More than 200 years have passed since the discovery of morphine in 1804 (http://hcp.lv/dCk9eP). Although the management of pain has come a long way-incorporting new technologies and featuring more diverse pharmacologic solutions-the price of seeking relief still comes with many of the same consequences, mainly in the form of addiction.
By Diana Pichardo
More than 200 years have passed since the discovery of morphine in 1804 (http://hcp.lv/dCk9eP). Although the management of pain has come a long way—incorporting new technologies and featuring more diverse pharmacologic solutions—the price of seeking relief still comes with many of the same consequences, mainly in the form of addiction. Now, more than ever, with easy access to pain medication and higher prescribing rates due to the recognition of pain as a specific medical subfi eld, the problem of addiction is growing, leaving physicians and biochemical researchers looking for solutions. Within the last decade, they’ve been turning to natural compounds and investigating the phenomena of pain at the cellular level, in an attempt to develop new classes of non-addictive pain medications. But, the road hasn’t been easy.
Anti-nerve growth factor antibodies
In 2008, the industry was abuzz with news of a new development in the understanding of pain sensation involving nerve growth factor (NGF; http://hcp.lv/9iV7t6). Pfizer developed tanezumab, which had been shown to be effective in an initial study of patients suffering from osteoarthritis (OA) of the knee. The drug stood out as a non-addictive biologic agent; tanezumab is a humanized monoclonal antibody for NGF, which plays an essential role in nerve cell growth and maintenance. In the event of an injury, the level of NGF rises in the body and creates pain sensation. The drug was designed to act against NGF to prevent the increase in pain sensation during injury or in certain diseases.
Tanezumab was in phase III clinical trials for osteoarthritis when it was abruptly halted by the FDA in June 2010 due to “reports that patients’ conditions worsened and led to joint replacements” (http://hcp.lv/cb9MNg). The drug was also being tested by Pfizer in separate trials for diabetic peripheral neuropathy and lower back pain. Drug companies Regeneron Pharmaceuticals and Ortho-McNeil-Janssen Pharmaceuticals have their own similar formulations in the works, but information was yet to be released on their progress at writing. Regeneron’s product, REGN-475, had completed phase II testing with results that indicated it had produced signifi cant improvements in patients with knee OA (http://hcp.lv/9gjVZJ), while Ortho-McNeil-Janssen’s product, JNJ-42160443, is being used in a study that is currently recruiting patients with OA (http://hcp.lv/cEbC7M).
Looking for solutions based on the body’s natural mechanisms may be the “next big thing” in research on a new class of biological pain relievers, but the latest developments with tanezumab indicate that much more needs to be uncovered (http://hcp.lv/arvLOZ).
Found deep on the ocean floor among coral reefs are a group of marine creatures known for their intricately decorated shells and their toxic, immobilizing venoms (http://hcp.lv/cmVUbR). For centuries, these creatures have preyed on fish, worms, and
crustaceans, but now their dangerous venoms, known to have a severe sedative effect, are also helping people suffering with pain. Researchers like Bruce Livett, a University of Melbourne biochemist, began studying the analgesic effects of these conotoxins several decades ago (http://hcp.lv/cI9Uit).
Conotoxins work by targeting certain receptors and sensory nerves, but unlike opioids, don’t travel through the central nervous system. Conotoxins consist of neuroactive protein fragments, or conopeptides. Currently, Prialt (ziconotide), a synthetic omega-conotoxin, is available and FDAapproved to treat severe to intractable nerve pain (www.prialt.com). Ziconotide “inhibits presynaptic voltage-gated calcium channels and neurotransmission across nerve synapses” (http://hcp.lv/bY2xKp). The drug works by binding to the N-type calcium channel receptor, located on pain fibers within the spinal cord, and produces an “analgesic effect by inhibiting the firing of sensory fibers entering the dorsal laminar of the spinal grey matter.” Essentially, it prevents sensory fibers from shooting messages of pain to the brain, preventing the sensation.
In a blog post on the introduction of ziconotide to the market, Lawrence M. Kamhi, MD, wrote, “in intrathecal ziconotide we appear to have the first of a new class of neuropeptide pharmaceuticals with potent pain-relieving proper-ties and a relatively
safe profi le free from addictive properties and depression of consciousness and respiration” (http://hcp.lv/bY2xKp). The drug must be administered intrathecally, which may knock off some points in ease of use, but appears to be a viable option for
addiction-free pain medication. Kamhi wrote that he fi rst became familiar with conotoxins through meeting Frank Mari, MD, associate professor, Florida Atlantic University. Mari is an expert in marine biology and biotechnology and has performed
extensive research on conotoxins. Mari’s research mostly focuses on discovering new types of conotoxins and characterizing them, or uncovering their particular sequence, he says. What he fi nds interesting about studying cone snails and conotoxins is not just that each particular animal has its own unique venom, but that the research encompasses marine biology, intricate aspects of neuroscience, and the study of the central nervous system and the brain. “Basically, these conotoxins are molecular tools that can be used from many points of view and they are markers even within the field of studying venom and toxins,” he says, adding that the study of conotoxins has the potential to make a large impact on the fi eld of pain medicine.
“Pain is an interesting fi eld, because there are all kinds of pain.” Ziconitide is an exemplary drug from many points of view, notes Mari, particularly, because it is the first drug of marine origin; it is a peptide that targets calcium channels; and it has to be administered intrathecally.
Whereas the last point may not be ideal for patients, since they would have to have a pump surgically installed, he says the drug has garnered enough interest to warrant a spot on the market. “So, the next challenge is to fi nd a conotoxin or a conotoxin analogue that can be administered orally and there is signifi cant progress towards that,” says Mari. There are a few barriers that stand in the way of producing orally administered conotoxins, however. Most of the targets of conotoxins are in the brain, and “peptides like conotoxins usually do not go across the blood brain barrier very well.” Work is currently being done on producing orally viable conotoxins, he says, which will no doubt be “the next generation of conotoxins in terms of treatment of pain.”
Another conopeptide pain drug is currently in clinical trials in Australia; pharmaceutical company Zenome has developed Xen2174, which belongs to the chi-conopeptides and targets the norepinephrine transporter. In addition to pain treatment, conotoxins are being studied for the treatment of Alzheimer’s disease, multiple sclerosis, addiction, and Parkinson’s disease.
By studying chili peppers and their capsaicins, researchers at the University of Texas Health Science Center at San Antonio were able to discover a family of “endogenous capsaicins” in humans and develop two drugs designed to treat pain manifestation (http://hcp.lv/cGsN8N).
Lead researcher Kenneth M. Hargreaves, PhD, professor and chair, Endodontics, UT Health Science Center at San Antonio, and colleagues discovered these endogenous capsaicins while studying the receptor known as transient potential vanilloid 1 (TRPV1), typically activated in the presence of injury or high heat. Chili peppers contain capsaicins that can cause a painful sensation by activating TRPV1 in humans; natural “endogenous capsaicins” are formed by pain cells in response to high heat or injury, his team discovered.
Hargreaves identifi ed these capsaicin-like substances as oxidized linoleic acid metabolites (OLAMs). “We found that tissue injury, or heating skin or neurons, releases OLAMs that then activate the TRPV1 receptor,” he says. “In a sense, we discovered a family of endogenous capsaicins.” Hargreaves and his team developed two new drugs designed to block the synthesis of OLAMS or the antibodies that activate them. This finding, he says, is “important since it both teaches us about how our bodies respond to injury and infl ammation and reveals potentially novel approaches for treating pain.”
Various studies that have used TRPV1 knockout mice or TRPV1 antagonists have provided “good evidence that this receptor is involved in many diverse types of pain,” he adds. These include inflammation, cancer pain, burn pains, and other chronic pain conditions. “Therefore, drugs that block OLAMs may constitute novel approaches for pain control,” he notes. Unlike opioids, these drugs do not have a chemical addiction factor. Hargreaves and his team also published a paper last fall that demonstrated anti-OLAM antibodies signifi cantly reduce mechanical pain (“allodynia”) in rats using the CFA model of infl ammation. These drugs, however, are not currently on the market.
Although the addictive properties of opioids are well documented, their powerful effect on pain relief cannot be discounted. That’s why researchers around the world have their sights set on developing drugs that target glial cells in an attempt to stop tolerance and dependence at the source and keep the analgesic effect of opioids intact. Among these researchers is Haroon Hameed, MD, of Johns Hopkins Hospital, who recently co-authored the article, “The effect of morphine on glial cells as a potential therapeutic target for pharmacological development of analgesic drugs,” featured in the April issue of Current Pain and Headache Reports (http://hcp.lv/a78vuP).
Glial cells play an important role in providing support and maintaining the healthy function of neurons in the brain. However, opioids, including morphine, tend to over-activate glial cells, which in turn begin to oppose the pain suppression properties of the drugs. Opioids not only connect with the appropriate receptors, but also to glial cell receptors, which then leads to greater tolerance and dependence, affecting the addiction factor. Researchers have been working on methods to prevent opioids from stimulating glial cells in order to deliver pain relief without the side effects of addiction.
Experimental drugs like AV411 work to block morphine’s effects on glial cells. Hameed studied the effects of this drug and others, including, MK-801, AV333, and SLC022, in the article he co-authored. “My research in this area has been inspired by the vast possible utility of these medications for the treatment of subacute and chronic pain,” Hameed says. “Our recent article in Current Headache and Pain Reports is a good place to start understanding the role of glia in mediating many of the unwanted effects of chronic opioid use—such as reward, hyperalgesia, and tolerance—as well as the possible new roles of many glia-modifying medications that might mitigate or possibly even reverse these opioid side effects.”
Hameed says research into the fi eld may allow for a way to “effectively treat patients with low doses of opioids” without the need to adjust for tolerance or without the “serious side effects, such as reward, dependence, and hyperalgesia.” Whereas Hameed says research into glial cells is promising, he feels it will certainly take some time “before these medications are ready to be used by patients at-large.”
The trouble with producing on-addictive drugs The CDC reported that between 1999 and 2006, “the number of poisoning deaths in the United States nearly doubled” (http://hcp.lv/blTr0K), “largely because of overdose deaths involving prescription opioid painkillers.” Yet, the use of opioid analgesics remains high because of their indisputable effectiveness on pain relief. Also, research in the production of non-addictive drugs for moderate to severe pain is complex, according to Hargreaves.
“Progress has actually been fast due to the concerted efforts of many labs; however, the translation of these findings into clinically useful non-addictive drugs has been slow.”
Hargreaves says he believes the major barrier to research is in having a novel mechanism, or target, for development. The ideal target would not engage the central nervous system mechanisms, since that would increase the risk of activating central dopamine systems and produce analgesic tolerance, he says. Hargreaves believes the “OLAM system satisfies at least some of these criteria.”
For Mari, the complex process of addiction is one of the main barriers in developing non-addictive pain drugs. “Opioid receptors are responsible in great part for all of these addiction problems,” he says. “They are good pain killers, but only last very shortly; after a while, some people develop tolerance to morphine, so they no longer get analgesia from it.” The alternatives currently are slim, he says.
“Ziconotide is the fi rst major pain killer approved by the FDA in the past 25 years. So, it’s taken 25 years to come up with something that is better than morphine.” At least it’s better for certain patients, he notes, especially for those who no longer respond to morphine. “Ziconotide does not give you addiction because it works by a totally different mechanism. Basically, it’s by neuronal transmission, and all you’re doing is blocking the transmission at a level that has nothing to do with addiction.”
Additionally, creating solutions targeted at a certain type of receptor, protein, or other biological component, without adversely affecting other biological components, is an issue, Hameed adds.
“There is always a difficulty in producing receptor specific medications that do not also act on identical or like receptors in similar tissues. In the central nervous system, we are especially dealing with a great number of complex functions, including its perceptions and responses to internal and external stimuli in the form of immediate and adaptive responses.” Often times, opioids and other medications can unintentionally produce somatic effects, including dry mouth and constipation, and sensory effects that can alter the perception of pain, he says. “To counteract these unwanted effects, it appears that in the foreseeable future—when using opioids for acute, subacute, and chronic pain relief—we may need to use dual therapy, such as treatment with glia-modifying agents, to maximize their safety and effi cacy.”
Whether the focus is blocking the transmission of pain signals by targeting certain substances and processes, blocking glial cells to maximize the analgesic effect of opioids, or using genomic sequencing to knockout certain players in the manifestation of pain, the research is on its way, and the goals are the same: to offer effective pain relief without the pitfalls of addiction.