In a collaborative effort between Cambridge University, UK, and the University of Cadiz, Spain, researchers have elucidated a new role for the HCN2 gene in chronic pain regulation. The study opens up the possibility of targeting drugs to block the protein produced by the gene in order to combat chronic pain, a condition which is estimated to affect approximately one in seven people in the UK. The findings appear in the September 2011 issue of the journal Science.
Lead author of the study, Peter McNaughton, head of the Department of Pharmacology at the University of Cambridge, enthused: “Individuals suffering from neuropathic pain often have little or no respite because of the lack of effective medications. Our research lays the groundwork for the development of new drugs to treat chronic pain by blocking HCN2.”
The expression of the HCN2 gene in pain-sensitive nerve endings was already known; however, the gene‘s role in pain regulation has, up until now, been poorly understood. It was initially hypothesized that the HCN2 gene regulated electrical frequency activity in pain-sensitive nerve endings as the related HCN4 gene is closely involved in controlling electrical frequency activity in the heart.
The Biotechnology and Biological Sciences Research Council and EU-funded research involved genetic deletion of HCN2 from pain-sensitive nerves. After deletion, these nerves were then subjected to electrical stimuli in cell culture with the aim of deciphering the changes in properties that the HCN2 removal had caused. The positive results obtained from these initial studies prompted the researchers to study genetically modified mice lacking the HCN2 gene. By measuring how quickly the mice moved away from various types of painful stimuli, they were able to determine that the deletion of the HCN2 gene led to the eradication of neuropathic pain. This deletion, however, was found to have no affect on acute pain.
“Many genes play a critical role in pain sensation, but in most cases interfering with them simply abolishes all pain, or even all sensation. What is exciting about the work on the HCN2 gene is that removing it – or blocking it pharmacologically – eliminates neuropathic pain without affecting normal acute pain. This finding could be very valuable clinically because normal pain sensation is essential for avoiding accidental damage,” explains McNaughton.
Speaking to Pharmacogenomics about how this work could be translated into the field of pharmacogenomics, McNaughton comments: “We currently plan to look for SNPs in a local database and then contact individuals to explore which of these may be associated with abnormal pain phenotypes.”
Source: Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333(6048), 1462–1466 (2011).
A first step towards uncovering a diagnostic tool to measure the presence of pain in a physiological assessment, without the use of self-reporting, has been taken by researchers from the Stanford University School of Medicine, CA, USA. The new device would use patient‘s brain activity to give an assessment of whether someone is in pain.
The study, published in 13 September edition of the online journal PLos One, used 16 subjects, spilt into two randomized groups of eight. The first eight subjects were MRI scanned in a 3.0 Tesla, whole-body scanner, whilst a heat probe was applied to their forearms, causing a self-reported pain score of seven out of ten. The brain patterns both with and without pain were then recorded and interpreted by advanced computer algorithms to create a model of what pain looks like. This process was then repeated with the second group of eight subjects.
The idea was to train a linear support vector machine on the neurological responses of a set of individuals, and then use that computer model to accurately classify pain in a completely new set of individuals. The computer was asked to consider the brain scans of the eight new subjects and determine whether they had thermal pain, when the procedure was repeated and performed admirably, predicting thermal pain correctly 81% of the time.
Chronic pain is a huge issue in medicine and in June the Institute of Medicine released a study reporting that more than 100 million Americans suffer chronic pain, costing an estimated US$600 billion each year in medical expenses and lost work.
“We have a lot of work to do before this will be ready as a clinical tool,” explains Sean Mackey, the lead researcher on the project, “We need to determine if this technology can distinguish chronic pain from a healthy individual. Also, whether it can separate pain from other emotionally salient experiences such as anxiety, depression or fear and also whether or not it can distinguish physical pain from imagined pain or even deception of pain.”
However, the applications of this device are far reaching, with the authors believing that it could be used as a method to detect pain in those that cannot communicate pain. It could also be used as an effective biomarker of pain to track treatment efficacy in research trials and ultimately personalize treatments to improve therapy and it could also be used in the medical–legal field. Mackey had this to say to Expert Review of Neurotherapeutics, “This last category carries the largest ethical worries for me. I do not want this technology to be abused or misused, and the legal field is where there is the largest potential for that to occur. We need to monitor carefully how this is used and make sure it is not hijacked and used for purposes it is not ready for.”
Source: Brown JE, Chatterjee N, Younger J, Mackey S. Towards a physiology-based measure of pain: patterns of human brain activity distinguish painful from nonpainful thermal stimulation. PLoS One 6(9), E24124 (2011).
The US FDA has announced the approval of Janssen Pharmaceuticals oral painkiller tapentadol extended-release tablets (Nucynta® ER). The twice-daily medication serves to control moderate-to-severe chronic pain in adults when a continuous, 24-h opioid analgesic is required for an extended period.
The approval of the extended-release form follows that of the immediate-release version, which was approved by the FDA in 2008, for the treatment of acute pain in adults aged at least 18 years.
The efficacy of the drug was evaluated in a double-blind, randomized, placebo-controlled Phase III investigation. The safety profile of tapentadol extended-release tablets was assessed in over 1100 patients with moderate-to-severe chronic long-term pain over a 12-month period. Results of the study additionally demonstrated tapentadol extended-release tablets to be effective, with a favorable tolerability profile as well as discontinuation rates.
Sunil J Panchal, President of the National Institute of Pain, enthused: “Chronic pain is difficult to manage, and even with the treatments available today, it can be a challenge to balance pain relief with a patient‘s ability to tolerate the medicine. People with chronic pain will continue to need additional options, so an approval like this is welcome news for this community and the people who suffer from this often debilitating condition.”
However, it has been noted that there is a risk of abuse with tapentadol extended release, but drug companies are currently endeavoring to manufacture more abuse-resistant opioids.
Source: Janssen Pharmaceuticals: www.janssenpharmaceuticalsinc.com/assets/nucyntaer_press_release.pdf
Positive proof-of-concept data on NKTR-181 announced by Nektar Therapeutics was recently presented at the American Academy of Pain Management (AAPM) 22nd Annual Meeting.
The oral opioid analgesic candidate is a novel µ-opioid agonist that was engineered using the company‘s small molecule polymer conjugate technology. NKTR-181 is currently in development for chronic pain, specifically to target the “abuse liability” and “serious [CNS] side effects” that can be linked to existing opioid-based therapies.
The researchers state that “the objective of this Phase I clinical study was to determine the safety, tolerability, pharmacokinetic profile and opioid pharmacodynamics of single oral ascending doses of NKTR-181 in healthy human subjects.” The results presented at the AAPM Annual Meeting demonstrate a dose-dependent analgesic response when NKTR-181 was investigated in a model of pain known as the cold pressor test. This model of pain is used in healthy individuals to analyze CNS analgesic activity.
Using data obtained from the study, researchers were able to show that the centrally mediated effects of the study drug were dose-linear and, furthermore, that NKTR-181 demonstrated slow entry to the brain. Due to this slow rate of entry into the brain, it is possible that NKTR-181 can lower the euphoria that results in opioid abuse liability and opioid dependence.
Lynn Webster, Lifetree Clinical Research, Salt Lake City, UT, USA, explains: “The result of this Phase I study for NKTR-181 is very promising for clinicians in pain management. The profile and properties observed with NKTR-181, particularly its extended pharmacokinetic profile and its slow rate of entry into the brain, are interesting because they appear to be a result of the molecule‘s novel structure. Further, the rapid rate of entry of most traditional opioids into the CNS causes euphoria, which can lead to their abuse, and usually cause unwanted CNS side effects. The clinical data for NKTR-181 demonstrate that it enters the CNS slowly, which should make it less attractive for abuse, while at the same time reduce its CNS-related side effects. This, combined with a remarkably consistent analgesic response that has a linear relationship to dose, makes NKTR-181 a tremendously interesting potential new pain therapy.”
The pharmacodynamic data obtained by study investigators in the Phase I and preclinical studies also demonstrates that other serious CNS side effects associated with existing opioid treatments may potentially be reduced by NKTR-181.
Study investigators quote that the Tmax of NKTR-181 is 2–4 h and the average half-life of the compound is approximately 12 h after oral administration. They state that this could support once- or twice-daily dosing.
Robert Medve, Nektar Therapeutics, San Francisco, CA, USA, states: “Our Phase I results for NKTR-181 reinforce our belief that this novel µ-opioid analgesic could play a transformational role in the treatment of pain. NKTR-181 exhibits a wide therapeutic window that is inherent to its molecular structure, without the use of a formulation approach to achieve its clinical profile. As a result, it could provide potent analgesia for chronic pain patients while greatly reducing the abuse liability and dangerous CNS-related side effects of currently available therapies. The exciting data from this first Phase I study support Nektar‘s continued rapid development of NKTR-181.”
The multidose Phase I study is scheduled to be completed in the second half of 2011 and Phase II studies are planned for next year.
Sources: Nektar press releases: http://ir.nektar.com/releasedetail.cfm?ReleaseID=607129; Webster L, Iverson M, Medve R, Odinecs A, Eldon MA. Pharmacokinetics and pharmacodynamics of oral NKTR-181, a novel opioid analgesic: results of a single ascending dose Phase I study. Presented at: American Academy of Pain Management (AAPM) 22nd Annual Clinical Meeting. Las Vegas, USA, 20–23 September 2011.
New data has recently been presented at the 21st Annual Meeting of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) from a study of EMA401, an angiotensin II type 2 (AT2) receptor antagonist, in a diabetes neuropathy model. The announcement of the new data presentation was made by Spinifex Pharmaceuticals, Australia, and the drug is also in the clinical development phase for other neuropathic pain indications.
Tom McCarthy, Spinifex Pharmaceuticals, states: “The discovery that AT2 receptor antagonists offer an innovative approach to the treatment of neuropathic and inflammatory pain was originally made by Professor Maree Smith at The University of Queensland and we have good earlier data on the impact of EMA401 on neuropathic pain in preclinical models. This new study we initiated with Professors Cameron and Cotter not only reinforces our earlier data on the impact of EMA401 on neuropathic pain but also confirms our hypothesis that EMA401 may treat the underlying nerve conduction velocity deficits that are the hallmark of diabetic neuropathy. This expands the range of potential indications for the compound and, importantly, provides a new therapeutic target for what is a particularly devastating form of neuropathy.”
Study results demonstrated that, in an established model of diabetes, EMA401 corrected motor and sensory nerve conduction velocity. Additionally, the drug corrected sciatic nerve nutrition blood flow and lessened sensitivity to both pain and heat.
Researchers were able to demonstrate that EMA401 was effective at a 1 mg/kg/day dose, with no observed CNS side effects. These results were in line with previous studies carried out at the above named dose, and higher doses.
Diabetic neuropathy, a side effect of diabetes, is the damage of nerve fibers caused by high blood sugar levels. According to The National Institute of Diabetes and Digestive and Kidney Diseases (of the NIH), approximately 60–70% of diabetes patients have some form of neuropathy and the risk of nerve damage “rises with age and longer duration of diabetes.” Symptoms can vary from some patients with nerve damage having no symptoms at all, to others experiencing symptoms such as pain, a tingling or burning sensation, numbness, nausea and diarrhea.
Norman Cameron, University of Aberdeen, Scotland, UK, said: “Inhibition of the renin-angiotensin system can reduce the development of diabetic complications including neuropathy but most attention has focused on AT1 receptor-mediated mechanisms. This is the first study of the effect of an AT2 receptor antagonist on nerve function in an appropriate diabetes model. In showing EMA401 corrects aspects of neurovascular dysfunction the data suggest the AT2 receptor is a valuable new potential therapeutic target in diabetic neuropathy.”
Spinifex licensed the technology from the University of Queensland, Australia, and has since carried out a preclinical and early clinical development program. EMA401 has demonstrated “good human safety and pharmacokinetics” in Phase I studies and Phase II clinical trials are upcoming. Spinifex reports that existing therapies for neuropathic pain need to be improved, as side effects experienced with current treatments results in limited doses and furthermore, a “significant proportion” of patients with neuropathic pain do not respond to existing therapies.
Spinifex state that “as a result, EMA401 is being developed as a potential first-in-class oral treatment for neuropathic pain and related symptoms without [CNS] side effects.”
Sources: Spinifex Media Release: www.spinifexpharma.com.au/news.htm; PR Newswire: www.prnewswire.co.uk/cgi/news/release?id=332482; The National Institute of Diabetes and Digestive and Kidney Diseases (of the NIH): http://diabetes.niddk.nih.gov/DM/pubs/neuropathies