In research published in the journal Neuron, scientists report the discovery of two molecules that have been shown to be involved in maintaining chronic pain in mice. It seems that these two molecules could be involved with the event in which uninjured parts of the body are more sensitive to pain as a result of injury to a nearby area.
Xinzhong Dong (Johns Hopkins University School of Medicine, MD, USA) explains, “With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain. We found that persistent pain does not always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it.”
Investigators looked at a specific set of nerves in the faces of the mice, collectively known as the trigeminal nerve. This nerve is composed of a very large number of pain-sensing nerves, and has branches of nerves projecting from it, known as V1, V2 and V3. Researchers found that pinching the V2 branch of the trigeminal nerve for an extended period of time leads to both the V2 and the V3 areas being “extra sensitive to additional pain.” This spreading of pain to areas that are uninjured is actually not unusual in chronic pain patients, but it can also be seen in those experiencing acute pain.
To investigate further, researchers studied pain-sensing nerves located in the skin of mouse ears. The scientists were able to examine the responses of two unrelated nerve groups that were close together, owing to the fact that the smaller branches of the V3 branch extend up to the skin of the lower ear, while a different set of nerves is found in the skin of the upper ear. A gene was inserted into the mice DNA so that nerve responses could be monitored when activated by painful stimuli the nerves glowed green.
Researches bathed skin patches in the active ingredient of hot peppers, namely, capsaicin. The pain-sensing nerves lit up in both areas of the ear with the V3 nerves in the lower ear being much brighter than the nerves in the upper ear. Scientists thought this could be down to the fact that by pinching the V2 nerve branch, that was connected to, but separate from, the V3 branch, the V3 nerves had been sensitized to over-react to the same level of stimulus.
After adding capsaicin to other areas, researchers found that a larger number of nerve branches originating from a pinched V2 nerve lit up compared with nerves coming from an uninjured nerve, leading them to conclude that nerves that do not usually respond to pain could potentially modify themselves during a long period of injury and, thereby, add to the amount of pain signals reaching the brain. During the study it was also discovered that TRPV1, a protein with a role in the activation of pain-sensing nerve cells, was hyperactive in injured V2 nerve branches, uninjured V3 nerve branches and in certain branches that extend from the trigeminal nerve into the spinal cord.
In analyzing the role of serotonin in TRPV1 activation, Dong explains the findings, “Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some nonpain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain.”
Sources: Kim YS, Chu Y, Han L et al. Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron doi:10.1016/j.neuron.2013.12.011 (2014) (Epub ahead of print); Johns Hopkins Medicine: Brain uses serotonin to perpetuate chronic pain signals in local nerves: www.hopkinsmedicine.org/news/media/releases/brain_uses_serotonin_to_perpetuate_chronic_pain_signals_in_local_nerves
A technology that has been used for over 25 years in hospitals and other medical centers is now available for home use. The US FDA-approved treatment known as Painmaster® is a ‘noninvasive patch‘ using Micro Current Therapy, allowing a “safe, effective and longer-term approach” for the relief of pain.
Micro-currents use low-level electrical cell stimulation in order to penetrate at a cellular level. This aids in the healing of inflamed cells from the inside, by promoting oxygenation, absorption of nutrients, elimination of waste products and enhanced protein synthesis.
Two reusable and discreet patches are positioned on either side of the painful area. An undetectable pulsating current is delivered via a micro-current controller to these patches. This then stimulates the injured tissue and both soothes inflammation and relieves pain at the same time.
The current emitted by Painmaster is carefully tuned to “mimic the body‘s own electrical exchange, detect any abnormal cell activity and flow through the affected tissue” between the two patches. Upon tissue injury, normal electric current flow is blocked by cells, and Painmaster acts to improve the circulation through the injured area and, thereby, offer quick pain relief by allowing the blood to return to normal flow.
Asher Nathan, founder of RNV Europe and UK distributor of Painmaster, states, “We are thrilled to be launching Painmaster to consumers in the UK. As a company, we are excited to distribute a product that we believe will revolutionize the way individuals manage and treat common pains … Painmaster is cost effective, easy to use and completely drug free. Because, unlike other products, there is no physical sensation, it is a truly accessible product; helping to overcome the growing issue if consumers‘ reliance upon over-the-counter and prescription pain relief.”
According to the press release, Painmaster can be used to treat many different injuries and conditions, including migraines, sciatica, upper back pain and sports-related injuries, among others. One single micro-current therapy controller has up to 300 h of reusable applications and has been costed at 10 pence/h. Application instructions and safety information are available and should be checked carefully before using.
It is stated that Painmaster can be used up to “24 h per day on an ongoing basis to treat varying degrees of aches and pains” depending on where the pain has originated and how severe it is. The best results are usually seen after 3–5 days of continuous use.
Source: Press release: Painmaster® Micro Current Therapy (October 2013).
Scientist are looking at the possibility that abciximab (ReoPro®), currently given to heart patients undergoing angioplasties, could also potentially help children and young adults who experience severe pain as a result of sickle cell disease. William Ferguson (Saint Louis University, MO, USA) explains, “Sickle cell crises, which are acute episodes that can land patients in the hospital, can be excruciatingly painful. The typical vaso-occlusive crisis puts patients in the hospital for 3–5 days on intravenous medications. All we can do is give supportive care, such as pain killers, and wait for the crisis to run its course. Our research will tell us if using a medicine like ReoPro could be a valuable strategy in treating a sickle cell crisis.”
Clots forming in small blood vessels stops the free flow of blood to organs. Patients with sickle cell disease have abnormally shaped red blood cells with sharp edges that can get stuck inside the walls of blood vessels, and can build up to result in blockages. Sickle cell crises means that red blood cells and platelets stick to blood vessel wall lining and, therefore, causes a second blood vessel blockage. Ferguson explains, “It is like there‘s a traffic accident and a quarter mile down the road, you slow down again. Right now, we do not have anything that directly targets that secondary blockage. These traffic pile ups can decrease blood flow and can damage the organ on the other side, such as the spleen, eyes or lungs.” He goes on to say, “As far as I know, no one has targeted the increased stickiness of both platelets and red blood cells in the context of crisis. We hope our research will tell us more about treating the disease and potentially open an avenue of research and drug development.”
Peter Ruminski (Saint Louis University‘s Center for World Health and Medicine, MO, USA) explains that ReoPro targets both of the proteins that affect the stickiness of platelets, as well as the flow of red blood cells through the blood vessel walls. He states that, “sickle cell disease is a neglected disease that dramatically affects members of the St Louis community who are African–American. It is devastating for those who have it in terms of diminished quality if life and shortened lifespan.” He hopes that this research will aid in discovering whether medications that properties similar to ReoPro could have an effect against sickle cell disease.
So far, abciximab has been approved by the FDA to prevent clotting during angioplasty procedures. It has not yet been investigated as a treatment for sickle cell disease and Janssen Biotech (PA, USA) is donating the medication and providing funding for the study. The double-blind, randomized study will recruit 100 patients aged between 5 and 25 years. Half of the patients will receive the study drug and half will receive placebo, within 16 h of being hospitalised for a sickle cell pain crisis. Standard of care, including pain medication, will be given to all patients while in hospital and when they are released.
Sickle cell disease can impact a persons quality of life. If an individual experiences multiple pain crises and consequently has to be admitted to the hospital many times a year, “it is hard to go to school or keep a job,” as Ferguson explains. He also states that many people have moderate or minor crises in between hospitalizations and take narcotics to relieve the pain. That can compromise a person‘s ability to function as well.”
The study will document how long patients remain in hospital. Once pain can be controlled using oral medications, study participants will be discharged from hospital, given no other medical problems. The routine follow-up visit with the patients‘ hematologist 1 week to 10 days after discharge will occur as usual.
Source: Saint Louis University: www.slu.edu/rel-news-sickle-cell-trial-127
Research published in the Journal of Neuroscience has discovered a channel found in certain pain-detecting neurons that appears to limit spontaneous pain by effectively acting as a brake. It is hoped that this new research could contribute to novel pain relief therapies.
Spontaneous pain can occur constantly, with patients experiencing slow burning pain, or intermittently, where the experience is one of sharp shooting pain, with no clear cause or trigger. Constant pain, in particular, can be very debilitating, and can be difficult to treat successfully, since the mechanisms responsible for this form of spontaneous pain is not very well understood.
Peripherally occurring spontaneous pain can be linked to different disease types, such as inflammation or damage to tissues or organs. Nerve damage or neuropathic pain can include postoperative pain and painful diabetic neuropathy. Past research has demonstrated that continuous activity in C-fiber nociceptors causes spontaneous burning pain, and although it is known that ‘greater activity‘ means ‘greater pain‘, the finer details still need to be uncovered.
Scientists reported that there is a specific ion channel, TREK2, that is “selectively expressed in IB4 binding rat C-nociceptors.” TREK2, a “leak potassium channel,” presents a natural and innate protection against spontaneous burning pain. TREK2-expressing C-nociceptors have a more negative membrane potential in comparison with those C-nociceptors that do not express TREK2.
The potential in neurons became less negative upon removal of TREK2 from around the cell membrane. The membrane potential also became less negative when TREK2 synthesis in the neuron was stopped. When levels of TREK2 synthesis were lowered in the C-fiber nociceptors, the spontaneous burning pain usually associated with inflammation of the skin, increased.
Explaining the conclusions reached in the study, Sally Lawson (University of Bristol, UK), states “It became evident that TREK2 kept the C-fiber nociceptor membrane at a nore negative potential. Despite the difficulties inherent in the study of spontaneous pain, and the lack of any drugs that can selectively block or activate TREK2, we demonstrated that TREK2 in C-fiber nociceptors is important for stabilizing their membrane potential and decreasing the likelihood of firing. It became apparent that TREK2 was thus likely to act as a natural innate protection against pain. Our data supported this, indicating that in chronic pain states, TREK2 is acting as a brake on the level of spontaneous pain.”
It is hoped that this research could contribute to potential relief for patients experiencing spontaneous burning pain, by further investigating the action of TREK2.
Sources: Acosta C, Djouhri L, Watkins R, Berry C, Bromage K, Lawson SN. TREK2 expressed selectively in IB4-Binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. J. Neurosci. 34(4), 1494–1509 (2014); University of Bristol: Researchers identify innate channel that protects against pain: www.bristol.ac.uk/news/2014/january/10088.html
Fibromyalgia syndrome (FMS) is a long-term condition. It causes widespread pain throughout the body and extreme tiredness. Other symptoms include trouble with sleep, stiff muscles, irritable bowel syndrome, headaches and poor concentration. FMS patients can also experience mild-to-severe mental symptoms, such as depression.
Patients with FMS can experience a reduced quality of life, and there is currently no cure; certain symptoms can be reduced by treatments, such as cognitive behavioural therapy, physical therapy and multimodal therapies among others.
Researchers explain that vitamin D supplements administered to patients with low levels of vitamin D, can result in reduced pain, and could be “a cost-effective alternative or adjunct to other treatment.” In the research published in Pain, scientists set out to determine whether vitamin D supplementation would lower chronic pain levels in patients with FMS, who also have low levels of calcifediol.
The prehormone calcifediol is produced in the liver by the cholecalciferol enzyme. Following this, calcifediol is converted to the active form of vitamin D, namely, calcitriol. Authors explain that “low serum levels of calcifediol are especially common in patients with severe pain and fibromyalgia.” It is known that blood calcifediol concentration is a good indication of vitamin D status.
Florian Wepner, lead investigator, (Spine Unit, Center of Excellence for Orthopaedic Pain Management, Vienna, Austria) explains, “Although the role of calcifediol in the perception of chronic pain is a widely discussed subject, we lack clear evidence of the role of vitamin D supplementation in fibromyalgia patients. We therefore set out to determine whether raising the calcifediol levels in these patients would alleviate pain and cause a general improvement in concomitant disorders.”
In this investigation, a total of 30 women with FMS and serum calcifediol levels of <32 ng/ml were randomized either to the treatment group or the control group. The treatment group received oral supplementation with cholecalciferol with the aim of reaching serum calcifediol levels between 32–48 ng/ml for 20 weeks. Placebo medication was administered to the control group. Both groups were re-evaluated after an additional 24 weeks in which no cholecalciferol supplementation was given.
Authors state that a “marked reduction in pain was noted over the treatment period” in the treatment group. Furthermore, they explain that “optimization of calcifediol levels in FMS had a positive effect on the perception of pain.”
While Wepner acknowledges that “FMS is a very extensive symptom complex that cannot be explained by a vitamin D deficiency alone,” he states that, “vitamin D supplementation may be regarded as a relatively safe and economical treatment for FMS patients and an extremely cost-effective alternative or adjunct to expensive pharmacological treatment, as well as physical, behavioral and multimodal therapies.”
This research is still in the early stages however, and authors conclude that more studies, with higher patient numbers will be needed to confirm findings.
Sources: Wepner F, Scheuer R, Schuetz-Wieser B et al. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. Pain 55(2), 261–268 (2014); IASP news release: www.iasp-pain.org/AM/AMTemplate.cfm?Section=Press_Releases1&Template=/CM/ContentDisplay.cfm&ContentFileID=3556
– All stories written by Roshaine Gunawardana
Illustration by Clare Dolan