New Understanding of Chronic Pain
Jan. 23, 2012 — Millions of people worldwide suffer from a type of chronic pain called neuropathic pain, which is triggered by nerve damage. Precisely how this pain persists has been a mystery, and current treatments are largely ineffective. But a team led by scientists from The Scripps Research Institute, using a new approach known as metabolomics, has now discovered a major clue: dimethylsphingosine (DMS), a small-molecule byproduct of cellular membranes in the nervous system. In their new study, the scientists found that DMS is produced at abnormally high levels in the spinal cords of rats with neuropathic pain and appears to cause pain when injected. The findings suggest inhibiting this molecule may be a fruitful target for drug development.
“We think that this is a big step forward in understanding and treating neuropathic pain, and also a solid demonstration of the power of metabolomics,” said Gary J. Patti, a research associate at Scripps Research during the study, and now an assistant professor of genetics, chemistry, and medicine at Washington University in St. Louis. Patti is a lead author of the report on the study, which appeared online in the journal Nature Chemical Biology on January 22, 2012.
Scientists who want to understand what makes diseased cells different from healthy cells have often looked for differences in levels of gene expression or cellular proteins — approaches known respectively as genomics and proteomics. Metabolomics, by contrast, concerns differences in the levels of small-molecule metabolites, such as sugars, vitamins, and amino acids, that serve as the building blocks of basic cellular processes. “These are the molecules that are actually being transformed during cellular activity, and tracking them provides more direct information on what’s happening at a biochemical level,” Patti said.
Metabolomics is increasingly used to find biochemical markers or signatures of diseases. One of the most relied-upon “metabolome” databases, METLIN, was set up at Scripps Research in 2005, and now contains data on thousands of metabolites found in humans and other organisms. However, in this case the research team hoped to do more than find a metabolic marker of neuropathic pain.
“The idea was to apply metabolomic analysis to understand the biochemical basis of the neuropathic pain condition and reveal potential therapeutic targets,” said Gary Siuzdak, a senior investigator in the study, who is professor of chemistry and molecular biology and director of the Scripps Research Center for Metabolomics. “We call this approach ‘therapeutic metabolomics’.”
The scientists began with a standard model of neuropathic pain in lab rats. Patti, Siuzdak, and their colleagues sampled segments of a previously injured tibial leg nerve triggering neuropathic pain, as well as the rats’ blood plasma and tissue from the rats’ spinal cords. The scientists then determined the levels of metabolites in these tissues, and compared them to levels from control animals.
Unexpectedly, the scientists found that nearly all the major abnormalities in metabolite levels were present not in the injured leg nerve fiber, nor in blood plasma, but in tissue from the “dorsal horn” region of the spinal cord which normally receives signals from the tibial nerve and relays them to the brain. “After the nerve is damaged, it degrades and rebuilds itself at the site of the injury, but remodeling also occurs, possibly over a longer period, at the terminus of the nerve where it connects to dorsal horn neurons,” Patti said.
Next, the researchers set up a test to see which of the abnormally altered metabolites in dorsal horn tissue could evoke signs of pain signaling in cultures of rat spinal cord tissue. One metabolite stood out — a small molecule that didn’t appear in any of the metabolome databases. Patti eventually determined that the molecule was DMS, an apparent byproduct of cellular reactions involving sphingomyelin, a major building block for the insulating sheaths of nerve fibers. “This is the first characterization and quantitation of DMS as a naturally occurring compound,” Patti noted. When the scientists injected it into healthy rats, at a dose similar to that found in the nerve-injured rats, it induced pain.
DMS seems to cause pain at least in part by stimulating the release of pro-inflammatory molecules from neuron-supporting cells called astrocytes. Patti, Siuzdak, and their colleagues are now trying to find out more about DMS’s pain-inducing mechanisms — and are testing inhibitors of DMS production that may prove to be effective treatments or preventives of neuropathic pain.
“We’re very excited about this therapeutic metabolomics approach,” said Siuzdak. “In fact, we’re already involved in several other projects in which metabolites are giving us a direct indication of disease biochemistry and potential treatments.”
Oscar Yanes, a postdoctoral fellow in the Siuzdak laboratory, was Patti’s co-lead author of the study, “Metabolomics Implicates Dysregulated Sphingomyelin Metabolism in the Central Nervous System During Neuropathic Pain.” The other contributors were Leah Shriver and Marianne Manchester of the University of California, San Diego (or UC San Diego) Skaggs School of Pharmacy and Pharmaceutical Sciences; Jean-Phillipe Courade, then at Pfizer, now at UCB Pharma in Belgium; and Ralf Tautenhahn of the Siuzdak laboratory.
Funding for the research was provided in part by the U.S. National Institutes of Health and the California Institute of Regenerative Medicine.
The effect of 300 mW, 830 nm laser on chronic neck pain: a double-blind, randomized, placebo-controlled study.
Castle Hill Medical Centre, 269-271 Old Northern Road, Castle Hill, NSW 2154, Australia. firstname.lastname@example.org
A randomized, double-blind, placebo-controlled study of low-level laser therapy (LLLT) in 90 subjects with chronic neck pain was conducted with the aim of determining the efficacy of 300 mW, 830 nm laser in the management of chronic neck pain. Subjects were randomized to receive a course of 14 treatments over 7 weeks with either active or sham laser to tender areas in the neck. The primary outcome measure was change in a 10 cm Visual Analogue Scale (VAS) for pain. Secondary outcome measures included Short-Form 36 Quality-of-Life questionnaire (SF-36), Northwick Park Neck Pain Questionnaire (NPNQ), Neck Pain and Disability Scale (NPAD), the McGill Pain Questionnaire (MPQ) and Self-Assessed Improvement (SAI) in pain measured by VAS. Measurements were taken at baseline, at the end of 7 weeks’ treatment and 12 weeks from baseline. The mean VAS pain scores improved by 2.7 in the treated group and worsened by 0.3 in the control group (difference 3.0, 95% CI 3.8-2.1). Significant improvements were seen in the active group compared to placebo for SF-36-Physical Score (SF36 PCS), NPNQ, NPAD, MPQVAS and SAI. The results of the SF-36 – Mental Score (SF36 MCS) and other MPQ component scores (afferent and sensory) did not differ significantly between the two groups. Low-level laser therapy (LLLT), at the parameters used in this study, was efficacious in providing pain relief for patients with chronic neck pain over a period of 3 months.
- The efficacy of low level laser therapy for chronic neck pain. [Pain. 2006]
- The effect of 300 mW, 830 nm laser on chronic neck pain. [Aust J Physiother. 2006]
16806710 [PubMed – indexed for MEDLINE]
Surgeons Report Two New Approaches to Lessen Postoperative Pain
(Taken from ScienceDaily.com, intended for human medicine audience, however the principles are good and some are interchangeable. Italics mine)
Oct. 8, 2013 — New combinations of postoperative pain treatment decreased both pain and the use of narcotic pain relievers according to two studies presented this week at the 2013 Clinical Congress of the American College of Surgeons. One pain treatment utilized the simple but nonstandard application of ice packs after major abdominal operations in patients, and the other treatment was a prolonged drug delivery method using nanotechnology in animals.
Past research has shown that postoperative pain is often under-treated The standard pain treatment after most major (human) operations is narcotics, also called opioids, such as morphine. However, these medicines have many possible side effects, including sleepiness, constipation, and — when used long term — the risk of drug dependence. (we don’t see this issue in veterinary medicine, not in the same way, so for now don’t worry about your pet becoming an addict!)
“A growing body of scientific evidence shows that narcotics may not be the best way to control pain,” said the principal investigator of the ice pack study, Viraj A. Master, MD, PhD, FACS, associate professor of urology at Emory University School of Medicine, Atlanta. “We now know that it is more effective to use combination treatments that reduce the amount of narcotics needed.”
New use for ice following open abdominal procedures
Multiple studies have found that cryotherapy — application of ice to the surgical wound — is safe and effective at reducing pain after some types of operations, such as orthopedic procedures. However, researchers have not studied the use of cryotherapy in patients undergoing major, “open” (large-incision) abdominal operations, Dr. Master explained.
For the Emory study, Dr. Master and his colleagues compared the effect on postoperative pain of applying soft ice packs to the incision area after open abdominal operations (27 patients), versus no ice application (28 patients).
Patients in the cryotherapy group applied ice packs to the wound at desired intervals for at least 24 hours. They also had the option of taking prescribed opioids, whereas the other group received only opioids for pain relief. Twice a day the patients rated their pain intensity on a line indicating a range from no pain (zero) to severe pain (100).
The results showed that patients who used ice packs reported significantly less pain than those who did not ice their surgical wounds. On average, the cryotherapy group had about 50 percent less pain on the first and third days after the operation compared with the no-ice control group, according to the investigators. In addition, on the first postoperative day, the cryotherapy group used 22.5 percent less opioid pain medication than controls, while some patients who iced reportedly used no narcotics.
According to Dr. Master, surgeons should recommend that their patients who have open abdominal operations intermittently apply ice packs to the surgical wound, removing the ice when it becomes too cold. “An ice pack,” he said, “is safe and inexpensive, gives the patient a sense of empowerment because it is self-care, and doesn’t require high-tech devices.”
Prolonged delivery of lidocaine effective in animals
The pain treatment utilized in the second study used a high-tech device — nanoparticles — to create a controlled-release delivery system for the nonopioid numbing medication lidocaine. Although the effects of lidocaine injections usually are short-lived, nanotechnology allowed researchers at Houston Methodist Research Institute to extend the drug’s delivery time so that pain relief lasted all seven days of the study.
Led by Jeffrey L. Van Eps, MD, a research associate at the institute and general surgery resident at Houston Methodist Hospital, the research team developed an injectable hydrogel containing lidocaine. The gel also held microscopic spheres of a biodegradable polymer called polylactic-co-glycolic acid (PLGA), which the U.S. Food and Drug Administration has approved for drug delivery. This polymer acts as an “envelope” for nanoparticles — molecular-sized structures — of the mineral silica, whose spongelike holes take up the lidocaine gel, Dr. Van Eps explained.
“Nanotechnology with PLGA makes an ideal drug delivery system because we can tailor the nanoparticles to allow prolonged delivery,” Dr. Van Eps said. He said that this method re-duces or avoids side effects.
After first testing their lidocaine delivery system in the laboratory, Dr. Van Eps’ team obtained results in an animal model of postoperative pain. In groups of rats under different experimental conditions, the investigators rated the animals’ pain by measuring their withdrawal response to mechanical force applied around the surgical wound.
Rats that received lidocaine gel through the novel delivery system needed twice the amount of force to elicit a pain response compared with control rats that received no pain medication after the incision, the researchers reported. Using this same technique of measuring the pain response, the investigators reported that the lidocaine gel also was superior to daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) alone.
The best study results were seen with combination therapy using lidocaine gel and daily NSAIDs. This combination therapy reportedly showed equivalent effect to daily opioid narcotic treatment by mechanical-force withdrawal testing and superior results by daily scoring of pain-related adaptive behaviors. This finding is important because it shows that the experimental drug delivery system is not inferior to standard opioid treatment of pain, according to Dr. Van Eps.
Studies in larger animals will take place before the research team can test this therapy in patients, he said. Yet he called the new technology an “exciting potential treatment of post-surgical pain, the largest barrier to successful postoperative care.”
The research team developed and is testing the drug delivery system in the Houston Methodist Research Institute’s Surgical Advanced Technology Lab, which was created to accelerate transition of new products to the clinic.
The above story is based on materials provided by American College of Surgeons, via EurekAlert!, a service of AAAS.