Sunday, November 24, 2013

Anticipation of pain can be worse than pain itself - health - 22 November 2013 - New Scientist

"The only thing we have to fear is fear itself," said Franklin D. Roosevelt. He might have been onto something: research suggests that the anticipation of pain is actually worse than the pain itself. In other words, people are happy to endure a bit more pain, if it means they spend less time waiting for it.

Classical theories of decision-making suppose that people bring rewards forward and postpone punishments, because we give far-off events less weight. This is called "temporal discounting". But this theory seems to go out the window when it comes to pain.

One explanation for this is that the anticipation of pain is itself unpleasant, a phenomenon that researchers have appropriately termed "dread".

To investigate how dread varies with time, Giles Story at University College London, and his colleagues, hooked up 33 volunteers to a device that gave them mild electric shocks. The researchers also presented people with a series of choices between more or less mildly painful shocks, sooner or later.

During every "episode" there was a minimum of two shocks, which could rise to a maximum of 14, but before they were given them, people had to make a choice such as nine extra shocks now or six extra shocks five episodes from now. The number of shocks they received each time was determined by these past choices.

No pain, no gain

Although a few people always chose to experience the minimum pain, 70 per cent of the time, on average, participants chose to receive the extra shocks sooner rather than a smaller number later. By varying the number of shocks and when they occurred, the team was able to figure out that the dread of pain increased exponentially as pain approached in time. Similar results occurred in a test using hypothetical dental appointments.

"This study demonstrates that the fear of anticipation is so strong it can reverse the usual pattern of time discounting," says George Loewenstein, a professor of economics and psychology at Carnegie-Mellon University in Pittsburgh, Pennsylvania. "It's probably not an exaggeration to say that as much, or more, of the pains of life come from anticipation and memory than from actual experience."

The study could well have implications for medicine and health policy, because an understanding of how people judge pain is important for presenting them with options about potentially painful treatments.

"You should avoid emphasising waiting times," says Story. "And if you can make something seem unavoidable, people may be more likely to confront it to minimise dread."

Story hopes that this kind of psychological study will aid the development of diagnostic tools. "Looking at these kinds of preferences might help predict whether people will make healthy or unhealthy choices," he says.

Journal reference: PLoS Computational Biology, DOI: 10.1371/journal.pcbi.1003335

Wednesday, November 06, 2013

Pain and Relief Signals Muted in Fibromyalgia - MedPage Today

Patients with fibromyalgia showed less activation in brain responses to pain-related "punishment and reward" anticipatory signaling on functional MRI than healthy controls, a small study showed.

Compared with patients with fibromyalgia, controls had significant increases in signaling in the right ventral tegmental area (VTA) while anticipating pain (P<0.01) and a trend for greater signal activation while actually experiencing pain (P=0.059), according to Marco L. Loggia, PhD, of Harvard Medical School, and colleagues.

Controls also had greater decreases in VTA signaling when anticipating relief from pain (P<0.05), suggesting that patients with fibromyalgia experienced blunting of these anticipatory pain and relief responses, the researchers reported online in Arthritis & Rheumatism.

It's becoming widely recognized that fibromyalgia is characterized by heightened sensitivity to pain, most likely because of abnormal central processing of painful stimuli.

However, little is known about how anticipation of pain and relief may contribute to the affective and cognitive aspects of the experience of pain.

"Expectancy and pain-relevant anxiety, in particular, have been shown to shape subsequent perceptual states. Relief from pain, on the other hand, is a positive hedonic experience intrinsically linked to pain," Loggia and colleagues explained.

To explore whether these components of pain might be altered in chronic pain states such as fibromyalgia, the researchers performed functional MRI studies in 31 patients with fibromyalgia and 14 controls, primarily focusing on the VTA and the nucleus accumbens.

These are areas of the brain involved in reward and punishment processing that also have been linked with fibromyalgia on positron emission tomography.

The pain stimulus for each participant was provided by an inflated pressure cuff on the lower leg, which initially was inflated to 60 mm Hg. Pressure then was increased until participants reported a pain rating of at least 50 out of 100.

Color-coded visual cues were used to induce anticipation of pain and relief. Before inflation of the cuff, a black cross was projected into the participant's visual field, changing to green to signal that the painful stimulus was about to begin. With cuff inflation, the cross then became black again.

Then, shortly before the cuff was deflated, the cross turned blue, signaling anticipation of relief from pain.

At each point, participants pushed buttons to report the intensity of pain and the associated unpleasantness. Simultaneous brain responses to anticipation, pain, and anticipation of relief were assessed on MRI.

Patients' mean age was 44, most were women, and symptoms had been present for 12.5 years. Baseline clinical pain intensity was rated as 34.3 on a 100-point scale, and pain unpleasantness was rated at 32.3.

The initial MRI scan assessed the entire brain, and found increased activation in multiple areas with the pain anticipation cue in both patients and controls, including the basal ganglia, thalamus, and the cerebellum. No differences were seen between patients and controls in anticipation of pain or relief in these whole-brain scans, however.

In addition, there were no significant differences for the nucleus accumbens. Only in the VTA region were there significant between-group differences, as seen using blood oxygen level-dependent functional MRI.

Also, responses to anticipation of pain among controls showed a negative correlation with responses in the VTA to anticipation of relief (r = 0.76, P=0.002). That correlation was not seen in patients with fibromyalgia (r = -0.12, P=0.52).

The VTA is intensely dopaminergic, and, while it has conventionally been thought to participate in reward signaling, it also appears to be involved in punishment and aversion signaling.

"Our observation that a region rich in dopaminergic neurons such as the VTA exhibits less reactivity ... is compatible with the results of other studies showing altered dopaminergic neurotransmission in fibromyalgia patients," the researchers wrote.

The finding that patients with fibromyalgia had diminished responses to painful stimuli in so-called reward regions of the brain may help explain the fact that they also don't typically respond to opioid-induced analgesia, the researchers noted.

Among the factors that may further explain the differences in brain activity in patients with fibromyalgia was a reduced level of activity in the midbrain periaqueductal gray, which helps regulate behavioral responses to pain. This suggested that patients also may have a diminished ability to upregulate brain-centered coping mechanisms.

A limitation of the study was a lack of correlating behavioral data.

Study Finds Blind People Hypersensitive to Pain - National Pain Report - National Pain Report

People who are born blind experience pain differently than sighted individuals and are hypersensitive to pain caused by hot or cold stimulation, according to a small study by researchers in Europe.

The results indicate that congenitally blind people are more attentive and more sensitive to external threats — suggesting their brains are "rewired" by their disability. The study is being published in the journal PAIN.

"We have shown that the absence of vision from birth induces a hypersensitivity to painful stimuli, lending new support to a model of sensory integration of vision and pain processing," says lead investigator Ron Kupers, Director of the BRAINlab, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences at the University of Copenhagen, Denmark.

The findings are important because a key biological function of acute pain is to prevent bodily injury. Vision plays a critical role, as it allows a person to immediately detect and avoid potentially hazardous situations.

Previous studies conducted in sighted individuals had already demonstrated the link between vision and pain perception. The research team hypothesized that the absence of visual cues may lead to heightened vigilance for painful stimuli.

Investigators recruited 11 congenitally blind and 15 sighted participants from Italy and a second group of 18 congenitally blind and 18 sighted participants from Denmark.

Researchers used thermal probes on the forearms of each participant to measure their thresholds for pain. The congenitally blind participants were allowed to touch the equipment beforehand and received verbal descriptions to reduce any anxiety. Sighted subjects were blindfolded during the actual testing.

Participants pushed a button whenever the thermal probe was hot or cold enough to cause pain. They also completed a questionnaire on their vigilance and awareness of pain.

The study team found that compared with sighted subjects, congenitally blind people had lower thresholds for pain caused by heat, rated heat pain as more painful, and had increased sensitivity to cold pain.

"The novel finding of pain hypersensitivity in blindness has several important implications for both basic and clinical science," said Flavia Mancini, PhD, Institute of Cognitive Neuroscience, University College in London.

"This study is noteworthy for research on multisensory interactions and plasticity, because it shows a strong link between vision and pain. The next step is to understand the nature of the interaction between visual loss and pain sensitivity. Which aspect of pain processing is involved in the interplay with vision, and what is its neural basis? The hope is that this work will open the door to pain investigations into the world of sensory loss, left unexplained for too long."

Interesting cultural differences also emerged from the study. People in Italy were found to be more emotionally expressive and responsive to pain than people in Denmark.

Tuesday, November 05, 2013

Welcome | Cochrane Pain, Palliative and Supportive Care Group


The PaPaS Review Group was registered with the Collaboration on the 28th January 1998. Exploratory meetings for the PaPaS Review Group were held on the 3rd of June 1996 (Oxford) and the 22nd of June 1997 (Boston). Mr Phil Wiffen was involved in the set-up of the PaPaS Review Group and held the post as Co-ordinating Editor until March 2008 when he stepped down to become an Editor for PaPaS. Chris Eccleston, one of our long standing Editors, then took up the post as Co-ordinating Editor in April 2008.


We are interested in studies of interventions for

• Acute pain arising accidentally or through deliberate injury
• Chronic pain (lasting 3 months or longer)
• Headache and migraine
• Palliative care for those with life-limiting disease or illness 

Welcome | Cochrane Back Review Group

The Cochrane Back Review Group (CBRG) is one of 53 international Review Groups. The CBRG coordinates the publication of literature reviews of diagnosis, primary and secondary prevention and treatment of neck and back pain and other spinal disorders, excluding inflammatory diseases and fractures.

The CBRG is hosted by the Institute for Work & Health (IWH) in Toronto, Canada. The Institute for Work & Health is an independent, not-for-profit organization. Its mission is to conduct and share research that protects and improves the health of working people and is valued by policy-makers, workers and workplaces, clinicians, and health & safety professionals.

The Cochrane Collaboration, established in 1993, is an international network of more than 28,000 dedicated people from over 100 countries. The Collaboration works together to help health care providers, policy makers, patients and their advocates and caregivers, make well-informed decisions about health care, based on the best available research evidence, by preparing, updating and promoting the accessibility of Cochrane Reviews.

Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognized as the highest standard in evidence-based health care. They investigate the effects of interventions for prevention, treatment and rehabilitation. They also assess the accuracy of a diagnostic test for a given condition in a specific patient group and setting. Cochrane Reviews are published online in The Cochrane Library.

Thursday, October 31, 2013

Pain Medicine News - American Pain Society President: Budget Cuts Not Only Reason for Underfunded Pain Research

New Orleans—Pain research in the United States is severely underfunded, despite the fact that chronic pain costs the economy more than $600 billion annually in medical expenses and lost productivity. Although the 5% cut to the National Institutes of Health (NIH) budget across the board is partly to blame, it is not the only contributing factor, according to Roger B. Fillingim, PhD, professor, College of Dentistry, University of Florida, Gainesville, and director of the university's Pain Research and Intervention Center of Excellence. Dr. Fillingim, who also is president of the American Pain Society (APS), spoke with Pain Medicine News at the annual scientific meeting of the APS, and provided insight and recommendations on how to address this health issue that affects an estimated one in three Americans. Here is an abridged version of the discussion.

PMN: Apart from the cut in federal funding, what are other reasons for the lack of financial support for pain research?

Roger B. Fillingim, PhD
Professor, College of Dentistry
University of Florida
Gainesville, Florida

Dr. Fillingim: Part of it is, I think, a historical view that pain is simply a symptom of another thing; fix that other thing and the pain will go away. So [the view is] we don't have to fund pain research; [instead] we can fund cancer research and if we cure the cancer, any pain that may have been associated with it will be taken care of. Or the same thing for arthritis or whatever other condition pain may be associated with. It's relatively new that we more clearly view pain as a result of a pathophysiologic process of its own. For example, some of the recent studies in humans showing certain areas of the brain shrink as a consequence of chronic pain bring pain into the realm of a neurologic disease all its own. And there are many examples of pain conditions—even disease-associated pain conditions—that show that when you manage the disease process, the pain still persists. So pain can become a somewhat independent phenomenon, especially when it has persisted for a long period of time, and that's a relatively new appreciation. It's also relatively new that we fully understand how big a problem pain is: It has become a more substantial problem because we're aging, and a lot of conditions associated with aging are associated with pain. It's also because of the increasingly sedentary nature of society. But the economic analysis that identified that pain costs $635 billion a year was only published last year in the Journal of Pain.That fed into the Institute of Medicine's report that came out about a year earlier, which put a spotlight on the magnitude of pain many of us in the pain field had recognized before, but outside the pain field had been under-recognized.

PMN: How big an issue is pain?

Dr. Fillingim: Pain is responsible for roughly 10% of health care costs, and it is the No. 1 reason people seek health care. So we think, even with funding of 1% or 1.3% of the NIH budget, pain is woefully underfunded. Pain is an incredibly complex health problem because it has many shapes and forms, so to understand pain is going to take a lot of effort. Some decades ago, the government declared a "War on Cancer" and I think—although cancer hasn't been cured—there have been substantial advances in cancer survivorship. It would be wonderful if we declared a "War on Pain" and decided we're going to devote appropriate resources to understanding its pathophysiology; to developing new treatments; to making sure currently available treatments are disseminated to the patients who need them; and to better match patients to treatments—the whole personalized medicine approach. And I think, as a field, we are at a very exciting crossroads: We benefit from discoveries from other fields like the Human Genome Project. Our basic science community has made tremendous advances in understanding the neurobiology of pain mechanisms, and I think we're in a great position now to take all of those foundational areas of knowledge and those methodologies and translate them into reducing human pain-related suffering. But that takes people, that takes resources and that takes technology, and we're going to have to be adequately resourced to do that.

PMN: In an ideal world, if appropriate funding were available for pain research, how much money would suffice?

Dr. Fillingim: Maybe an ideal to strive for is a level of funding that's proportionate to the magnitude of the health condition. So how about 10% of the NIH budget? I just can't imagine that ever happening, but what I'd like to see is for our government to acknowledge pain as the major public health problem it is, and to make a clear commitment with resources behind it. I really don't want to take money from other health conditions. We want a bigger piece of the pie, but we need to grow the whole pie, and so we definitely need more funding across the board for biomedical research. I'd rather have new money infused into the pain research enterprise in order to make some of these targeted advances that I think we're poised to make. We're in a situation where we can't rely exclusively on the federal government to help us solve all our problems. We need to identify other sources of funding, like public–private partnerships. One concern is that industry is leaving the pain space. They find it challenging to develop pain drugs that ultimately make it to market or make business sense for them.

PMN: What, in your experience, is the general public's perception of the issue of pain?

Dr. Fillingim: A recent survey by Research America clearly reveals to us that the public doesn't acknowledge chronic pain as the major health problem it is.2 In the survey, more people thought the misuse of prescription drugs was a bigger issue than actually treating chronic pain: They were looking at it from a standpoint of "well, let's do something about these pain drugs and the abuse of them" as opposed to thinking about pain as a problem. That was a wake-up call for us when we saw that. But if we had better pain management, if more interdisciplinary pain management was available to patients who were suffering, I'm confident we would greatly reduce the need for prescription opioids and the frequency of prescription opioid adverse outcomes, whether that is abuse or other medical adverse effects. If we could do a much better job of managing pain with a multidisciplinary approach, which has been shown time and again to be the most effective, then we could take care of some of these unintended consequences as well.

—Maureen Sullivan


  1. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain.2012;13:715-724.
  2. Relieving Pain in America: A blueprint for transforming prevention, care, education, and research. Institute of Medicine; June 29, 2011.​Reports/​2011/​Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx

Wednesday, October 30, 2013

The Pain And Interoception Imaging Network (PAIN)

The Pain And Interoception Imaging Network (PAIN) seeks to improve understanding of the brain's role in chronic disease, with a particular emphasis on chronic pain states.  PAIN provides an infrastructure for storage of functional and structural brain imaging data and associated behavioral metadata from multiple scanning sites and provides infrastructure for automated analysis of the resulting comprehensive data sets. Through these efforts, PAIN facilitates new discoveries in brain endophenotypes and biomarkers of chronic pain states.

UCLA To Host Global Chronic Pain Database - HDM Latest News Article

A new database at the University of California, Los Angeles, featuring hundreds of brain scans and other key clinical information will help researchers tease out similarities and differences between migraine, irritable bowel syndrome, fibromyalgia, rheumatoid arthritis, and many other chronic-pain conditions, UCLA Health officials say.

The Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress at UCLA will serve as the main hub for this new Pain and Interoception Imaging Network (PAIN); UCLA Health says it is the first-ever standardized database for brain imaging associated with chronic pain. So far, 14 institutions in North America and Europe are participating.

Building upon their experiences creating a similar but smaller network to study pelvic pain, the UCLA team is now developing this larger chronic-pain network with the help of a $300,000 grant from the National Institutes of Health.

"We are now recognizing that chronic pain is a brain disease, and if we want to treat it more effectively, we need to better understand and treat the mechanisms in the brain that are driving it," Emeran Mayer, M.D., director of the Oppenheimer Center, said in a statement announcing the project.

According to Mayer, brain imaging is one of the most promising technologies for breakthrough findings in chronic pain. However, research is currently significantly limited, due to the fact that most institutions can only support small studies on their own and lack access to large samples of patients. In addition, there is no standardization of acquired data, making it difficult to combine brain scans from multiple investigators that are obtained using different scanners, techniques and sets of clinical data.

That will change with the new PAIN. The aim is for the network to include information from more than a thousand patients, including both adults and children.

In addition to brain scans, researchers will also have access to patient metadata, including symptom measures; psychosocial factors; gene expression; immune system information; data on bacteria in the intestines, known as gut microbiota; and environmental data. Researchers can then develop large, overlapping data sets to pinpoint similarities and differences among chronic-pain conditions and correlate brain scans with clinical metadata.

How A Wandering Brain Can Help People Cope With Pain : Shots - Health News : NPR

When some people are in pain, the experience is so intense that they can't think of anything else. But others can turn their minds elsewhere and feel better.

Why? The difference may be due in part to brain wiring, researchers say, and knowing more about how it works may someday make it easier to match people with effective pain treatments.

Prescription painkillers like Vicodin don't work for everyone, and alternative treatments like meditation or cognitive behavioral therapy work for some but not all. Right now, doctors can't tell in advance which pain treatment will work best for a patient.

The problem intrigued Karen Davis, a neuroscientist at the University of Toronto's Centre for the Study of Pain, who was in misery from a pinched nerve in her neck. But grant application deadlines loomed, so she just kept working.

"I tried a lot of painkillers, and it didn't do much," Davis tells Shots. But she noticed that when she was focused on her work, the pain didn't bother her as much. "I don't know if the pain went away, but I certainly didn't notice it."

So Aaron Kucyi, a graduate student in Davis' lab, recreated the painful experience with small electric shocks to volunteers' wrists. After each zap the researchers asked how the test subjects were feeling and what they were thinking about. Some people's thoughts wandered from the pain, while others couldn't disengage.

Then they gave people cognitive tests while zapping them. The mind-wanderers did well. The people focused on the pain floundered.

This isn't standard-issue daydreaming, Davis says. "Mind-wandering away from pain is different than daydreaming in general."

Diving deeper, the researchers put 32 of the study participants in an MRI scanner to see what was going on. They found that people who were good at letting their minds wander away from pain had more nerve connections to a brain region that produces painkilling substances. The brain made that connection using a system called thedefault-mode network, which people typically use for thinking.

And finally, they used newer MRI technology to see how flexible people could be in responding to pain. The mind-wanderers were more flexible.

Overall, most people in the study fell somewhere in the middle, doing some mind-wandering and some focusing on pain. Davis says that suggests that for most people there is a range of pain management techniques that could work.

"People who mind-wander, they might be more able to vary their response to pain on their own," Davis speculates. They also might be more adept at learning pain-control methods like yoga, meditation or cognitive behavioral therapy. And non-wanderers may need different forms of help.

This is preliminary science. For now, it's probably not useful in personalizing pain treatment outside the research lab. But it marks a potential path away from a one-size-fits-all approach to pain management that often fails to connect people with treatments that help.

'Chimera' protein could lead to drug treatments for chronic pain - ScienceDaily

Scientists have manufactured a new bio-therapeutic molecule that could be used to treat neurological disorders such as chronic pain and epilepsy.

A team of 22 scientists from 11 research institutes, including Dr Enrico Ferrari from the University of Lincoln, UK, created and characterised a new molecule that was able to alleviate hypersensitivity to inflammatory pain.
The work is featured on the cover of the October 2013 issue of the scientific journal Bioconjugate Chemistry.
Dr Ferrari joined the School of Life Sciences in October last year from the Medical Research Council's Laboratory of Molecular Biology in Cambridge, where he took part in the development of a new way of joining and rebuilding molecules in the research group of Professor Bazbek Davletov -- now at the University of Sheffield.
Now, by separating elements of clostridium botulinum andclostridium tetani neurotoxins, commonly known as Botox and tetanus toxin respectively, the scientists were able to develop a model to re-join the molecule proteins yielding new biomedical properties, without unwanted toxic effects.
While the Botox element is able to block neuronal communication -- and therefore pain signals -- for months, the tetanus component targets the engineered toxin to the central nervous system, rather than stopping at exterior neurons that are the normal target of Botox. The combination of the two effects is of great interest for neuroscience and can be applied to the treatment of several neurological disorders, particularly chronic pain conditions.
Botox and tetanus neurotoxins hold great promise for clinical applications, but since they are the most lethal proteins known to man, their paralytic activity was a stumbling block until now.
Dr Ferrari, who is one of the lead authors of the study, said: "The toxins were split into parts so they were unable to function. Then later they were reassembled using a 'zipping' system so they can operate in a safe way. The re-engineered chimera toxin has very similar characteristics to Botox and is still able to block neurotransmission release, but the paralytic effect is a lot less. We then added a tetanus molecule which targets the chimera to where the pain signals travel towards the central nervous system."
Preliminary data on animal models has now been collated at University College London and future clinical trials are expected to fully characterise the new bio-therapeutic.
Dr Ferrari added: "Many painkillers relieve the pain temporarily and have various side effects. The selling point of this molecule is that the pain relief could last up to seven months, in a similar way that Botox injections for removing wrinkles last for several months. Engineering this kind of toxin has many uses and would be a major improvement in the quality of life for those people who suffer from chronic pain. It is very exciting to know that a protein you made could be one of the future drug treatments."
The crux of Dr Ferrari's research is now aimed at creating a method where more than two protein elements can be combined together and their exact order dictated, which will open up further avenues to explore possible medical uses in the future.

New Wrinkle for Old Drug It’s not just for smoothing laugh lines. Botulinum toxin may have the potential to ease OA pain.| Arthritis Today Magazine

Widely used by doctors to soften forehead wrinkles and reduce uncontrollably sweaty armpits, researchers now are exploring botulinum toxin as a potential therapy for osteoarthritis (OA) pain.

Although botulinum toxin (Botox, Dysport, Myobloc) has been studied since the 1950s, recent studies on its use in osteoarthritis pain suggest it could be a new analgesic option for a group of patients that's been hard to treat.

"The Botox story is very intriguing," says David Felson, MD, professor of medicine and epidemiology at Boston University. "It isn't just muscles. It can paralyze nerves. Just like celebrities injecting it into wrinkles, it could have the same effect on a hip muscle. Botox could paralyze the muscle that is transmitting pain."

A powerful neurotoxin produced by a bacterium that can cause deadly botulism poisoning at higher doses, botulinum toxin has an anticholinergic effect, meaning it can block the delivery of the neurotransmitter acetylcholine to the central nervous system, an action which can cause the body to produce chronic pain signals. The substance can temporarily paralyze muscles for a few months, easing painful spasms and tightness in muscles around OA-affected joints. It can also have an antinociceptive effect, meaning it can block nociceptors, or pain receptors, from sending a pain signal up the spinal cord to the brain.

This toxin may eventually be used to treat OA patients whose pain is not sufficiently controlled by traditional medicines like NSAIDs or analgesics, and for patients who may experience adverse effects from those medicines, says Dr. Felson.

Blocks Pain Signals

In the same action that botulinum toxin flattens wrinkles for up to six months, the substance "blocks the neuromuscular junction, so the nerve can't transmit signals to the muscle and it prevents contraction," says Eric Hsu, MD, a pain specialist at Ronald Reagan-UCLA Medical Center in Los Angeles.

These early, small studies on the pain-fighting potential of botulinum toxin are promising for people who have chronic osteoarthritis pain due to muscle spasms and tightness, or myofascial pain, says Dr. Hsu. Doctors don't know why some people have this type of chronic muscular pain that never shuts off, he notes. "It's still a controversial issue and we can't pinpoint the reason, but there is a theory that chronic inflammation can trigger primary or secondary muscle spasm. This induces the neurotransmitters to be consistently aroused, and it triggers the central nervous system" to send continuous pain signals to the joint.

Botulinum toxin, which can block the transmission of these neurotransmitters for several months at a time, might be a useful treatment for this type of pain, says Dr. Hsu.

Although the studies conducted so far are small and look at short-term results, the results of these recent studies are "impressive," says Dr. Felson. "A lot of [current treatments for OA pain] don't work, and this one may actually work."

He points to a Minneapolis-based study published in the Journal of Rheumatologyin 2010 that looked at 54 patients experiencing chronic pain after total knee arthroplasty. Some were given an intraarticular injection of 100 units of botulinum toxin type-A and some were given an identical placebo. The results were significant: 71 percent of those injected with botulinum toxin achieved clinically meaningful reduction in pain and improved, measurable physical function in the joint compared to 35 percent of those receiving the placebo shot.

Even surgical replacement of a hip or knee joint eroded by OA may not eliminate pain and mobility issues, says Dr. Felson.

"No one is quite sure of the reason for pain after knee arthroplasty, but a significant percentage of patients have pain after surgery," he says.

Traditional medications to treat OA pain include NSAIDs or corticosteroids, which target inflammation, and analgesics, which act on the central nervous system to block pain signals. Botulinum toxin could be a welcome alternative, says Dr. Hsu, because it appears that the localized injections do not cause the type of systemic side effects of NSAIDs or corticosteroids, or the dependence issues of narcotic analgesics.

"If it does get widespread use at some point, then I anticipate people would get maintenance injections every three to four months or so," he notes. Some studies are exploring the use of the toxin in conditions like hip and knee OA and frozen shoulder, or adhesive capsulitis, the inflammation of connective tissue in the shoulder joint capsule. Dr. Hsu sees botulinum toxin as a potential auxiliary treatment for OA patients with uncontrolled pain. "I cannot predict that this will be the only treatment people with osteoarthritis will get, but for people with advanced disease, people who feel hopeless, this may provide hope that something can be done" to treat their pain.

Pain Results Promising

Recently published studies explore the use of botulinum toxin in different joints and in patients who have either had total joint replacement or not. Another study has raised further interest by suggesting that botulinum toxin might someday be used to treat inflammation as well.

An Italian study published in the Journal of Rehabilitative Medicine in 2010 looked at the efficacy of botulinum toxin type-A injections in the thigh muscles of patients experiencing pain due to hip OA. Each subject received two injections of the solution for a total of 400 units: 250 units in the adductor longus muscle and 150 units in the adductor magnus muscle of the thigh on the same side of the body as the affected hip. Results were equally promising. The patients were evaluated to measure hip function, pain, and overall well-being and quality of life before the study, and all saw improvements in these areas in follow-up evaluations at two, four and 12 weeks after the injections.

Another study conducted by University of Wisconsin researchers published in the journal Biochemistry in 2011 explored a future use of botulinum toxin: Treating chronic inflammation, not just temporarily relieving pain. Felix Yeh, PhD, who led the study and is now working in the private sector in San Francisco, said the focus of the study was to learn how toxins get into neurons, something he calls "a Trojan horse strategy."

Using botulinum toxin type B, a relatively new product on the market, on laboratory mice, Yeh and his colleagues showed that the neurotoxin could be retargeted to inhibit the release of tumor necrosis factor alpha, a key cytokine that is one of the possible causes of inflammation in autoimmune diseases like rheumatoid arthritis.

"Toxins cannot naturally get into non-neural cells," says Yeh. "But we found if we coated our toxins with antibodies, we could drive them through." The re-engineered toxins could enter cells and cleave to SNAREs, key proteins that play a role in the secretion of inflammation-causing substances. In their mouse study, the researchers measured about a 50-percent decrease in TNF-alpha release after treating the tissue with the engineered toxin, without significantly affecting other cells. "Since we were able to inhibit its secretion, we were able to lower overall inflammatory phenotypes," says Yeh. "We saw the potential for all toxins. All of these could be retargeted to non-neural cells for therapeutic use."

Physicians treating patients with serious chronic joint pain see botulinum toxin as potentially useful, but urge caution at this point. Although studies haven't shown serious adverse effects, Dr. Felson speculates that injecting it into large muscles supporting weight-bearing joints, such as the thigh, might impair one's ability to walk, for example.

So far, the results look promising, so Dr. Hsu is hopeful. "I think things like this, which do not cause the systemic, multi-organ side effects of other treatments, are potentially an option for us to help our patients."

Saturday, October 26, 2013

Judy Foreman's pain book and blog

A Nation in Pain: Healing our Biggest Health Problem

Judy Foreman

  • Based on interviews with hundreds of scientists and many hundreds of research studies
  • Written in an informal, conversational tone, and accessible to anyone interested in pain
  • Includes a thoughtful analysis of the politics of opioid and marijuana regulation
  • Explores the many possible reasons for women's extra pain burden, including the complex role of estrogen, and the reasons why women receive inferior pain treatment,

Friday, October 25, 2013

F.D.A. Urging a Tighter Rein on Painkillers -

The Food and Drug Administration on Thursday recommended tighter controls on how doctors prescribe the most commonly used narcotic painkillers, changes that are expected to take place as early as next year.

The move, which represents a major policy shift, follows a decade-long debate over whether the widely abused drugs, which contain the narcotic hydrocodone, should be controlled as tightly as more powerful painkillers like OxyContin.

The drugs at issue contain a combination of hydrocodone and an over-the-counter painkiller like acetaminophen or aspirin and are sold either as generics or under brand names like Vicodin or Lortab. Doctors use the medications to treat pain from injuries, arthritis, dental extractions and other problems.

The change would reduce the number of refills patients could get before going back to see their doctor. Patients would also be required to take a prescription to a pharmacy, rather than have a doctor call it in.

Prescription drugs account for about three-quarters of all drug overdose deaths in the United States, with the number of deaths from narcotic painkillers, or opioids, quadrupling since 1999, according to federal data. Drugs containing hydrocodone represent a huge share — about 70 percent — of all opioid prescriptions, and the looser rules governing them, some experts say, have contributed to their abuse.

Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said she expected the new regulations to go into effect in 2014. The recommendation requires the approval of the Department of Health and Human Services and adoption by the Drug Enforcement Administration, which has long pushed for the measure.

For years, F.D.A. officials had rejected recommendations from the D.E.A. and others for stronger prescribing controls on the drugs, saying the action would create undue hardships for patients. A number of doctors' groups, including the American Medical Association and pharmacy organizations, have continued to fight the measure, citing the impact on patients.

In a telephone interview, Dr. Woodcock said that F.D.A. officials were aware that changing the prescribing rules would affect patients. She said, however, that the impact on public health caused by the abuse of the drugs as well as their medical use had reached a tipping point.

"These are very difficult trade-offs that our society has to make," she said. "The reason we approve these drugs is for people in pain. But we can't ignore the epidemic on the other side."

The new regulations would reduce by half, to 90 days, the supply of the drug a patient could obtain without a new prescription.

Currently, a patient can refill a prescription for such drugs five times over a six-month period before needing a new prescription. Federal data suggest that most patients take such medications for only 14 days, creating the potential for excess pills to be sold or to be taken out of medicine chests by curious teenagers and others.

The F.D.A. recommendation is likely to have a significant impact on the availability of the drugs, as well as on how pharmacies operate and even the types of medical professionals who can prescribe the medications.

In 2011, about 131 million prescriptions for hydrocodone-containing medications were written for about 47 million patients, according to government estimates. That amounts to about five billion pills.

Technically, the change involves the reclassification of hydrocodone-containing painkillers as Schedule II medications from their current classification as Schedule III drugs. The scheduling system, which is overseen by the Drug Enforcement Administration, classifies drugs based on their medical use and their potential for abuse and addiction.

Schedule II drugs are those drugs with the highest potential for abuse that can be legally prescribed. They include painkillers like oxycodone — the active ingredient in OxyContin — methadone and fentanyl, as well as Adderall and Ritalin, which are prescribed for attention deficit hyperactivity disorder.

In recent years, the question of whether to tighten prescribing controls over hydrocodone-containing drugs has been the subject of intense lobbying.

Last year, for example, lobbyists for druggists and chain pharmacies mobilized to derail a measure passed in the Senate that would mandate the types of restrictions that the F.D.A. is now recommending.

At the time, the lobbying arm of the American Cancer Society said that making patients see doctors more often to get prescriptions would impose added burdens and costs on them.

Senator Joe Manchin III, Democrat of West Virginia, expressed dismay when the proposal died in the House of Representatives.

"They got their victory — but not at my expense," said Mr. Manchin, whose state has been hard hit by prescription drug abuse. "The people who will pay the price are the young boys and girls in communities across this nation."

Dr. Woodcock, of the F.D.A., said that requiring patients with long-lasting pain to see a doctor after three months, rather than six, for a new prescription could benefit them. "If you are needing chronic therapy of this magnitude," she said, "you should be seeing your prescriber."

A D.E.A. spokeswoman, Barbara Carreno, said that agency officials would not comment on the agency's recommendation.

One of the trade groups that opposed the change, the National Community Pharmacists Association, said in a statement on Thursday that the move would "likely pose significant hardships for many patients and delay relief for vulnerable patients with legitimate chronic pain."

Penney Cowan, the executive director of the American Chronic Pain Association, an advocacy group, said she believed that drugs like Vicodin should be only one part of a treatment program for patients with long-term pain. But she added that the new rules could make it harder for some patients to find doctors to prescribe the drugs or pharmacies to fill the prescriptions.

"We are hearing from more and more people having difficulty finding access to care," Ms. Cowan said.

Earlier this year, an expert advisory panel to the F.D.A. voted 19 to 10 in favor of reclassifying hydrocodone-containing painkillers as Schedule II drugs. While such recommendations are not binding, the agency often follows them.

Along with changing how doctors prescribe these drugs, the classification change would also impose added storage and record-keeping requirements on druggists. In some states, nurse practitioners and other health care professionals who can currently prescribe hydrocodone-containing drugs may no longer be able to do so.

Wednesday, October 23, 2013

'Love Hormone' May Mediate Placebo Effect - MedPage Today

Intranasal oxytocin, sometimes called the "love hormone," intensified the painkilling effect of placebo in a clinical study, suggesting a physical basis for the placebo effect, researchers said.

Among 75 healthy young men exposed to painful heat stimuli on their forearms in the randomized, double-blind study, ratings of a placebo cream's analgesic effect were greater after the participants received active intranasal oxytocin than when they snorted a saline solution, with a difference of 5.76 points out of 60 (95% CI 0.59-10.93, P=0.03), according to Ulrike Bingel, MD, of the University of Duisberg-Essen in Germany, and colleagues.

"To our knowledge, our study provides the first experimental evidence that placebo responses can be pharmacologically enhanced by the application of intranasal oxytocin," they wrote in a research letter appearing in the Oct. 23/30 issue of the Journal of the American Medical Association.

The experiment was designed in such a way as to exclude the possibility that oxytocin itself affected pain sensitivity, the researchers said.

"We hypothesize that oxytocin might have increased the believability of the instructions by the study physician," Bingel and colleagues wrote. Also, they suggested, the hormone may have reduced anxiety and stress, which in turn could have increased the placebo response.

They had hypothesized that oxytocin might have such an effect because earlier research had associated its release with psychological traits such as trust, empathy, and socialization.

In the current study, participants were first randomized to receive either 40 IU of intranasal oxytocin or a saline solution. After 45 minutes, a cream was applied to each of their forearms. Participants were told that the cream on one arm was an anesthetic and that the other was an inert control product. They were also told that the anesthetic cream would take effect in 15 minutes.

During this period, heat was applied and increased until the participant rated the pain at 60 on a 100-point scale. The actual test phase then began, with 10 applications of heat at the 60-point intensity lasting for 20 seconds each, in 1-minute cycles. Participants rated the pain in each forearm for each of these applications.

At the "control" cream site, mean pain ratings averaged 59.96 in the oxytocin group and 58.31 in the saline group, effectively ruling out any real anesthetic effect of oxytocin.

Pain ratings for the "active" cream site averaged 47.11 in the oxytocin group versus 51.23 in the saline group. Bingel and colleagues then calculated the placebo response at each site by subtracting the "active" site rating from the "control" site rating. For the oxytocin group, this worked out to 12.84 points (95% CI 8.67-17.01); in the saline group, it was 7.08 points (95% CI 3.84-10.31).

There were no significant differences between the groups in other measures, such as the temperature needed to achieve the 60-point rating at baseline (46° C [115° F] in both groups) or in anxiety or depression levels.

After the experiment, participants were asked to guess whether they had received oxytocin or saline. Most of those guessing oxytocin had actually received saline, Bingel and colleagues indicated. Just over half of those who guessed saline were in the oxytocin group.

"Further studies are needed to replicate our findings in larger clinical populations, identify the underlying mechanisms, and explore moderating variables such as sex or aspects of patient-physician communication," the researchers concluded.

Tuesday, October 22, 2013

Prescription Drug User Fee Act (PDUFA) > Public Meeting on Fibromyalgia Patient-Focused Drug Development

Public Meeting on Fibromyalgia Patient-Focused Drug Development

On  December 10, 2013, FDA is conducting a public meeting on Patient-Focused Drug Development for fibromyalgia. FDA is interested in obtaining patient input on the impact of fibromyalgia on daily life and patients' views on currently available therapies to treat the condition.

This website will be updated as registration and additional meeting information become available.

Date: December 10, 2013 
Time: 1:00 p.m. to 5:00 p.m. 
Location:FDA White Oak Campus
10903 New Hampshire Ave.
Building 31, Room 1503A (Great Room)
Silver Spring, MD 20993
(Information about arrival to FDA's White Oak campus)  
To register for this meeting, visit:
Registration will close on November 27, 2013.

Thursday, October 17, 2013

Brain treats rejection like physical pain say scientists - Science - News - The Independent

The human brain treats rejection in a similar way to the way it process physical pain, new research has suggested.

A scientific study conducted by the University of Michigan Medical School has shown that the brain uses a similar reaction to ease the pain of social rejection as it does to deal with pain caused by physical injury.

A team led by Dr David T. Hsu also found that people who showed high levels of resilience on a personality test also had higher levels of natural painkiller activation.

When the body experiences physical pain, the brain releases chemical opioids into the empty space between neurons, which "dampens" pain signals.

The team asked 18 adults to look at photos and fictitious personal profiles of hundreds of other adults. Each selected some who they might be most interested in romantically, as they would do on a typical online dating website.

Afterwards, when the participants were lying in a PET scanner, they were informed that the individuals they found attractive and interesting were not interested in them.

Researchers monitored the mu-opioid receptor system in the brain, which the team have been examining for the last decade in response to physical pain.

The brain scans of participants who were experiencing this form of social rejection showed highly active opioid systems, meaning the brain was releasing its natural painkiller.

Before beginning the study, researchers told participants that the "dating" profiles were not real, and neither was the "rejection." However, the simulated social rejection was enough to cause both an emotional and opioid response.

"This is the first study to peer into the human brain to show that the opioid system is activated during social rejection," Dr Hsu said.

"This suggests that opioid release in this structure during social rejection may be protective or adaptive.

"In general, opioids have been known to be released during social distress and isolation in animals, but where this occurs in the human brain has not been shown until now."

Dr Hsu noted that the underlying personality of the participants appeared to play a role in how active their opioid system response was.

"Individuals who scored high for the resiliency trait on a personality questionnaire tended to be capable of more opioid release during social rejection, especially in the amygdala," he said.

"This suggests that opioid release in this structure during social rejection may be protective or adaptive."

He added: "It is possible that those with depression or social anxiety are less capable of releasing opioids during times of social distress, and therefore do not recover as quickly or fully from a negative social experience."

The team concluded that the brain pathways activated by physical and social pain are similar. Studying this response, and the variation between people, could aid understanding of depression and anxiety.

 New opioids could therefore potentially be developed as effective treatments for depression and anxiety.

Congress Probes VA Painkiller Prescribing - MedPage Today

Lawmakers on Capitol Hill hammered the Department of Veterans Affairs (VA) for the way it handles pain management in patients during a hearing Thursday on the topic.

Rep. Dan Benishek, MD (R-Mich.), chair of the House Veterans Affairs Health Subcommittee, questioned the VA's pain management approach, which places primary care providers at the center of care teams.

"As I know from personal experience, the multifaceted nature of chronic pain, particularly when multiple medications are being prescribed, should not be managed by primary care physicians but rather by a qualified pain specialist who is trained to understand the complexities of treating these conditions," said Benishek, a general surgeon who has worked part time at the Oscar G. Johnson VA Medical Center in Iron Mountain, Mich., for 20 years.

Thursday's hearing drew tears from widows of veterans who died from prescription drug overdoses and others who have worked in and navigated the VA system as physicians and patients.

Rep. Jeff Miller (R-Fla.), chair of the full House Veterans Affairs Committee, said the VA must curtail its reliance on painkillers.

The number of patients treated by the VA is up 29% in the last 11 years, while narcotics prescriptions written by VA providers are up 259%, the House committee said. VA prescriptions for hydrocodone, oxycodone, methadone, and morphine have risen 270% in the last 12 years.

Additionally, as many as 60% of veterans returning from Iraq or Afghanistan report some form of pain.

"Our intent here today is to initiate better provider practices and, most importantly, better care coordination for our veterans and their loved ones," Benishek said, adding that the VA needs better pain management protocols. He called its current process a "Band-Aid approach."

"In my own personal practice, I realize I just don't know everything there is to know about pain," Benishek said. "We always, always send people with chronic pain to a specialist. To not do that and just appoint a specialist is just inconceivable to me."

Even then, the health system is short on pain specialists.

Pamela Gray, MD, an internist and rheumatologist by training, was told when she started working at the VA hospital in Hampton, Va., in 2008 that she would be the pain management specialist. Gray left her private practice to work for the VA but was later fired when she tried to speak out about her concerns over opioid prescribing.

A nurse practitioner holds the pain management specialist title for the facility in Wilmington, Del., according to Claudia Bahorik, DO, who along with Gray testified at Thursday's hearing.

With or without the specialists, patients are getting multiple pain medications. Heather McDonald, widow of VA patient Scott McDonald, reported that her late husband was seeing multiple providers who each prescribed a different medication before his overdose in 2012.

"Why is there not continuity between doctors at the VA?" McDonald told the lawmakers. "Nobody was going through his records to say 'This doctor already gave you this, so I'm not going to go do this.'"

Raul Ruiz, MD (D-Calif.), an emergency room physician and health subcommittee member, said they had a policy at the Eisenhower Medical Center in Rancho Mirage, Calif., where he used to work, to review drug interactions for every prescription. Similar care coordination efforts should be installed if they don't already exist, he said.

"I think these are approaches and policies that the VA may have," Ruiz said. "The other thing is to make sure we look at pain in a holistic manner, to look at the complexity of pain not only on the science but also the effects of the interactions with family, their ability to function, their mental health."

"These are questions that we will be asking the VA and we'll be looking thoroughly into," he added.

Gray, the physician who was fired after she spoke out about her prescribing concerns, testified that she was strong-armed into prescribing medication to treat pain rather than using nonprescriptive treatment. Robert Jesse, MD, principal deputy undersecretary for health at the Veterans Health Administration, told lawmakers it's "indefensible" for providers to only prescribe narcotics and not be allowed to use other forms of therapy.

"We are strongly committed to ensure that veterans do have what they need to manage their pain," Jesse said. "That includes, not just medications, but to truly get to the root cause of this."