia. There are four known genes whose protein products bind endogenous opioids, the mu receptor known as Oprm1, kappa receptor (Oprk1), delta receptor (Oprd1) and orphanin receptor (Oprl1). “We identified a protein generated by the mu opioid receptor gene, Oprm1, that is unrelated to morphine actions”, Pasternak explained. “However, we have identified a series of compounds that can produce analgesia through this site, but lack respiratory depression and reward behaviour. Furthermore, these drugs show no physical dependence with chronic dosing and are not cross-tolerant to morphine 3. […] Since then, we have made several hundred analogues and are now planning on taking one into the clinic”. New targets for treating chronic pain There is also interest in developing drugs that act on different targets because opioids, even without their normal side effects, are not appropriate or efficient in all cases of chronic pain. This includes many cases of neuropathy associated with nerve damage, where opioids often work no better than placebo. One approach is to target synaptic plasticity, which is part of the response to nerve damage and transmission of pain signals, but it was not clear which sites or receptors could be targeted. Then, almost by serendipity, a research team at Thomas Jefferson University in Philadelphia, PA, USA, discovered a potential drug candidate by analysing synaptic plasticity without initial interest in pain at all. They found that one particular receptor involved in the regulation of synaptic plasticity, the N-Methyl-D-aspartic acid receptor (NMDAR), is involved in pathological pain associated with neuropathy as well as tension headaches 4. “The NMDAR is a critical regulator of synaptic plasticity”, explained Matthew Dalva, Director of the Jefferson Synaptic Biology Centre at Thomas Jefferson University and lead author. “The NMDAR is a glutamate receptor that functions at excitatory synapses to flux calcium and this regulates activity-dependent plasticity. The EphB protein is a receptor tyrosine kinase […] that binds to the NMDAR. This binding not only helps to keep the NMDAR localized at synapses, but also can modulate NMDAR function”. Dalva added that diseases linked to this interaction appear to arise either through over-activation of maladaptive plasticity or through the loss of NMDAR from synaptic sites owing to disruption of the interaction between EphB and NMDAR. “We think that the interaction is important in pain because we can induce it by transducing spinal cord neurons with constitutively interacting EphB proteins”, he explained. “In mice this results in long lasting allodynia (hypersensitivity to pain stimuli). Remarkably even after these mice have been in this state for 2 months, if we give the animals a compound that blocks the interaction, it blocks the allodynia”. As this interaction is mediated by extracellular phosphorylation, the phosphorylation process itself is also a potential target for drug development. “We think this is a very promising area and are interested in following up on it”, Dalva commented. “An important step will be to determine how the phosphorylation occurs. This is mediated by a kinase and while we don't yet know what this kinase is, one good thing is that there are already many drugs and tools that exist which can target kinases. So once we find this kinase we might be able to make rapid progress”. Non-drug therapies There is no universal panacea for all categories of pain. Migraine in particular often does not respond to traditional drugs including opioids. A recent study has shown some efficacy for a surprising therapy against migraine based on green light 5. The researchers bathed rats under LED light at various wavelengths in the visible spectrum for 8 h a day and compared their tolerance to neuropathic pain. Rats exposed to 525 nm, corresponding to green light, exhibited significant long-lasting antinociception. To investigate the mechanism further, rats were fitted with opaque contact lenses and exposed to green light or fitted with green contact lenses and exposed to room light. In the former case, antinociception was prevented, while in the latter, antinociception was exhibited, indicating that the visual system plays a role in pain relief. There is no universal panacea for all categories of pain. According to Mohab Ibrahim of the Comprehensive Pain Management Clinic at the University of Arizona, USA, and lead author on the study, the study was motivated by anecdotal observations. “My brother, Wael Ibrahim, gets occasional headaches and noticed that they improve when he is in his garden. I also noticed that my headaches improve when I sit under trees and I thought to myself it may be related either to some chemical released into the air by trees or the colour green”, he explained. “I finally decided on testing the theory of the colour green on rats, and it worked”. Ibrahim is now identifying the underlying molecular mechanisms, and he is convinced that visual input plays a role at least in some instances of migraine. “We are currently running clinical trials with the green light for people with fibromyalgia or migraine”, he said. “The initial findings are promising. We are also in the process of getting approval to see the effect of green light on surgical incisional pain”. Another slightly unexpected avenue for pain research concerns the placebo effect: a recent study identified aspects of brain physiology correlated with the placebo response in patients suffering from arthritic pain 6. The study's objective was to examine whether placebo response could be predicted for patients suffering from chronic osteoarthritis. The authors showed that placebo pill ingestion resulted in stronger analgesia in some cases than no treatment and could be predicted from resting state blood-oxygen-level-dependent (BOLD) fMRI. The study concluded it was possible to determine a correction for the placebo effect and that the active drug tends to enhance the predicted placebo response in some patients, while actually interfering with it in others. It also raised a number of questions that merit further investigation, according to lead author Apkar Apkarian from Northwestern University in Chicago, USA. One aspect regards which drugs are enhanced by the placebo effect and which are blocked, which is subject of a study concluding soon. This in turn raises the fundamental question of which molecular mechanisms underlie the placebo effect, given that the data so far indicate that at least half of all people are susceptible to it significantly while the rest are not much. One practical immediate benefit could be using fMRI measurements to eliminate placebo responses from clinical trials and thereby reduce the number of people who would need to be recruited to obtain statistically significant results. “The other aspect that is more interesting is that we want to use placebo as treatment, because in these patients the response is as big as any drug on the market in pain relief”, Apkarian commented. He speculated that similar results could be expected for other conditions mediated by neural pathways, notably anxiety and depression. “We have just got big funding from the NIH (National Institutes of Health) to start studying chronic pain relief in patients who are opioid users and see how much of it is placebo”, Apkarian added. “That will take five years to do”. Relieve for intense pain Some of the most intense pain is associated with terminal metastatic cancer, especially when cancer cells have invaded bone. As opioids have mixed results in these cases, research has focused on elucidating the pathways and mechanisms involved in these specific cases. One recent study on cancer-induced bone pain (CIBP) noted that preclinical models had demonstrated the role of the bone-marrow microenvironment in mediating pain caused by invasive cancer cells. In particular, mast cells, white blood cells that release inflammatory mediators such as histamine and heparin, instigate transmission of pain 7. Some of the most intense pain is associated with terminal metastatic cancer, especially when cancer cells have invaded bone. The study also highlighted the role of the protease-activated receptor 2 (PAR-2) for relief of CIBP. PAR-2 is one of four known protease-activated receptors that are involved in various aspects of tumour development and associated pain signalling; PAR-1, for example, the first of these four proteins to be discovered, is a promising target for therapy against cancers themselves. PAR-2 modulates inflammatory responses and levels of various neuropeptides such as calcitonin gene-related peptide (CGRP). This is relevant for CIBP because sensory nerve sprouting from CGRP-expressing neurons is associated with skeletal pain and levels of plasma CGRP correlate directly with pain intensity. PAR-2 antagonists that dampen down this expression combine well with morphine and crucially allow significantly lower doses of the latter for a given level of analgesia. PAR-2 in general is likely to receive increasing focus as evidence of its role in tumour development and cancer pain continues to accumulate. Another recent study, for example, showed that PAR-2 signalling contributes to pancreatic cancer pain, which is often particularly severe 8. Opioids will remain the most important and most efficient drugs to treat severe pain for a while, but the opioid crisis in the USA along with the need to find new therapies against forms of pain that are hitherto untreatable has revived research on chronic pain relief as a whole. Many of these activities have identified novel drug candidates and targets, as well as continuing efforts to optimize treatments involving other existing proven therapies.