Tuesday, January 31, 2012

Burn Victim Sam Brown Treated With Virtual-Reality Video Game SnowWorld: Newsmakers: GQ

On his first tour of duty in Afghanistan, Sam Brown was set on fire by an improvised explosive device. He survived, only to find himself, like thousands of other vets, doomed to a post-traumatic life of unbearable pain. Even hallucinogen-grade drugs offered little relief, and little hope.

Then his doctors told him about an experimental treatment, a painkilling video game supposedly more effective than morphine. If successful, it would deliver Brown from his living hell into a strange new world—a digital winter wonderland


At will and sometimes against his will, Sam Brown can return in his mind to that hour in the Kandahar desert when he knelt at the edge of a blast crater and raised his flaming arms to the Afghanistan sky. He'd already run through the macabre slapstick routine of a man on fire, trying to put himself out by rolling on the ground. He'd resorted to pelting his face with fistfuls of sand. That failing, he'd run in helpless circles. Finally he'd dropped to his knees, lifted his arms, and screamed Jesus, save me. Each scream drew fire deeper into his lungs. Behind him his Humvee was a twisted inferno. Bullets whizzed around him. His men were scattering, taking cover, moving dreamily in clouds of so-called moondust, that weird powdery talc, which hung in the air and gave the soldiers the appearance of snowmen. It was going on dusk, and in the fading light the enemy gunfire blazed behind the walls of the village.

Only the day before, Brown's brother, Daniel, had told him, in a phone call, You're invincible, they can't kill you. Best he could remember, he'd always felt invincible. Pretty much right up to the instant they rolled over the IED, he had remained the same man he'd been at West Point. That is, he was a man whose life still had meaning. Every action had been meant to hone him for the glory of battle. Even as varsity stroke, in command of a shell on the rowing team, out on the water every morning at dawn, the sun dripping off his oars, his arms burning as he counted off the strokes, welcoming the pain into his body, bronzed, sculpted, almost too good-looking, he sought hard perfection in himself and those around him.

A diligent cadet who would spend the whole of an afternoon in the library reading about ancient Greek wars in Herodotus, immersed in the virtual reality of history, yearning for his own chance to test his mettle—but that was before eight brain-dead weeks of providing security for the construction of a new FOB in the middle of nowhere, watching bulldozers push sand, anxious for anything to break up the tedium, anything. When he was told his platoon would have to help provide security for a convoy coming through his sector on its way to a hydroelectric dam out in Helmand—delivering turbines, on a hearts-and-minds mission—he was all for the diversion, almost ecstatic when the call came from First Platoon reporting they'd been ambushed and needed backup. Brown had responded immediately. He was on the radio to his lead vehicle when he saw the bright flash. His body went inert as the Humvee lifted into the air. How he escaped from the wreck he couldn't recall.

Kneeling there, on fire, he'd resigned himself to death. All he'd wanted to know was how long? How long would he have to burn? How many more torturous fractions of a second would he have to remain alive?

His gunner, Jensen, had come to his rescue, extinguishing the fire with sand, helping him to his feet. Running for cover, Brown had kept his arms held out in front of him, as if he were carrying an infant that he did not know what to do with. The sleeves of his uniform were burned off, with patches of the desert camo fused to his skin, and the visible bits of his own flesh either meat-raw or charred black. It felt as though his gloves—made of thick leather and fire-retardant Nomex—were somehow cooking his hands.

Crouching behind a wall, he turned to the private beside him and said, "Take my gloves off."

The private hesitated, but then took hold of the glove and started pulling. "Sir," he said, "it's not coming off."

"Take the glove off," First Lieutenant Brown said.

The soldier grimaced but put his strength into it, and the glove came off, and with it, Brown's flesh. They all looked at the glove on the ground and then at his hand. Or tried not to look.

Brown extended the other hand. "This one."

It was dark before vehicles from the other platoon managed to reach them. In the back of a Humvee, Brown watched the hot .50-cal brass shells raining down from the turret. After a few moments, he could hear the battle fading behind, and then they were out bumping across the poppy fields. At one point, Brown caught a glimpse of himself in the side mirror. His hair was ash. His nostrils were black. His face was unrecognizable.

Before the Humvee reached the appointed helicopter landing zone, whatever Brown had been running on was gone. After helping him out of the Humvee and onto a stretcher, Brown's men had wrapped gauze around his eyes to protect them from the flying dust the helicopter would kick up, and when they saw that he was having difficulty breathing, they began to sedate him in preparation to intubate. His arms were too badly burned, so they had to run the IV through his sternum. By the time they heard the Black Hawk and saw its search beam twitching over the poppy fields, the giant blades shredding the dark, the morphine had begun to find its way.

More …

Friday, January 27, 2012

Pain is top concern in Ohio and the nation

CLEVELAND, Ohio -- High costs and the alarmingly high number of accidental deaths linked to prescription pain pills have made pain treatment a central issue in health care across Ohio and the nation.
A recent report by the Institute of Medicine underlined the urgency of developing better pain-management strategies in the United States, where chronic pain affects more than 116 million people and costs as much as $650 billion yearly in direct medical treatment and lost productivity.
"Pain is a major driver for visits to physicians, a major reason for taking medications, a major cause of disability, and a key factor in quality of life and productivity," the report stated. "Given the burden of pain in human lives, dollars and social consequences, relieving pain should be a national priority."
Americans make up 4.6 percent of the world population and consume 80 percent of the global opiate supply, including nearly all of the hydrocodone supply, according to the American Society of Interventional Pain Physicians.

In August, an Ohio law went into effect requiring special licensing for pain clinics and doctors with 50 percent or more of patients being treated with controlled substances for chronic pain. The law tightly regulates record keeping on patients and mandates subspecialty certification and continuing education in pain management for physicians. The law also limits how many pills doctors can dispense and establishes a system for collecting unused narcotics.
In Ohio, deaths from unintentional prescription drug overdoses have increased more than 350 percent between 1999 and 2008, making it the leading cause of accidental death in the state since 2007.
With the tightening of regulations, learning the best way to prescribe painkillers, including narcotics, is critical for doctors.
The Institute of Medicine report said more research is needed so that physicians have better data to guide them when treating patients -- especially children and the elderly who sometimes cannot express their needs.
"Pain is something that the U.S. health care system doesn't deal with well," said Dr. Alan Hull, associate dean for curricular affairs in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. "We need to work on recognizing and treating pain appropriately."
Given the restraints on doctors' time during standard appointments, he said, "there certainly is a science and art to being able to read patients and develop a relationship with them."
The Institute of Medicine report recommended that medical education programs expand curriculum about pain.
Limited instruction for medical students 

A separate study released last month by researchers from Johns Hopkins School of Medicine found that medical school curriculum addressing pain is limited and often fragmented.
"Health care has undergone dramatic changes in the last 25 years," stated the study published in the American Pain Society's Journal of Pain , "but inadequate treatment of pain has persisted." The study stated that the areas of cancer, pediatric and geriatric pain treatment are unaddressed by the vast majority of medical schools.
Dr. Jennifer Kriegler, associate professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, said unlike when she was receiving her training, schools have been doing a much better job of teaching medical students and residents about pain -- especially chronic pain.
Medical schools throughout Ohio are devoting more time to classroom curriculum on chronic pain -- often linked to cases of drug abuse -- and to student observation of patients.
"Treating pain is much more than giving somebody medication," Kriegler said. "That's what students need to know. It takes a multifaceted approach."
Dr. David Ryan, who runs the pain management program at MetroHealth Medical Center, said doctors have to look at the whole patient. "The best pain physicians take time to listen to the patient and understand their problems, taking into consideration both the physical and emotional complexities," he said.
"Because pain is so complicated, it covers almost the entire spectrum of medical training," Ryan said, "as doctors learn the intricacies of how pain works."
'Not all pain is the same pain' 

Research shows that pain tolerance varies from person to person, according to the Institute of Medicine report, which recommended that pain management be tailored to each patient's experience.
Dr. Salim Hayek, division chief of pain medicine at University Hospitals Case Medical Center, said patients -- even those with the same injury or illnesses -- perceive twinging, throbbing, aching or soreness very differently.
Pain is important, he said, because it's the body's signal that something is wrong. And, Hayek said, "Not all pain is the same pain." Acute pain from surgery, for example, eventually goes away, but chronic pain in the lower back may linger for months.
Yet, even if levels of discomfort are similar among people, Hayek added: "The drugs don't work on 100 percent of the patients or 100 percent of the pain." Everyone builds up a tolerance to a pain drug, he explained, but this occurs more quickly with younger patients. Doctors need to keep this and other factors in mind when considering a course of action.
The Institute of Medicine report said that managing pain is a challenge, and more research needs to be done to better understand treating pain.
Research already is revealing the negative effects of underdiagnosing and undertreating pain and that the "wait to see if it goes away" approach could have consequences.
Recent studies show that acute pain -- such as that accompanying burns or kidney stones -- should be treated immediately. Otherwise, there can be changes in the central nervous system and spinal cord that cause the pain to become worse. These changes can result in severe pain that lingers long after the original injury or disease is resolved.
Dependence after an acute condition

Physicians strive to find the balance of keeping patients comfortable and avoiding dependency on these powerful drugs.
"If someone has an acute condition, such as a broken ankle, by all means pain drugs can be safely prescribed for a short period of time -- two to five days," Hayek said.
Doctors said that the vast majority of the patients who need pain medications don't abuse them.
Medical students, Kriegler said, learn to start with where the pain begins and then move to family history and what's going on in the patient's life. "You can't get away from the brain being both an emotional and physiological organ," she said.
Dependence on drugs can occur for many reasons.
"A lot of times people take medication for an acute problem," she said, "but then what happens is, when the pain is gone, they realize the medication helped them in terms of something else -- such as easing their anxiety."
In cases where the injury has healed, other physiological sources have been ruled out and the pain continues, Kriegler said, "we need to treat the problem in the brain because that's where the change has occurred."
Even if there is no obvious source, the pain is very real to the patients. So doctors in training are being taught to find additional means to help patients get some relief.
"If a person says they cannot go to work because of pain," Kriegler said, "then maybe what they need is physical therapy." For other patients, regular exercise may help them begin to feel better, and that's a subject worth discussing.
Counseling could be in order for a patient who, for example, has suffered past abuse or has a fear of illnesses recurring because of family history, she said. "Medical students need to understand that if they cannot help patients, they need to get them to the right specialist who can."
Kathy Cole-Kelly, professor of family medicine at Case Western Reserve School of Medicine, said putting the patient in the center of treatment is key.
Cole-Kelly, who teaches communication skills at the medical school, said students are trained to look at the situation from the patient's perspective. That involves asking questions about a patient's life and listening. A patient with headaches may be worried because his uncle died of a brain tumor.
Family beliefs based on different cultures or heritages could be at the center of a patient's complaints about pain, she said. A patient is more likely to understand his situation if the doctor talks through the beliefs with the patient rather than just dismissing him, she said.
Cole-Kelly said medical students can learn these communication skills just as they learn to recognize physical ailments.
Once medical students get to the hospital floors, Kriegler said, they soon realize how emotional the pain can be for patients and their families.
"If you don't deal with the emotional aspects, you are not going to be a good doctor," Kriegler said.

Monday, January 23, 2012

In Rating Pain, Women Are the More Sensitive Sex - NYTimes.com

Do women feel more pain than men?

It has long been known that certain pain-related conditions, like fibromyalgia,migraine and irritable bowel syndrome, are more common in women than in men. And chronic pain after childbirth is surprisingly common; the Institute of Medicine recently found that 18 percent of women who have Caesarean deliveries and 10 percent who have vaginal deliveries report still being in pain a year later.

But new research from Stanford University suggests that even when men and women have the same condition — whether it's a back problem, arthritis or asinus infection — women appear to suffer more from the pain.

There is an epidemic of chronic pain: Last year, the Institute of Medicineestimated that it afflicts 116 million Americans, far more than previously believed. But these latest findings, believed to be the largest study ever to compare pain levels in men and women, raise new questions about whether women are shouldering a disproportionate burden of chronic pain and suggest a need for more gender-specific pain research.

The study, published Monday in The Journal of Pain, analyzes data from the electronic medical records of 11,000 patients whose pain scores were recorded as a routine part of their care. (To obtain pain scores, doctors ask patients to describe their pain on a scale from 0, for no pain, to 10, "worst pain imaginable.")

For 21 of 22 ailments with sample sizes large enough to make a meaningful comparison, the researchers found that women reported higher levels of pain than men. For back pain, women reported a score of 6.03, men 5.53. For joint and inflammatory pain, it was women 6.00, men 4.93. Women reported significantly higher pain levels with diabeteshypertension, ankle injuries and even sinus infections.

For several diagnoses, women's average pain score was at least one point higher than men's, which is considered a clinically meaningful difference. Over all, their pain levels were about 20 percent higher than men's.

Unfortunately, the data don't offer any clues as to why women report higher pain levels. One possibility is that men have been socialized to be more stoic, so they underreport pain. But the study's senior author, Dr. Atul Butte, an associate professor at Stanford's medical school, said that explanation probably did not account for the gender gap.

"While you can imagine such a bias," he said, "across studies, across thousands of patients, it's hard to believe men are like this. You have to think about biological causes for the difference."

An extensive 2007 report by the International Association for the Study of Pain cited studies showing that sex hormones may play a role in pain response. In fact, some of the gender differences, particularly regardingheadache and abdominal pain, begin to diminish after women reachmenopause.

Research also suggests that men and women have different responses toanesthesia and pain drugs, reporting different levels of efficacy and side effects. That bolsters the idea that men and women experience pain differently.

One reason for the lack of information about sex differences is that many pain studies, in both animals and humans, are done only in males. One analysis found that 79 percent of the animal studies published in a pain journal over a decade included only male subjects, compared with 8 percent that used only female animals.

In addition, experiments testing pain in men and women have shown that they typically have different thresholds for various types of pain. In general, women report higher levels of pain from pressure and electrical stimulation, and less pain when the source is from heat.

Melanie Thernstrom, a patient representative on the Institute of Medicine pain committee from Vancouver, Wash., said the newest research "really highlights the need for more treatment and better treatment that is gender-specific, and the need for far more research to really understand why women's brains process pain differently than men."

Some researchers believe the pain experience for women may be even more complicated. Women who have given birth, for instance, may have a different threshold for "worst pain ever," causing them to underreport certain types of pain. The bottom line, Dr. Butte said, is that far too little is known about how men and women experience pain and that more study is needed so that, ultimately, pain treatment can be customized to each patient's needs.

"If doctors have a threshold for when they give a dose or start a medication," he said, "you could imagine that the number they are using is too high or too low because a person may be in more pain than they are saying.

"In the end, it comes down to what the brain perceives as pain."


Rat helps pinpoint pain molecule : Nature News & Comment

An uncharted trawl through thousands of small molecules involved in the body's metabolism may have uncovered a potential route to treating pain caused by nerve damage.

Neuropathic pain is a widespread and distressing condition, and is notoriously difficult to treat. So Gary Siuzdak, a chemist and molecular biologist at the Scripps Research Institute in La Jolla, California, and his team decided to take an unusual route to finding a therapy. Their results are published today in Nature Chemical Biology1.

They took rats with surgically damaged paws, who were consequently suffering from neuropathic pain, and instead of analysing changes in gene expression and proteins in the animals, focused on metabolites – the biochemical intermediates and end-products of bodily processes such as respiration and the synthesis and breakdown of molecules. The science that looks at the body's metabolite composition is known as metabolomics. Using mass spectrometry, which can detect many different chemicals simultaneously, the researchers were able to identify the metabolites present in these animals 21 days after surgery.

Surprise finding

The team analysed samples of the injured rats' blood plasma, of tissue near the injured paw, and of tissue from different areas of the spinal column, and compared the metabolites present with that of the same site in healthy rats. One particular area differed markedly between the two cases: the dorsal horn in the spinal column.

"It took me by surprise," says Siuzdak, who had expected to see most differences in metabolite composition near the site of injury.

The researchers then looked more closely at the metabolites and recognized that the ones that were changing the most were associated with the metabolic pathway that synthesizes and breaks down the phospholipid sphingomyelin, a component of cell membranes, and its ceramide precursors.

"It was a huge flare to us that this was something we should home in on," says team member Gary Patti, a chemist at Washington University School of Medicine in St Louis, Missouri.

Using cultures of spinal cord cells the researchers then tried to work out which of the altered metabolites might be responsible for pain. One molecule, the previously unidentified metabolite N,N-dimethylsphingosine (DMS), stood out for the amount of pain signalling it triggered in the cells.

Untargeted screening

To test experimentally whether this molecule was involved in neuropathic pain, the team then injected small amounts of DMS into healthy rats, and sure enough, those rats showed signs of pain.

The team hopes that DMS might prove to be important in the biochemistry of pain, and perhaps offer a target for drug manufacturers. But neuropathic pain expert Andrew Rice at Imperial College London says that in the past 30 years he has seen many targets identified, but virtually none of them has made it into the clinic as an effective pain-relief drug.

Rice lauds the attention shown to neuropathic pain but is concerned that the current animal model for pain is limited: it only corresponds to pain resulting from trauma, and not to the many other sources of neuropathic pain, which include diabetes, HIV infection and stroke. "I'd like to see if this is more than a peripheral nerve damage model," he says.

Siuzdak says his untargeted screening technique could prove useful in identifying drug targets for many other conditions. The more conventional way of using metabolomics is with targeted searches, where the molecule of interest is identified first, before seeing where it might be present. "[Our approach] is more challenging than targeted analyses," he says. "You have to be open to any possibility of what pathways are affected."

When Patti and Siuzdak started to work on this project, their technique was very time consuming, but as methods have improved and their database of metabolites has grown, they are confident that they could use an untargeted metabolite screen in many other scenarios. The potential of this technique, they say, is to find things that would never have been considered before – like that unknown metabolite DMS.


Wednesday, January 18, 2012

Reports of Lost or Stolen Medications: Difficult Conversations - PainEdu.org

It is not unusual for a patient to report to their prescribing clinician that they have discovered that their prescription pain medication (or the written prescription) has been either lost or stolen, leading them to request a new prescription. It is important to distinguish between lost medications and stolenmedications.

Losing a prescription form or a vial of medications may result from the occasional lapses that all patients may have. If this occurs only once it may not have significant medical implications, and the prescriber may choose to replace it without much concern. Losing a medication more than once, however, may imply that something else is going on. There are many possibilities. Is the patient experiencing some type of cognitive impairment, perhaps one that is being made worse by the medication? Does the patient need a further neurological evaluation? Is the patient impaired by the use of other substances? Should a urine drug screen and some simple labs including CBC, metabolic panel, and thyroid function studies, be done even as early as the first incident of a lost prescription? Is the patient misusing the prescription and running out of it early because they are taking more than prescribed, giving it away, or selling it?

Taking a consistent approach to a lost prescription is made much easier if the provider has reviewed their policy about this with the patient ahead of time. If this has not been done, the first time there is a lost prescription is not too late to create a written patient/provider agreement, outlining each of their roles and responsibilities.

Clinicians in practice with multiple-providers should establish and circulate a uniform, clinic-wide policy among patients and staff, to avoid confusion about what they do. Some practices choose a "one and done" policy, (the first time you lose it I will refill it, but never again), or a stricter policy of zero-tolerance, and no early refills, under any circumstance.

If you are not replacing the lost medication, you will need to inform the patient about the potential for withdrawal, and offer to prescribe medications to help diminish withdrawal symptoms. Prescribing these medications needs to be individualized, based upon the patient's age, presence of other medical problems, use of other medications, and the patient's ability to follow-up.

The problem of reports of stolen prescriptions is more ominous because there is another person involved, and potentially, another person has been put at risk. Medication theft is a situation that requires some form of investigation and should be reported to the appropriate authorities. It is important for the patient to think about who might have stolen the medication.

In my clinical practice I do not provide an early refill for a stolen prescription. Other providers may take a "one and done" approach to stolen prescriptions as well as lost prescriptions. Again, with stolen medication, I will educate the patient about withdrawal symptoms and develop a plan to manage them if they occur.

Repeated medication loss, or theft, is a strong indication that the patient is at high risk and that it is not safe for this patient to remain on this medication. If a medical reason, like cognitive decline, is discovered, this may be successfully addressed so that the patient can continue on the medication. However, if this cannot be done, or if the patient lives in an unsafe environment, the best course may be to taper and discontinue these medications, substituting treatments that are lower risk.

Describing how you address these problems before the patient has begun treatment, and before incidents of lost or stolen medication, is part of your description of the treatment plan, and it demonstrates the principal of shared responsibility.


Compact Clinical Guide to Geriatric Pain Management - An Evidence-Based Approach for Nurses | Ann Quinlan-Colwell / Yvonne D'Arcy

The care of older adults suffering with pain is a difficult task that calls for understanding as well as compassion. Dr. Quinlan-Colwell has written an excellent book that deals with every facet of the problems that are encountered by caregivers. Elderly people present challenges that call for recognition of the fact that pain affects sleep, appetite, social interactions, and many other facets of life that require attention. Dr. Quinlan-Colwell carries the reader into the lives of elderly people and provides the information necessary to bring psychological comfort as well as knowledge to help people control pains that destroy the quality of their lives. Needless pain is a tragedy that calls for a better understanding of the psychological, social, and medical dimensions of life. This book highlights all of these dimensions and provides the reader with valuable knowledge that will diminish suffering and enrich the lives of people confronting new, often frightening, problems.

The recognition that pain is a multidimensional experience determined by psychological as well as physical factors has broadened the scope of pain therapies. Patients with chronic pain need every possible therapy to battle the pain. Chronic pain is not a symptom but a syndrome in its own right and requires therapists from a wide range of disciplines.

Psychological therapies, which were once used as a last resort when drugs or neurosurgery failed to control pain, are now an integral part of pain management strategies. The recognition that pain is the result of multiple contributions gave rise to a variety of psychological approaches such as relaxation, hypnosis, and cognitive therapies. So too, transcutaneous electrical nerve stimulation and other physical therapy (PT) procedures emerged rapidly, bringing substantial pain relief to large numbers of people. Nursing is an integral part of all therapies and provides the binding unity essential for the elderly patient.

The field of pain continues to develop and there are reasons to be optimistic about its future. First, imaging techniques have confirmed pain-related activity in widely distributed, highly interconnected areas of the brain. An implication of the concept is that neural programs that evolved in the brain to generate acute pain as a result of injury or disease may sometimes go away and produce destructive chronic pain. Future imaging research may reveal the sites of abnormally prolonged activity in chronic pain patients. Second, the detailed knowledge and technical skills developed by scientists for research on the spinal cord can be used to explore brain mechanisms in humans and animals, especially in the brain stem reticular formation, which is known to play a major role on chronic pain. Third, our knowledge of the genetic basis of pain as well as the development of the brain is growing rapidly. Genetic factors are known to contribute to a large number of chronic pain syndromes, and future research will highlight their brain mechanisms. The inevitable convergence of these three approaches will hopefully lead to the relief of pain and suffering now endured by millions of people.

Ronald Melzack, PhD, FRSC

Professor Emeritus McGill University 


Monday, January 16, 2012

High-dose opiates could crack chronic pain : Nature News & Comment

Has a cheap and effective treatment for chronic pain been lying under clinicians' noses for decades? Researchers have found that a very high dose of an opiate drug that uses the same painkilling pathways as morphine can reset the nerve signals associated with continuous pain — at least in rats.

If confirmed in humans, the procedure could reduce or eliminate the months or years that millions of patients spend on pain-managing prescription drugs. The results of the study are described today in Science.

"We have discovered a new effect of opiates when they are given, not constantly at a low dose, but at a very high dose," says Jürgen Sandkühler, a neurophysiologist at the Center for Brain Research of the Medical University of Vienna, and a co-author of the paper.

Chronic pain is a nerve condition that lingers long after the immediate, or acute, pain-causing stimulus has receded. It can follow surgery or injury, and is also associated with conditions such as rheumatoid arthritis and cancer.

Sandkühler says that the original stimulus changes how the central nervous system deals with pain over time. In a model known as long-term potentiation, nerves carrying pain signals fire repeatedly, turning on a cellular pain amplifier that causes anything from exaggerated pain to outright agony on a long-term basis.

Opiates such as morphine and heroin remain the 'gold standard' in pain relief, but they work only temporarily for those with chronic pain. Sandkühler and his colleagues decided to push the boundaries of the opiates' action and measure whether the drugs could have any effect on the underlying problem.

The team induced long-term potentiation in 25 rats by exposing nerve fibres known to carry pain signals to low-frequency electrical stimulation. They subjected some of the rats to high-frequency electrical stimulation, or gave them injections of capsaicin, the pain-causing ingredient in chill peppers, as alternative stimuli.

After the pain stimulus ceased, the researchers gave the rats a very high intravenous dose of the opiate remifentanil. As expected, the pain signals slumped at once — remifentanil is an extremely fast-acting painkiller, and was chosen because its effects tend to wear off in rats after just 10 minutes.

When the drug's effects did wear off, the chronic pain was significantly reduced in the rats treated with low-frequency stimulation. A second infusion of the drug an hour later abolished the long-term potentiation and restored these rats' pain levels to normal. A high dose of remifentanil was also effective in reducing the pain of the rats treated with capsaicin or high-frequency stimulation.

Treating the rats with half the dose of remifentanil did not produce the same effect. Sandkühler suggests that a threshold level of the drug is needed to disrupt the movement of calcium signalling ions between nerves and neutralize the long-term potentiation.

"The dose of drugs we use is very high, probably 2–4 times higher than used for normal pain control," says Sandkühler. "The animals almost stop breathing, which is probably one reason why this was not discovered before."

But he adds that the equivalent amount of the opiate for a human is well below a fatal dose. He and his colleagues have conducted pre-clinical experiments that have shown that people can tolerate it.

Michael Serpell, a consultant anaesthetist and pain doctor at the University of Glasgow School of Medicine, UK, is impressed with the paper's methodology. He says the idea has always been that if you hit acute pain hard enough, then you can reduce the chance of it becoming chronic. "It would be appropriate to try this. It could be rolled out into the clinical arena in high-risk patients first," he says.

However, Serpell cautions that a similar approach, applying a pre-emptive analgesic before surgery that was likely to cause chronic pain, produced promising results in animal studies but later trials in humans were "a complete failure".

Treatments are certainly needed for chronic pain, which may affect up to one in six adults across the world; Serpell says that 3–5% of the adult population in the United Kingdom is prevented from working by pain. The condition is the second most common reason for claiming incapacity benefit.


Tuesday, January 10, 2012

Resolving Chronic Pain | The Scientist

Resolving Chronic Pain

The body's own mechanism for dispersing the inflammatory reaction might lead to new treatments for chronic pain.

By Claudia Sommer and Frank Birklein

Inflammation is correctly blamed as one of the root causes of both acute and chronic pain—and more. Not only does chronic inflammation underlie disorders such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases, it has also been implicated in the pathogenesis of cancer, chronic heart failure, and neurological disorders such as Parkinson's and Alzheimer's diseases. These conditions affect millions, and carry high health-care and socioeconomic costs. And yet, inflammation is an important physiological response that jump-starts tissue repair and more carefully tunes immune reactions. Without it, we could not fight off infection or heal from injury. Why and how does this powerful ally turn into a foe?

A patient who had consulted us earlier about other problems came in complaining of swelling in her right hand, accompanied by incessant pain that left her unable to move her arm very much. An otherwise healthy 47-year-old, she had worked as a bookseller until slipping on ice and fracturing her wrist a few weeks earlier, experiencing what she described as the worst pain of her life. Surgery had been successful, but as she healed, the swelling in her wrist did not resolve. Instead, the swelling had extended to the whole hand, even increasing after her cast was removed, and the hand had become exquisitely sensitive. It appeared to be permanently swollen, reddish in color, and was usually warmer than her other hand. Because of the pain, she was unable to return to her job or perform any exercise, and needed help with many everyday tasks. X-rays did not reveal any pathology that would explain the pain. Treatment with anti-inflammatory drugs like aspirin was ineffective; even morphine provided little relief.

Her doctors finally arrived at a diagnosis of complex regional pain syndrome and she began a multicomponent pain treatment program. Treatment included very specific physical and cognitive therapies that resulted in a 90 percent restoration of hand function and a reduction in pain. Today, complex regional pain syndrome is thought to be initiated by an unusually strong and long-lasting inflammatory reaction to trauma, although its treatment is not always so successful.

Although not all cases of chronic pain involve inflammation, the majority do. Therapy options for chronic pain are complicated because of the ongoing nature of the symptom.

In chronic pain, the inflammatory factors are never completely cleared from the system.
While the causes of chronic pain are many and diverse, the pervasive effect it has on a patient's life—including inability to work, anxiety, depression, and even post-traumatic stress disorder—is universal. Opiates such as morphine are considered among the best medications for relieving pain, but they carry a risk of tolerance and addiction, especially with long-term use. Many doctors thus prefer to prescribe anti-inflammatory drugs such as cyclooxygenase (COX) inhibitors. COX inhibitors, like aspirin or ibuprofen, however, can cause gastrointestinal bleeding and kidney damage when used at high doses, and selective COX-2 inhibitors such as Vioxx have been shown to increase the risk of cardiovascular disease. In addition, these drugs are most effective for mild and moderate pain; they have a "ceiling" beyond which taking more provides no more relief.

One difference between acute inflammation and the persistent inflammation that leads to chronic pain, is that in the latter, the inflammatory factors are never completely cleared from the system. Recent research has revealed that the clearing of these inflammatory factors is an active process rather than a passive one that simply occurs over time. This insight offers the possibility that we might be able to harness resolution factors that clear inflammation and use them to ameliorate the pain that accompanies chronic inflammation.

Reducing inflammation

In 2000, while looking for bioactive molecules derived from the metabolism of omega-3 fatty acids, Charlie Serhan's laboratory at Brigham and Women's Hospital at Harvard Medical School discovered a compound that naturally reduces inflammation after an acute reaction.1,2 Omega-3 fatty acids, which can be found in foods such as fish and flaxseed oil, include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These two fatty acids have long been known to have beneficial effects in reducing the risk of several diseases, including atherosclerosis, asthma, heart disease, and cancer. The American Heart Association even recommends the consumption of fish rich in omega-3 fatty acids for cardiovascular disease prevention. However, it was not known whether omega-3 fatty acids actively reduced inflammation. The problem was confounded by the fact that many studies investigating the effects included patients who were also taking aspirin, making it difficult to tease apart the anti-inflammatory contribution of each. The Serhan laboratory set out to analyze the interaction of EPA and DHA with aspirin and to identify molecular components derived from the fatty acids.

First, they analyzed the composition of lipid-based compounds that were present in tissues during the resolution of acute inflammation in the mouse. Mice produced fatty acid metabolites that the investigators dubbed "resolvins" for their ability to reduce the inflammatory reaction. Although these compounds appeared to clear the inflammation, the process was different from active suppression of the immune system. The resolvins did not hinder immune cell action; rather, they reduced the inflammatory activity of specific populations of cells and blocked their production of pro-inflammatory chemokines, while increasing the action of immune cells that clear dead tissue.

Serhan's team also showed that these resolving molecules were naturally derived from omega-3 fatty acids—and that aspirin enhanced this conversion. When they then administered the resolvins to animal models of acute and chronic inflammation such as peritonitis, colitis, or asthma, they saw an accelerated return to homeostasis.

The study demonstrated how aspirin could increase the production of the body's own natural inflammation mediators by catalyzing the metabolism of the touted omega-3 fatty acids into chemical forms that diminish inflammation. In addition, it appeared that these newly discovered mediators permitted the aggressive acute inflammation stage to occur, which is so physiologically important, before then subduing the reaction and returning the body to homeostasis. But it was not yet clear whether the reduction in inflammation would also reduce pain.

Inflammation includes a number of processes, not all of which are associated with pain. For example, while systemic infections, like the flu or a cold, spur strong inflammatory reactions, they are only occasionally associated with pain. Pain only occurs when inflammatory cytokines are released near nociceptive, or damage-signaling, nerve fibers. Damaged tissues release their contents during injury or inflammation, flooding the surrounding tissues with prostaglandins (PGs) and bradykinin, which activate the secretion of histamines. Together, these chemicals make blood vessels leaky enough to permit immune cells to enter the damaged tissue from the circulation, releasing PGs creating the swelling that is a cardinal symptom of inflammation. When this process occurs in richly innervated tissues, the inflammatory mediators also cause nearby nociceptors to fire, conveying the sensation of pain.

Resolving the pain

Given that resolvins are derived from omega-3 fatty acids—that is, from essential nutritional factors—and that they are endogenous anti-inflammatory substances, it seemed a likely hypothesis that they would also have an effect on inflammation-related pain. In 2010, the lab of Ru-Rong Ji at Brigham and Women's Hospital in Boston, in collaboration with Serhan, explored this question.3

Using an animal model of pain, investigators injected the paws of mice with formalin, which produces two phases of pain: an immediate reaction, relayed by the peripheral nerves; and a delayed-onset reaction, mediated by inflammation and by spinal cord neurons.3The first phase is characterized by mice licking the injected foot for about five minutes after injection. Then, after a lag of 20–30 minutes, the second phase begins with another bout of foot licking. The researchers administered two different resolvin (Rv) molecules, RvD1 and RvE1, to test their ability to reduce this pain behavior, and found both molecules to be effective when injected either into the paw or directly into the spinal canal. They noted that RvE1 diminished swelling and reduced markers of the inflammatory response, and that, compared to either morphine or COX-2 inhibitors, a much lower dose of the resolvin effectively halted pain behavior. Interestingly, only the second phase of pain behavior—mediated by spinal cord mechanisms that are often associated with chronic pain—was attenuated, indicating that RvE1 and RvD1 were likely acting via a receptor known as ChemR23, a G protein–coupled receptor found on nociceptive neurons in the dorsal root ganglia and the dorsal horn of the spinal cord. These neurons also express the transient receptor potential vanilloid 1 (TRPV1), which is the receptor for the inflammation-producing irritant found in chili pepper, capsaicin. In living mice, RvE1 was able to block the pain induced by capsaicin.

The same researchers looked at another model of inflammatory pain induced by the injection of carrageenan, which also initiates two phases of pain, but is thought to more closely mimic standard muscle pain than the formalin model. When the mice were given RvE1 or RvD1 in the hindpaw before a carrageenan injection, the pretreatment markedly reduced inflammation: the mice showed diminished swelling, fewer immune effector cells called neutrophils infiltrating the damaged tissue, and a reduced level of pro-inflammatory cytokines. Just like morphine, RvE1 did not dull the ability to sense "normal" pain. In other words, the mice did not experience numbing, but rather a more specific alleviation of the pathologic pain associated with inflammation.

Recently, researchers have begun to investigate whether chronic persistent pain might be the result of a learning response in neurons of the spine. Neurons change shape when they are actively involved in learning, both in terms of the number of physical connections between cells and the number of receptors at the synapses of those connections. Researchers have proposed that when pain persists, the neuronal connections relaying that pain strengthen, making it easier to transmit the response—thus lowering the threshold at which something feels painful.

To test whether resolvins might prevent the formation of this learned pain reaction in the spine, researchers took slices of mouse spinal cord and tested how the transmission between neurons changed in the presence and absence of resolvins. Resolvins blocked an increase in the action of tumor necrosis factor-alpha (TNF-α)—a cytokine thought to increase the frequency of synaptic transmission, and thus possibly the likelihood of forming a "pain memory"—without blocking the normal levels of transmission. Then, the authors showed that RvE1 also inhibited glutamate release—required for some types of neuronal learning—by a pathway dependent on the extracellular signal-regulated kinase (ERK). Additionally, RvE1 changed the activity of the glutamate N-methyl-D-aspartic acid receptor (NMDAR), also via the ERK pathway, supporting the concept that blocking the ERK pathway could be a promising therapeutic target for the treatment of pain.

Since the publication of the first paper by Ji and colleagues describing the analgesic effect of resolvins, others have followed. These new studies described positive effects in other pain models, and have uncovered additional mechanisms by which resolvins can diminish pain. For example, RvD1 was shown to reduce, prevent, and transiently attenuate pain associated with operation trauma in a rat model.4 In this study, an oversensitivity to pain, in which a touch that is normally benign feels painful, was reduced or prevented by 20 to 40 nanograms of RvD1 injected into the spinal cord up to 2 days after the surgical trauma. However, if RvD1 was given on postoperative day 9 or 17, the reversal of pain was only transient and incomplete.

In a model of pain that mimics inflammatory arthritis in rats, RvD1 reduced an increased sensitivity to pain. The effect was partially mediated by a decrease in TNF-α and interleukin-1β—cytokines that drive inflammation and are also thought to increase pain hypersensitivity in the central nervous system.5 In this model, systemic injection, rather than spinal administration, of the resolvins was shown to be effective, providing a much more feasible clinical application, as spinal injections themselves are associated with significant pain. Furthermore, in cell culture, RvD1 inhibited other members of the TRP family of receptors.6 Subsequent in vivo experiments demonstrated that injecting RvD1 under the skin was sufficient to attenuate pain caused by direct activation of these TRP receptors in the mouse.

A clearer picture for the future

From the animal data summarized above, it appears that resolvins may be ideal candidates for novel analgesics. Because they are derived from lipid molecules normally produced in the body, resolvins counteract inflammation in a physiological way. Their precursors, the omega-3 fatty acids, have been tested with some success in treating pain conditions,7 although a recent meta-analysis did not show a definitive effect. However, resolvins appear to show effects at concentrations about 10,000 times lower than effective doses of omega-3 fatty acids—an advantage for drug development.

Intriguingly, one of the mechanisms that Ji and colleagues identified for the analgesic action of the resolvins is that they block various TRP receptors (particularly TRPV1) indirectly by blocking the TRPV1-dependent release of glutamate.3 This is particularly interesting insomuch as it may provide a better avenue for blocking TRPV. In fact, recently developed TRPV1 antagonists that have been tested in humans resulted in serious side effects such as high fever. The reason for this side effect is most likely that TRPV1 not only conveys information about pain, but also about temperature. Complete blockade of this receptor, therefore, would also block information about fever from reaching the brain, which would be unable to respond by initiating cooling mechanisms such as sweating. Since resolvins block glutamate rather than directly acting on TRPV1, they might avoid such life-threatening side effects.

Side effects of blocking TRP might be reduced even more with the use of resolvins that act specifically on certain TRP receptors, as recently demonstrated in vitro and in vivo with RvD1, which appears to be specific for TRPV3. This receptor specificity may potentially pave the way to a more tailored treatment for individual pain symptoms such as thermal or mechanical pain hypersensitivity. A further potential advantage of resolvins is that they may have a dual function as both an analgesic and an inflammatory disease-modifying drug. In fact, a number of molecules with this potential have already been investigated, including nerve growth factor and its antagonists in the treatment of nerve lesions, neuropathic pain, or osteoarthritis; erythropoietin in diabetic neuropathy; and cytokine inhibitors in rheumatoid arthritis.8Unfortunately, of these, currently only the cytokine inhibitors have made it to clinical application.

The challenge now, as it is for every promising molecule at the preclinical stage of investigation, will be to develop resolvins into a clinically applicable form. Many of the experimental applications have been via spinal injection, which would limit the use in humans. As drugs, these molecules would need to be stable—so that they could be taken orally, for example—and long-acting. Because they act on the immune system, they might have unwanted side effects, which will need to be investigated further. In addition, although the results reported by Ji and others are impressive and reasonable, the size of the effect on pain behavior in the animals is moderate. Other analgesic drugs, which had even stronger effects than the resolvins in animal models, have failed in human clinical trials because their impact was not sufficiently different from that of placebos. The reason might be that human pain still differs significantly from even the best and most elaborate animal pain models. With all these caveats, testing resolvins in clinical trials will be the best way to determine if alleviating chronic low-grade inflammation, a factor underlying not only pathogenic pain but diseases ranging from cancer to obesity, could reduce morbidity and mortality.

Claudia Sommer is at the University of Würzburg, in Germany, and Frank Birklein is at the University Medical Center of the Johannes Gutenberg University Mainz.

This article is adapted from a review in F1000 Medicine Reports, DOI:10.3410/M3-19 (open access athttp://f1000.com/reports/m/3/19/).


Thursday, January 05, 2012

How Yoga Can Wreck Your Body - NYTimes.com

On a cold Saturday in early 2009, Glenn Black, a yoga teacher of nearly four decades, whose devoted clientele includes a number of celebrities and prominent gurus, was giving a master class at Sankalpah Yoga in Manhattan. Black is, in many ways, a classic yogi: he studied in Pune, India, at the institute founded by the legendary B. K. S. Iyengar, and spent years in solitude and meditation. He now lives in Rhinebeck, N.Y., and often teaches at the nearby Omega Institute, a New Age emporium spread over nearly 200 acres of woods and gardens. He is known for his rigor and his down-to-earth style. But this was not why I sought him out: Black, I'd been told, was the person to speak with if you wanted to know not about the virtues of yoga but rather about the damage it could do. Many of his regular clients came to him for bodywork or rehabilitation following yoga injuries. This was the situation I found myself in. In my 30s, I had somehow managed to rupture a disk in my lower back and found I could prevent bouts of pain with a selection of yoga postures and abdominal exercises. Then, in 2007, while doing the extended-side-angle pose, a posture hailed as a cure for many diseases, my back gave way. With it went my belief, naïve in retrospect, that yoga was a source only of healing and never harm.

At Sankalpah Yoga, the room was packed; roughly half the students were said to be teachers themselves. Black walked around the room, joking and talking. "Is this yoga?" he asked as we sweated through a pose that seemed to demand superhuman endurance. "It is if you're paying attention." His approach was almost free-form: he made us hold poses for a long time but taught no inversions and few classical postures. Throughout the class, he urged us to pay attention to the thresholds of pain. "I make it as hard as possible," he told the group. "It's up to you to make it easy on yourself." He drove his point home with a cautionary tale. In India, he recalled, a yogi came to study at Iyengar's school and threw himself into a spinal twist. Black said he watched in disbelief as three of the man's ribs gave way — pop, pop, pop.

After class, I asked Black about his approach to teaching yoga — the emphasis on holding only a few simple poses, the absence of common inversions like headstands and shoulder stands. He gave me the kind of answer you'd expect from any yoga teacher: that awareness is more important than rushing through a series of postures just to say you'd done them. But then he said something more radical. Black has come to believe that "the vast majority of people" should give up yoga altogether. It's simply too likely to cause harm.

Not just students but celebrated teachers too, Black said, injure themselves in droves because most have underlying physical weaknesses or problems that make serious injury all but inevitable. Instead of doing yoga, "they need to be doing a specific range of motions for articulation, for organ condition," he said, to strengthen weak parts of the body. "Yoga is for people in good physical condition. Or it can be used therapeutically. It's controversial to say, but it really shouldn't be used for a general class."

Black seemingly reconciles the dangers of yoga with his own teaching of it by working hard at knowing when a student "shouldn't do something — the shoulder stand, the headstand or putting any weight on the cervical vertebrae." Though he studied with Shmuel Tatz, a legendary Manhattan-based physical therapist who devised a method of massage and alignment for actors and dancers, he acknowledges that he has no formal training for determining which poses are good for a student and which may be problematic. What he does have, he says, is "a ton of experience."

"To come to New York and do a class with people who have many problems and say, 'O.K., we're going to do this sequence of poses today' — it just doesn't work."

According to Black, a number of factors have converged to heighten the risk of practicing yoga. The biggest is the demographic shift in those who study it. Indian practitioners of yoga typically squatted and sat cross-legged in daily life, and yoga poses, or asanas, were an outgrowth of these postures. Now urbanites who sit in chairs all day walk into a studio a couple of times a week and strain to twist themselves into ever-more-difficult postures despite their lack of flexibility and other physical problems. Many come to yoga as a gentle alternative to vigorous sports or for rehabilitation for injuries. But yoga's exploding popularity — the number of Americans doing yoga has risen from about 4 million in 2001 to what some estimate to be as many as 20 million in 2011 — means that there is now an abundance of studios where many teachers lack the deeper training necessary to recognize when students are headed toward injury. "Today many schools of yoga are just about pushing people," Black said. "You can't believe what's going on — teachers jumping on people, pushing and pulling and saying, 'You should be able to do this by now.' It has to do with their egos."

When yoga teachers come to him for bodywork after suffering major traumas, Black tells them, "Don't do yoga."

"They look at me like I'm crazy," he goes on to say. "And I know if they continue, they won't be able to take it." I asked him about the worst injuries he'd seen. He spoke of well-known yoga teachers doing such basic poses as downward-facing dog, in which the body forms an inverted V, so strenuously that they tore Achilles tendons. "It's ego," he said. "The whole point of yoga is to get rid of ego." He said he had seen some "pretty gruesome hips." "One of the biggest teachers in America had zero movement in her hip joints," Black told me. "The sockets had become so degenerated that she had to have hip replacements." I asked if she still taught. "Oh, yeah," Black replied. "There are other yoga teachers that have such bad backs they have to lie down to teach. I'd be so embarrassed."

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