Researchers from the University of Calgary have shown that nabilone may help to treat nerve pain caused by diabetes.
Researchers from the University of Calgary‘s Hotchkiss Brain Institute (Alberta, Canada) have shown evidence that appears to support a novel therapeutic for diabetic neuropathy. The drug, nabilone, was part of a study in which 60 diabetic neuropathy sufferer participants enrolled in for 12 weeks. The study was placebo-controlled and with patient results reporting a decrease in pain and improvements in both sleep and anxiety levels when they took the drug rather then the placebo.
Diabetic neuropathy is a condition where damage occurs to the nerves. This results in pain, tingling and burning sensations, and feelings of numbness in sufferers. Approximately half of all patients diagnosed with diabetes suffer from diabetic neuropathy and of these a further half within this group will experience difficulties walking, intense pain and disturbances with sleep.
The lead researcher Cory Toth, from the University of Calgary explains, “This is a good option to help treat nerve pain due to diabetes, with very few side effects.”
The drug taken by the patients enrolled into the study is known by the generic name nabilone and is currently used in Canada for the treatment of nausea suffered by chemotherapy patients. The drug itself is a synthetic cannabinoid mimicking some of the chemical compounds of cannabis.
The study showing the drug‘s effectiveness in those with diabetic neuropathy will provide doctors with more evidence of its therapeutic potential for the condition. Mark Ware (McGill University Health Centre, Quebec, Canada) explains why the study has produced important implications within the healthcare setting, “This study is a further demonstration of the potential medical benefits of cannabinoids in a difficult pain condition. Dr Toth and his team have conducted a solid trial that, although small, validates our clinical experience. This study gives physicians support to consider further options in treating this devastating chronic pain disorder.”
– Written by Priti Nagda
Sources: University of Calgary, Faculty of Medicine: www.medicine.ucalgary.ca/research-pain-study-nabilone; Toth C, Mawani S, Brady S et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 153(10), 2073–2082 (2012).
A study published in Nature appears to have discovered two proteins with pain-relieving properties akin to morphine and with a smaller amount of side effects. The proteins are called mambalgins and were found on a search to find alternative therapeutics to opiate therapies such as morphine. Patients on morphine can build a tolerance to it, meaning that over time higher doses are required to produce the same pain-relieving properties. Morphine also causes undesirable side effects, such as drug dependency, nausea and constipation.
Eric Lingueglia (Molecular and Cellular Pharmacology, Valbonne, France) and research colleagues tested up to 50 various types of animal venom before they were able to identify the proteins derived from the Dendroaspis polylepis, more commonly known as the black mamba. The team found that when mice were injected with the mambalgins, they were able to tolerate the application of hot water on their tails and paws for nearly twice as long as mice that had not been treated with the proteins. Following tissue inflammation, it was also demonstrated that the mambalgins reduced the level of hypersensitivity to pain. It was shown that over the course of 5 days the mice built up a tolerance to both the mambalgins and opiates but the tolerance to the snake proteins was much less pronounced. Importantly, the study showed how the breathing rate of the mice was not slowed; this is a side effect common to opioids that can complicate their use clinically.
As Lingueglia points out, “It‘s important to try to develop new drugs that can have complementary or different types of action.”
Indeed, it seems as though rather than binding to opioid receptors, the snake proteins bind to and have an inhibitory mechanism of action on molecules from the family of acid-sensing ion channels (ASICs). These ion channels are still not fully understood but form pores in neuron membranes and have a suggested role in pain transmission. There appears to be several possible targets for drug development as the study showed that when the mambalgins were injected in the paw, different subtypes of ASICs were inhibited compared to when injected into the spinal cord and brain of the mice.
Lingueglia recognises the long road to eventually being able to bring these potentially viable molecules onto the market as painkillers, and discusses the next step for the study, “This study has been carried out in mice, so the first thing to do is make sure it‘s the same as in humans.” Some preliminary tests appear to show that in vitro, the snake proteins have some capabilities to block human ASICs.
– Written by Priti Nagda
Source: Diochot S, Baron A, Salinas M et al. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 490(7421), 552–555 (2012).
Research into the pain experienced by fibromyalgia sufferers shows that there may be abnormalities in the way that pain stimuli are processed within the brain. This aberrant processing of pain signals may also be the cause of a decreased or lack of responsiveness to opioids. The condition itself, fibromyalgia, causes tenderness and widespread pain, and is a common health complaint. In addition, symptoms such as problems with sleep, chronic fatigue and cognitive problems coexist alongside the disease.
Richard Harris (University of Michigan, MI, USA) the lead investigator of the study comments that “Although we have known for some time that the brain is a key player in the pathology of fibromyalgia, we have yet to understand how pain regulation is disrupted in this condition.” Previous research has shown that patients with the condition have heightened sensitivity to stimuli such as pressure, temperature and touch. Harris has conducted previous research that suggests that fibromyalgia patients produce an increased level of endorphins, which act upon the µ-opioid receptors within the brain to reduce pain levels via natural pathways.
This study, presented at the American College of Rheumatology annual meeting, was carried out to see whether the brain‘s increased response to pain and the modified µ-opioid receptors occurred at the same time in the same group of people who had fibromyalgia and whether the same regions of the brain were involved.
To investigate the team applied a painful stimulus to 18 patients who had the condition. Following application of the painful stimuli, the change in the blood flow within the brains of the patients was measured via MRI. In further experiments, µ-opioid receptor binding availability was assessed. The data was collected both before and after acupuncture and placebo acupuncture were administered to the patients. Acupuncture was carried out as a means to reduce pain sensations. The data was examined to investigate the association between how the brain responded to pain and the binding of the opioid receptors. The results showed a strong negative link; essentially the lesser the binding availability of the receptors, the higher the brain‘s response to pain was. The brain region involved, the right dorsolateral prefrontal cortex, showed a positive correlation in the results as this is a classic pain prevention region. Most importantly, the results deduced were in agreement with the feelings of pain sensations that the patients themselves reported.
This study has shown for the first time the tight relationship between opioid-receptor binding and how the brain responds to pain in those suffering from fibromyalgia. The data also leads to speculation that fibromyalgia may lessen opioid-receptor activity, which leads to an exaggerated sensitivity to pain. These individuals‘ lack of responsiveness to opioid therapeutics may be due to fewer functioning receptors, as Harris points out, “This data may also explain why some chronic pain states show similarities with paradoxical opioid-induced pain sensitivity.”
– Written by Priti Nagda
Source: American College of Rheumatology Newsroom Press Releases: www.rheumatology.org/about/newsroom/2012ASM/2012ASM_05.asp
A study carried out by researchers at the Hopital Henri Mondor (Créteil, France) seems to suggest that anti-TNF drugs do not offer respite to patients suffering from chronic pain as a result of hand osteoarthritis (OA).
OA is due to continual damage occurring to joint cartilage. Changes occur to structures around the joint, which include fluid accumulation, weakness in muscles and tendons, and bony growths. All of these contribute to a limitation in movement, as well as swelling and pain. Pain is experienced by sufferers in many joints, with previous research indicating that patients with this condition were not responsive to traditional therapies used as a course of treatment.
Researchers in the study compared how effective NSAIDs and TNF blockers were in controlling the pain in patients with hand OA. The study, named the DORA, also enrolled patients who had not responded to NSAIDs or painkillers. Before patients were enrolled onto the study they had to meet the American College of Rheumatology criteria for hand OA with significant pain. The criteria to meet was the presence of a minimum of three involved joints identified via x-ray and a minimum of three painful interphalangeal hand joints. The study took place across 16 clinical sites. Eighty five patients participated and were split into two groups. One group consisted of 41 patients and were administered with adalimumab and the second group, with 42 patients, were treated with a placebo. The study was carried out in a double-blind fashion and patients were monitored for 26 weeks. The group that was treated with the drug were given two injections in the the first and second weeks of the study.
The research team set the therapeutic success parameter as being a more than 50% improvement in pain scores after 6 weeks. In addition, other signs of success included a lessening in morning stiffness, fewer swollen and painful joints, and an improvement in patient and practitioner assessments. Use of painkillers by participants was observed, with acetaminophen 3 g daily being allowed up to week 6. The disease progression was checked upon using urine and blood tests. The mean level of pain measured at the start of the study was 65.4 mm on a scale measuring from 0 to 100 mm. However, after 6 weeks of the patients receiving placebo and adalimumab the average difference in mm was only 2.5 mm. By week 6 there was no difference between the two groups. The only difference reported was that in the adalimumab group there was a lessening of the number of swollen joints from week 0 to 26. There were no other changes of significance reported.
Xavier Chevalier, the lead investigator summarized the findings, “Our research found that two injections of anti-TNF failed to improve severe painful hand OA,” and commented on future trials, “New trials are needed to find the right target in painful hand OA because this is a disease where we have no real therapy, which leads to patients developing the feeling that it is a neglected disease.”
The study was presented at the American College of Rheumatology annual meeting 2012, which took place in Washington DC (USA).
– Written by Priti Nagda
Source: American College of Rheumatology News Room Press Releases: www.rheumatology.org/about/newsroom/2012ASM/2012ASM_01.asp
Testing new drugs on human volunteers may prove to be both cost effective and the most accurate way of predicting how well new drugs will work in different pain models.
New analgesics are heavily tested in animal models, where pain is most often measured by watching how the animals respond to painful stimuli. However, human volunteers would have the benefit of being able to report how they feel. This is particularly important when trying to understand how effective analgesic drugs with different mechanisms of action can be on different types of pain such as chronic lower back pain, cancer pain or even acute toothache.
Jörn Lötsch from the Institute of Clinical Pharmacology at Goethe-University (Frankfurt am Main, Germany) and co-author of the study published in British Journal of Pharmacology, said “We thought that if a pain-relieving drug was effective in a particular experimental pain model and also in a specific type of clinical pain, then the experimental model should be predictive for the particular clinical setting.”
The study revealed that human experimental pain models were an even more effective way of predicting pain models than expected. Bruno Georg Oertel, from the Fraunhofer Project Group Translational Medicine and Pharmacology (Frankfurt am Main, Germany), and study co-author, commented “Not using these pain models in drug development seems to be unjustified – in fact they should be used routinely in drug development programs.”
Lötsch explained that although testing on humans would be more effective than further animal models, it would be difficult to predict every clinical setting using this process. “However, by analyzing the way that drugs work in experimental and clinical settings, we identified that different sets of experimental pain models, rather than single models, may be best suited to provide cost-effective yet predictive studies in analgesic drug development.”
Oertel and Lötsch hope that more study in this area will allow researchers to gain valuable insights into how new analgesics work, and will prove to be a cost-effective approach for testing new drugs.
– Written by Sophie Breeze
Sources: Oertel BG, Lötsch J. Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. Br. J. Pharmacol. doi:10.1111/bph.12023 (2012) (Epub ahead of print); British Pharmacological Society press release: www.bps.ac.uk/details/news/3169981/Testing-Pain-Killers-on-Humans-Could-Save-Money-and-Speed-the-Arrival-of-New-Dru.html
Research conducted by scientists at Yale (CT, USA), and published in a recent issue of Nature Communications has revealed some insights into a condition termed erythromelagia (EM) and sometimes referred to as ‘Man on Fire‘ syndrome.
Previous research has shown that the Na(V)1.7 sodium channel plays a part in the regulation of different types of chronic pain. It is known that certain ‘gain-of-function mutations‘ can lead to particular pain syndromes such as inherited EM.
EM is a “rare and frequently devastating disorder” and according to The Erythromelagia Association, the cause of the disorder is unknown in the majority of cases. EM normally affects the skin of either the feet or hands; sometimes affecting both. Individuals with EM suffer from “visible redness, intense heat and burning pain.” Such effects can lead to difficulties in daily tasks including walking and sleeping. The Erythromelagia Association reports on recent research in the USA that discovered that the number of individuals diagnosed with EM each year is 1.3 per 100,000.
Research has found that the activation of Na(V)1.7-V400M mutant channels is normalized by carbamazepine. These mutant channels were from a family with carbamazepine-responsive inherited EM.
In the current study, the researchers from Yale used structural remodelling techniques along with thermodynamic analysis to “predict the pharmacoresponsiveness” of S241T – a mutant channel 159 amino acids away from the V400M channel. Researchers found that this mutation was also sensitive to carbamazepine treatment. This result could mean that chronic pain patients with this mutation could potentially respond to carbamazepine treatment.
Yang Yang (Yale University School of Medicine) is hopeful that this knowledge can be used “to help chronic pain patients in more systematic ways, and not depend on trial and error.” The research could lead to more personalized pain therapy, enabling a care provider to predict which chronic pain patient is likely to respond to treatment. Stephen Waxman (Yale University School of Medicine) states, “This work shows us that the goal of personalized, genetically-guided drug treatment for pain is not unrealistic.”
– Written by Roshaine Gunawardana
Sources: Yang Y, Dib-Hajj SD, Zhang J et al. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(v)1.7 mutant channel. Nat. Commun. doi:10.1038/ncomms2184; Yale News: http://news.yale.edu/2012/11/13/world-chronic-pain-individual-treatment-possible-yale-research-shows; The Erythromelalgia Association: www.erythromelalgia.org/WhatisEM.aspx
Researchers have been able to identify a gene associated with age-related degeneration of the intervertebral discs in the spine for the first time. Degeneration of the discs within the spine are a common cause of lower back pain, which burdens the UK alone with costs of GB£7 billion a year in treatment costs and days taken off as sick leave. The genetic cause of lower back pain associated with lumbar disc degeneration (LDD) has now been linked to the PARK2 gene. Research now needs to focus on how this gene ultimately leads to LDD.
LDD is common with increasing age, whereby discs become dehydrated causing them to lose height and the vertebrate next to the discs developing osteophytes. It is these changes that can either cause or add to lower back pain. As LDD is inherited in 65–80% of cases there is a strong suggestion that genes play a role in this condition.
The study, which was the largest to date, had scientists comparing MRI images of 4600 individuals‘ spines with genome-wide associated data. This mapped all of the genes of the volunteers in the study. The gene PARK2 was shown to be implicated in the condition and could also affect the speed at which the discs deteriorate. From the study results researchers deduced that the gene may potentially be switched in those suffering with LDD. It is not known exactly how this may happen but epigenetic modifications can occur to the gene via environmental factors such as diet and lifestyle.
Frances Williams (King‘s College London, London, UK) commented on why such an association had been difficult to make until now, “We have performed, using data collected from around the world, the biggest genome-wide association analysis of LDD. We know that people whose discs wear out are at increased risk of episodes of lower back pain, but normal human discs are hard to get hold of to study so until now our knowledge of normal human biology has been incomplete.” Williams explains what the next step is in this field of research, “Further work by disc researchers to define the role of this gene will, we hope, shed light on one of the most important causes of lower back pain. It is feasible that if we can build on this finding and improve our knowledge of the condition, we may one day be able to develop new, more effective treatments for back pain caused by this common condition.”
– Written by Priti Nagda
Sources: King‘s College London, News: www.kcl.ac.uk/newsevents/news/newsrecords/2012/09-Sept/new-back-pain-gene-identified-in-largest-genetic-study-of-its-kind.aspx; Williams FM, Bansal AT, van Meurs JB et al. Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Ann. Rheum. Dis. doi:10.1136/annrheumdis-2012-201551 (2012) (Epub ahead of print).