Tuesday, February 18, 2014

Itching: More Than Skin-Deep - NYTimes.com

The experiment was not for the squirmish. Volunteers were made to itch like crazy on one arm, but not allowed to scratch. Then they were whisked into an M.R.I. scanner to see what parts of their brains lit up when they itched, when researchers scratched them and when they were finally allowed to scratch themselves.

The scientific question was this: Why does it feel so good to scratch an itch?

"It's quite intriguing to see how many brain centers are activated," said Dr. Gil Yosipovitch, chairman of dermatology at the Temple University School of Medicine and director of the Temple Center for Itch (he conducted the experiment while working at Wake Forest School of Medicine). "There is no one itch center. Everyone wants that target, but it doesn't work in real life like that."

Instead, itching and scratching engage brain areas involved not only in sensation, but also in mental processes that help explain why we love to scratch: motivation and reward, pleasure, craving and even addiction. What an itch turns on, a scratch turns off — and scratching oneself does it better than being scratched by someone else. The study results were published in December in the journal PLOS One.

Itching was long overshadowed by pain in both research and treatment, and was even considered just a mild form of pain. But millions of people suffer from itching, and times have changed. Research has found nerves, molecules and cellular receptors that are specific for itching and set it apart from pain, and the medical profession has begun to take it seriously as a debilitating problem that deserves to be studied and treated.

Within the last decade, there has been a flurry of research into what causes itching and how to stop it. Along with brain imaging, studies have begun to look at gene activity and to map the signals that flow between cells in the skin, the immune system, the spinal cord and the brain.

The concern is not so much the fleeting nastiness of mosquito bites and poison ivy, but the unending misery caused by chronic itching — the kind that won't go away, that torments people night and day and very often resists remedies like antihistamines and cortisone cream.

For the first time in the United States, itching research and treatment centers have opened: Temple's in September, in Philadelphia, and Washington University's Center for the Study of Itch, in 2011, in St. Louis.
Scratching an Itch

Itching and scratching engage brain areas linked to reward, pleasure, craving and addiction.

"Itch is now where pain was probably 20 years ago," said Dr. Lynn Cornelius, chief of the dermatology division at Washington University School of Medicine. "It used to be lumped together with pain."

But now, she said, there is more interest in itching and in sorting out its different types, and more research money being spent on it.

"The science has to lead to treatment, I believe," Dr. Cornelius said. "If that happens, it will translate to better and better, more targeted therapies, so clinicians won't just look upon someone itching as someone who needs antihistamines."

Scratching, and therefore itching, appear widespread in the animal kingdom — though no one knows for sure why animals claw, bite or peck themselves, or scrape against trees or fences.

Even fruit flies engage in "robust grooming behaviors" that look a lot like scratching when they are infected with mites, said Diana Bautista, an assistant professor of cell and developmental biology at the University of California, Berkeley. Her research includes studying various strains of itchy mice that are models for human ailments.

"I have a collection of movies showing different animals scratching," Dr. Bautista said. "I'm hoping they will help me determine if there is a difference between itch-evoked scratching versus wiping and other behaviors in diverse species."

One of her favorite videos shows a seal lying on the beach, briskly rubbing its head with a flipper.
In people, there are different types of itching. The most familiar type, from a mosquito bite or hives, occurs when cells in the skin release histamine, which causes nerves in the skin to fire off signals to the spinal cord and brain. Antihistamine pills or creams usually bring relief.

But antihistamines are often no help to people with chronic itching, which can be caused by skin diseases like eczema or psoriasis, kidney or liver failure, dry skin, an overactive thyroid gland, certain cancers, and pinched or damaged nerves. And the itching from psoriasis almost certainly has a different mechanism from that caused by a pinched nerve.

"It's a very hot area," Dr. Cornelius said. "It's a huge clinical problem and a huge unmet market."

Recent research has shown that substances other than histamine, released from inflammatory cells, are involved in chronic itching, along with three different types of nerve cells, Dr. Bautista said. Drug companies are trying to find ways to block those substances.

"Before, the focus was on next-generation antihistamines," Dr. Bautista said. "Now, it's on new molecular and cellular targets to develop new therapies. The pharmaceutical industry is recognizing that they have to go beyond antihistamines."

But pain pathways have to be dissected in minute detail if new targets are to be found. Many researchers say that one of the most important advances in the field was reported in the journal Naturein 2007 by a Washington University team led by Zhou-Feng Chen, who is now director of the itch center. Working with mice, his team was studying receptors, molecules on cells that respond to certain chemical signals to change the cells' behavior.

The group was the first to find a receptor in the spinal cord that was specific for itching, called gastrin-releasing peptide receptor, or GRPR. The discovery helped to prove that signals for itching and pain travel on different pathways.

In an interview, Dr. Chen said that mice without the receptor — or with the receptor blocked by a drug — did not itch. Nor was the group without a receptor harmed by the lack of it.
"If you block function of this receptor alone, you pretty much stop chronic itching," he said.

The receptor is present in humans, too, and Dr. Chen said it might be possible to develop a drug that would block it.

For many patients, new treatments cannot come soon enough.

Chronic itching becomes more common with age. One reason is that older people often develop dry skin, but Dr. Yosipovitch said the itching also might occur because certain nerves in the skin deteriorate — nerves that transmit pain and inhibit itching. "Then itch kind of pops out," he said.

Aging monkeys have provided some clues. When Dr. Yosipovitch was still at Wake Forest, he and his colleagues noticed older femalemacaques scratching their backs and lower limbs, the same spots where older people tend to itch.

They sent samples from the monkeys to Dr. Chen, who found extra activity in the skin and spinal cord from the gene that produces GRPR, the itch receptor. Why the gene becomes more active with aging is not known, but this finding in a primate supports the idea that the receptor is a good target for new drugs in people, Dr. Chen said.

Many older people have trouble with itching in hard-to-reach spots on the back, between or just below the shoulder blades.
"It drives them crazy," said Dr. Cornelius, at Washington University. They rub against door jambs, stockpile back scratchers, and enlist others to scratch them.

The condition has a name, notalgia paresthetica, and is often associated with spine and disk problems that pinch or damage nerves. The skin in the itchy spots may darken.

"Some neurologists, I would say the majority, do not know about this," Dr. Yosipovitch said.

He and other doctors have prescribed various remedies — numbing patches, sometimes along with the hot-pepper ingredientcapsaicin; Botox injections; pills like gabapentin that affect nerve transmission; and physical therapy to change posture. Often, it is possible to find something that helps.

Dr. Yosipovitch said many patients found their way to him only after seeing multiple doctors who could not help and who sometimes misdiagnosed their problems as mental rather than physical.

"They're not crazy," he said.

One of the patients was a boy who had scratched his arms and legs raw. Unable to find a cause or a treatment that worked, doctors had referred him and his family to a psychiatrist.

In an interview, the patient, Joshua Riegel, now 18, said, "They said I was doing it to manipulate my parents." Thus began what he calls "that weird part of my life where they thought I was mentally ill."

He was 12 or 13 when the psychiatrist prescribed antidepressants, which he dutifully took for two or three years. But they brought on terrible side effects: At one point he was hospitalized with suicidal thoughts.

As a last resort, his parents took him from their home in Hillsville, Va., to see Dr. Yosipovitch, who was then at Wake Forest.

"He had a hunch on what it was," Mr. Riegel said.

Tests found a rare form of a genetic disease, epidermolysis bullosa, that was causing a particularly destructive set of symptoms: intense itching and skin so fragile that scratching ripped it to shreds.
Dr. Yosipovitch was quite angry I was being told I was mentally ill when I wasn't," Mr. Riegel recalled.

Getting off the antidepressants lifted his spirits and let him be normal again. Since then, other drugs have been prescribed for the itching, with mixed results. It never really goes away, but Mr. Riegel uses video games or his cellphone to take his mind off it and keep from scratching.

For people with other types of chronic itching, Dr. Yosipovitch said: "This is just the beginning of a big era. In the next five years I predict there will be drugs targeted specifically for itch. We're in the middle of the tip of an iceberg."


Saturday, February 15, 2014

When A Prescription For Pain Pills Becomes A Gateway To Addiction : Shots - Health News : NPR

On the surface, the 39-year-old construction worker looks like any other patient with back pain. He came to the Washington, D.C., emergency room, where I work, in severe discomfort after moving heavy cinder blocks a few days before.

The pain gets worse with twisting and bending, but he has no numbness or weakness in his legs. There's no tenderness along his spine, no difficulty urinating, no fever, so there's nothing to suggest a fracture, infection, spinal cord mass or anything other than a muscle strain.

The resident I'm supervising orders a Percocet pill, a sensible option we choose almost every day. But the patient refuses when the nurse offers it to him.

That's strange. On an average eight-hour shift in the ER, I see dozens of patients in pain. Sometimes, the pain is caused by a chronic condition like arthritis. Other times, it's an acute episode of muscle strain or a broken tooth.

Every patient in pain wants relief from it. Often, people ask for narcotics by name: Percocet, Vicodin, oxycodone and Dilaudid.

I was curious why this man was the exception. "That stuff messed me up bad," he tells me. In his early twenties, he'd had a similar episode of back pain after heavy lifting. Doctors prescribed opioid painkillers. He soon found himself addicted to them. He went from doctor to doctor to get prescriptions, then turned to buying drugs on the street. It took him 10 years to get clean.

His first exposure to narcotics had been in the ER. I can imagine myself as the well-intentioned doctor who aimed to take away his pain, not knowing the consequences that would follow. I began to wonder how many other patients I've prescribed narcotics to end up following the same path as this patient.

At first, I dismissed this possibility as preposterous. Physicians routinely order narcotic medications for patients in pain. It's not an unreasonable thing to do. After all, the pain is so bad the people come to us seeking emergency care. We doctors want to relieve their suffering.

In the ER, we meet patients for single encounters, and don't have time to track down whether they've received prescriptions from other hospitals. Besides, when patients demand pills, we don't usually give them more than a few days' worth.

Philip Seymour Hoffman's death raised renewed questions about drug addiction. I was horrified to learn that nearly one-third of people who used drugs for the first time began by using a prescription drug. Prescription painkillers are just as deadly as street drugs, according to the Centers for Disease Control and Prevention. In fact, they kill six times more people each year than heroin does.

In the meantime, narcotic prescriptions are multiplying. In 2009, pharmacies dispensed 257 million prescriptions for opioid painkillers — one for every adult American, and a 50 percent increase from 2000. While the U.S. makes up less than 5 percent of the world's population, Americans consume 80 percent of its total opioid supply.

Why are so many people receiving medications that have such high potential for abuse and overdose? While some patients are addicts shopping for doctors who will prescribe narcotics, most are seeking relief from pain, unaware of the risks of opioids.

And while there may be some doctors who knowingly prescribe too many painkillers, most are like me and struggle with how to responsibly help patients in pain without driving them to addiction.

There are some policies that attempt to reign in chronic abusers. New York City has limited ER providers to giving no more than a three-day supply of opioid pain medications. Many states have prescription drug monitoring programs that track narcotic prescriptions obtained from different providers.

Fewer resources exist to assist the majority of people who have discrete episodes of pain. Patients need to know that requesting narcotics as a quick fix to pain helps fuel the epidemic of prescription drug abuse. Many symptoms get better with time, and there are nearly always alternatives, including physical therapy and over-the-counter pain relievers.

Doctors also need resources to enable us to address patient expectations while upholding our oath to first do no harm. Hospital policies can help, with limits on the amount of narcotics prescribed and prompt follow-up with pain specialists. Some patients will still end up with narcotic prescriptions, but others, like the construction worker with an aching back, will decide to tough it out.

"I know what that stuff can do to you," he says. "I'd rather deal with the pain."

Dr. Wen is an attending physician and director of patient-centered care research in the Department of Emergency Medicine at George Washington University. She is the author of"When Doctors Don't Listen: How to Avoid Misdiagnoses and Unnecessary Care," and founder of Who's My Doctor, a project to encourage transparency in medicine.

Tuesday, February 11, 2014

The Collective Good: Pooling Data to Boost Brain Imaging Research | Pain Research Forum

The world of chronic pain research now has its eyes on the brain. Some quality of the brain—whether a particular gray matter distribution or the idiosyncratic configuration of a network—might be the key to the perpetuation of pain perception long after an initial injury, according to a growing number of studies.


However, finding that cerebral essence is hindered by the fact that most brain imaging studies of chronic pain are limited to small numbers of patients due to cost and practicality. Several researchers are now aiming to get more from those studies by establishing new resources that allow the sharing of magnetic resonance imaging (MRI) data.


One such effort is the Pain and Interoception Imaging Network (PAIN), headed by Emeran Mayer, a gastroenterologist and neuroscientist at the University of California, Los Angeles, US. PAIN provides the infrastructure for researchers to share resting-state functional MRI data and structural MRI data from patients with different chronic pain conditions, whether it be irritable bowel syndrome, lower back pain, or migraine. PAIN is the first standardized brain imaging database dedicated to chronic pain.


PAIN "will function as the lead site for collecting brain imaging data," said Mayer, where results from multiple groups will be pooled in one hub. The repository began on a smaller scale as part of the Multidisciplinary Approaches to Pelvic Pain (MAPP) Neuroimaging Network, part of a research consortium funded by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study pelvic pain. The new PAIN resource is funded by the US National Center for Complementary and Alternative Medicine (NCCAM) and the National Institute on Drug Abuse (NIDA). Other collaborators include the Laboratory of Neuro Imaging (LONI) of the University of Southern California, and the UCLA Center for Neurobiology of Stress.


A key feature of this database is the metadata, as Mayer calls it. In addition to brain images, information about experimental design and the patient's or participant's clinical, behavioral, and genetic data is also uploaded. So far, imaging and metadata from several hundred patients representing typical phenotypes of different kinds of chronic pain have been added to the repository through the efforts of 15 partner institutions in the United States and Europe. PAIN's goal is to collect scans and metadata from a total of 1,000 chronic pain patients after acquiring additional funding. The metadata will allow researchers to link disease states to brain biomarkers.


The PAIN network has two repositories, one for prospective studies that will adhere to standardized data acquisition parameters set by PAIN, called the PAIN Standardized Repository. Standardization of imaging will allow for sophisticated analyses combining data across sites. A second resource, the PAIN Archive Repository, has a more open policy where any researcher may upload already collected resting-state brain scans of chronic pain patients or healthy controls. So far, the network has focused on collecting three types of MRI scans, including high-quality structural images, diffusion tensor imaging data, and resting-state functional imaging data.


The standardized database, "is not a totally open repository," said Mayer. Researchers apply to be members and then agree to comply with PAIN imaging standards, including the requirement to contribute 20 scans per year. Members then have access to the full combined data in the repository.


"Neuroimaging data are very specific to an investigator," said Angela Laird, a cognitive neuroscientist and medical physicist at Florida International University. Laird is co-leader of the BrainMap project, a database of published functional and structural neuroimaging experiments. Neuroimaging results depend on the investigator's experimental parameters, as Laird points out. This is a reason why the PAIN network uploads details about experimental design along with imaging data.


Mayer's and other participating members' hope is that the increased number of brain scans of different chronic pain patients will help researchers sort out the finer distinctions within chronic pain subtypes. Patients often present with multiple kinds of chronic pain as assessed by their symptomatology, some variations of which may be overlooked in smaller studies. With researchers pooling their participant data together, new subcategories of chronic pain might be discovered based on the underlying biology. Chronic pain conditions that are now classified by a patient's body of symptoms may become recognized as the overlapping of several biologically unique disorders.


Additionally, PAIN provides tools and resources for researchers to interpret the collected data. The future vision for the network is to delineate brain signatures that characterize each unique chronic pain state. It is expected that with such precise information, researchers can eventually correlate individual brain signatures with genetics, epigenetics, behavioral data, and clinical parameters.


Another pain researcher is heading up a similar effort to create a neuroimaging database for pain research. Vania Apkarian, a neuroscientist at Northwestern University Feinberg School of Medicine, Chicago, US is introducing OpenPain to pain researchers.


OpenPain is a collaboration among Northwestern University, the US National Institute on Drug Abuse (NIDA), and the US National Institute of Neurological Disorders and Stroke (NINDS) to promote the sharing of brain imaging data for the purpose of pain research.


Even though Apkarian is a participating member of Mayer's PAIN network, he has designed OpenPain to be a little different. As indicated by its title, OpenPain will be open to any researcher who has published brain imaging data related to pain to share. "To make serious progress in the field, we need to put resources together and create something that we can all use," said Apkarian. He is leading by example by uploading brain imaging data he has collected in his own research. "It will be open access, no limits, and no requirements."


Unlike PAIN, the OpenPain database does not require metadata of any specific type, but simply any data collected from patients and participants used for published research, such as demographics, scanning parameters, and experimental procedures. Apkarian's hope is that open-access collaboration will break down barriers among academic circles and encourage increased cooperation among researchers.


Most pain research is publicly funded, so "the authors owe the public to make these data openly available," Apkarian said. OpenPain will be a Web-based facilitator in that exchange. Currently, the database is designed to allow researchers to share resting-state and task-related functional MRI, and diffusion tensor imaging data, similar to the PAIN network.


OpenPain is in the process of launching its servers in the next few weeks, with contributions anticipated from many pain researchers, Apkarian said.


This migration from single studies to shared data is not without precedent in the greater scientific community. Pooling data affords researchers greater statistical power to draw stronger conclusions at no additional cost. "I like the idea of databasing because it promotes data discovery: new ways of analyzing the data we haven't tried yet," said Laird. With databases, the interdisciplinary community can see brain data in new ways.


Many fields of science are headed in this direction, including genomics, microbiomics, and most recently, brain science. Biomedical research as a whole is moving toward big data. "The era of 'Big Data' has arrived," said Francis Collins during a recent announcement that welcomed the NIH's first Associate Director for Data Science. The PAIN network and OpenPain are two strides in that same direction.


Abdul-Kareem Ahmed is a medical student and freelance science writer in Providence, Rhode Island, US.


Friday, February 07, 2014

Pain | VQR Online

My father was never one to complain. On the morning of the day he died, an ulcer he'd suffered from for years, and left untreated, ruptured and began to bleed. Two days later I met with the town coroner. He told me the end had been painless, that, as his life leached away, my father would only have felt increasingly weak and light-​headed. The coroner, trying to make me feel better, was lying. By any other account, when an ulcer perforates and blood, bile, bacteria, and partially digested food begin to spill into the abdominal cavity, you feel as if a knife has just been buried in your guts. You might faint. You might vomit blood or something that looks like coffee grounds—​blood oxidized black by stomach acid. Or your body shuts down completely, total collapse its only remaining response to the shock and agony.

But my father, on the day he died, carried his burning, pleading stomach with him on his morning commute and worked his usual day at the plant, seven in the morning till seven at night. He told one of the other engineers he wasn't feeling well and then, schematics piled on his desk, worked straight through lunch. I don't imagine he would've felt much like eating. On the way home, a twenty-​minute drive, no longer able to endure his pain—​or finally, in privacy, willing to succumb to it—​he pulled to a soft shoulder and came to a stop.

Six months earlier he'd leased a brand new Chevy Impala. He loved that car. It was one of the few indulgences he allowed himself, and on my last visit home to Wisconsin, he'd been proud to show it off, especially the built-​in phone, which could be activated simply by saying, "Dial." Another feature of the system: It could instantly connect you to emergency assistance. You only had to push a red button and say, "Help."

But my father sat behind the wheel of his car—​pale, sweating, aching, losing his vision—​and did nothing. A passerby found him hours later, slumped back in the driver's seat.

Growing up, I thought he was unbreakable. My younger brother, Rory, and I wrestled with him on the grape-​juice-​stained shag carpet of the living room. Kick him, punch him, jump on his back, pull his hair (what little he had left)—​we could never hurt him. In the backyard, sawing old railway ties to make raised flowerbeds for Mom, he cut himself with his ripsaw, looked down impassively at his meaty, calloused hand, now torn open and bloody, as if it were a thing unconnected to him. In the kitchen, he picked up hot saucepans by their bare handles. When I tried, my hand shot back. On the coldest Wisconsin winter days, he went out gloveless and hatless, his face and fingers gone angry red in the frigid, prickling wind. Never bothered him. Freeze him, burn him, cut him, kiss him—​he wouldn't even flinch.

His stories about his schoolboy days back inEngland were litanies of brutality. His English master at Bishop Wordsworth's Church of England Grammar School for Boys, to give it its full name, was the author William Golding. Golding would later use his dreary tenure at Bishop Wordsworth's as inspiration and research for Lord of the Flies, in his boredom conducting social experiments on the boys, pitting them against one another in schoolyard battles. My father and his classmates—​who had nicknames like "Knocker" Nokes, "Taff" Thomas, and "Tarzan" Taylor—​not-​so-​affectionately referred to Golding as "Scruff," because of his scraggly beard. In the island-​tight schoolyard hierarchy, my father didn't fare badly. He wasn't Ralph or Jack—​and he definitely wasn't Piggy—​but I have little doubt that he ran with the choirboys and the hunters. He was on the boxing team and fought bare-​knuckle. By age thirteen, he was beating even the fifth-​form boys; he knew how to take a blow. As for a nickname, his classmates called him "Beastie."

Through his late teens, my father played rugby for club teams around Wiltshire, often taking the pitch with men twice his age, men who could only hope to compete by playing dirty. In a scrum, just as the ball was put in, they'd reach out and grab your balls ("goolies," my dad would say at this point in the story, his eyes lit with mischief), leaving you howling while they plucked the ball from the fray.

Dirtiest of all was Doc Mitchell, who played for my dad's club. If a player on the other team went down, however minor the injury, Doc Mitchell would dash across the pitch, do a quick examination, then send him off, saying, "Have that looked at straight away, lad." Club teams struggled to field a full side, never mind substitutes. With an injured player, the opposition would have to play one man short; they'd almost certainly lose.

Once, my dad was sent sprawling by a rough tackle. He went to the touchline, clutching his leg, gasping from the pain. Doc Mitchell huffed his way over and fingered a few bones like he was testing fruit at the market. "Oh, you're all right. Stop whinging and get back in." Only after they'd won and my father was hobbling off the pitch did Doc say a confidential word in his ear: "Get to hospital, Andrew. You've a broken shin."

A broken shin, a broken foot, a broken ankle—​the injury sometimes changed with the retelling. Yet I knew Dad wasn't exaggerating. He'd played out that game with an excruciating injury and done so with pride.

The point of the story, I understood, was not that winners could suffer through and losers could not. The point was that showing your pain was a choice, and the choice not to show it required only an exercise of will. How joyous to laugh and play on in the face of pain! Dad thought the story was hilarious, just another in an endless series of boyhood larks. He cracked up whenever he told it, and so did Rory and I. Even my mother had a thin smile for him.

But now I don't laugh. I think about his refusal, throughout his life, to see any doctor—​not Doctor Jacobsen, our family GP, not a specialist for his rotten stomach, and certainly not a therapist or a psychologist for his grief-​stricken heart. Too proud, too stubborn, too tough, too ashamed to be seen sidelined or entrust anyone else with his suffering.

My father's father, Alfred J. Boast, captain in the Welsh Guards, set an impossible bar for discipline and hardiness. As a young man, he worked long, dangerous, suffocating days in the coal mines of southern Wales. As soon as World War II broke out, he joined up and, in the last years of the war, commanded a POW camp in occupied Italy. Back home, he played rugby for both the Army and Wales. I barely remember the man—​he died when I was four—​but in photos I see all I need to know. On his wedding day, black busby hat in one arm, bride in the other, he stands bolt upright in dress uniform, still tanned from the Italian sun, looking like he was chipped from one massive block of shale. This was the man who taught my dad how to throw a punch and how to take one, how to lower a shoulder on the rugby pitch and lay the other man flat. The man who beat him when he trampled flowers in the garden, the man whose Army mementos formed a little shrine in our house, the man he hardly ever talked about—​neither fond nor sad memories of Captain Boast, whose mammoth shadow looms over the lives of all the men in my family.

Dad liked to play a game when we roughhoused on the carpet: Fraggles and Gorgs. He chased Rory and me around the living room, rumbling after us like one of the giants in the garden in Fraggle Rock. When he caught us, he'd give us Indian burns or pinches on the arm he called "Smurf bites" (he could never keep our Saturday-​morning TV shows straight). I remember how terrified I was of him, and, at the same time, how much I wanted him to catch me, to pull me close. I was enthralled by my dad's body—​the sharp stubble on his chin, his broad chest covered in delicate curls, his yellow, calloused feet that reeked like Stilton cheese—​and even when he exacted these reminders of his physical dominion over us, I'd cry out as much in pleasure as in pain. "That didn't hurt," he'd murmur in my ear as he twisted my arm just that little bit harder, "that didn't hurt, did it?"—​and I could only shake my head as I clenched my teeth and my eyes began to water, and then I broke out into frantic giggles. And when he released me, I'd rush right back to him.

Once, he went too far, and I struck out at him. He let me go, rumbling, "Fraggles! Fraggles! I'll get you, Fraggles!" in his belly-​shaking imitation of a Gorg (with his hairy, pendulous belly he looked like one, too). I fled across the room, picked up his slipper where he'd kicked it off on the carpet, and winged it at him. It hit him, heel first, square in the eye. I was surprised, as surprised as he was, to see him recoil from the blow.

When he caught me, he thrashed me with the same slipper, the only time I remember him really beating me. I can still see the shine in his eyes as he let himself go. He was, for a moment, enjoying himself, relishing pain and giving pain in a way he hadn't since his boxing and rugby days. I crawled away, sobbing, locked myself in the upstairs bathroom, stripped off all my clothes, and sat naked in the bath without turning the water on. I resolved to kill myself just to punish him. But the sting of the spanking had already faded. I got out of the tub feeling like I wanted to retch. What caused that terrible, devouring ache in my stomach? It wasn't that I'd been cast out forever (as I thought then) from my father's good graces but the shock of the realization: I'd wounded him. This unbreakable man—​I'd put the first chip in him.

The old wisdom tells us the longer we suffer, physically and otherwise, the more indifferent we become to pain: We cry out at the first lash, but the tenth is bearable, and the hundredth we hardly notice. Actually, the opposite may be true. During a long ordeal or a long depression, we begin to feel pain more acutely; we only learn to show it less. The stoic's creed, the stoic's prayer—​what doesn't kill you makes you stronger; bear down and take it, you'll get through; keep calm and carry on—​it all turns out to be nonsense. Only years later do I see that my father's upbringing and my own—​Midwestern and English—​left us uniquely, pathetically ill-​equipped for the course my family's life in America would take.

At the end of my senior year of high school,my mother started having bad headaches. She and I were on a road trip together, scouting colleges, when the first big one hit. She couldn't drive; she couldn't even stand. We cut the trip short, and I drove us from Iowa City back to Wisconsin while she lay curled in the backseat, her eyes squeezed tightly shut, unable to speak for the thumping and hammering in her skull. The next day, while Dad was at work, Rory and I took her to Doctor Jacobsen, then to the county clinic in Elkhorn, then to St. Mary's in Madison. The diagnosis came that evening—​a tumor in her brain the size of a jawbreaker. Glioblastoma, terminal cancer. Over the next six months of surgery, chemo, and radiation, my mother knew pain like none of us could imagine. Two days before Christmas, she died, a withered husk of the woman who, as the illness chewed up first her mind then her body, I had greater and greater difficulty remembering.

In the same awful week, my father's own mother also died, of old age. These two deaths hardly seemed to affect him; he kept calm, steady, and mostly sober, organizing two sets of funeral arrangements with the same frightening rigor he brought to his work at the plant. I followed his example. I felt I should cry, but I couldn't. I came up with a list of chores and went at them every day until I was too exhausted to do anything but crawl into bed. When I went back to college, I bore down, filling my schedule with as many career-​torpedoing courses (Early Baroque Music, Postmodern American Poetry, Existentialism) as I could, writing arts reviews and fluff pieces for the student newspaper, playing in five different bands, practicing trombone and tuba, practicing drum set, timbales, congas, bongos, laboring to do anything but grieve.

The day my mother died, Rory went up to his room and didn't come out, except for meals, until Christmas morning. When I passed his door, I could hear him sobbing. My father could never seem to compel my younger brother toward the application of discipline, delayed gratification, and tireless work as an antidote for grief. No doubt because Dad, as a young man, had run just as wild as Rory did. (Just how wild and how reckless my dad was at that age I wouldn't find out until later.) His junior year at Big Foot High, Rory started partying harder than ever, veering as far as he could from the straight-​arrow path I'd taken. He ditched school, quit doing homework, passed out in study hall after hotboxing a blunt in his friend's Jeep at lunch, tripped on shrooms and acid at Phish concerts, ran the second family car off the road and crashed it into a Cadillac parked in someone's driveway. And my father, who downed seven or eight whiskeys a night, tried to cajole, lecture, and bully him out of it. They went to war with each other, Dad threatening Rory with perpetual grounding, military academy, and expulsion from the house if he didn't shape up and fly right. Then, the following winter, every fear my dad ever had came true: Rory was killed in a car accident, driving with his buddies, slamming beers and smoking joints, on their way to a party in the Chicago suburbs.

My father, with no other means of understanding or coping with the pain of Rory's death, turned to the only medicine he knew. Broken by grief, unable to suffer more than he had already, he set to the business of drinking himself to death.

Most of his life he'd suffered from a shitty stomach. Hardly a day went by when he didn't bear some discomfort. Now, on ten or twelve whiskeys a night, every night, the stomach aches got worse. I saw the cabinet stocked with jugs of Seagram's Canadian and said nothing; it wasn't a son's place to tell his father his business. And when he tossed and turned in his sleep, groaning and calling out in the night, I tried not to hear. Some days his guts were so twisted up all he could do was sit in his easy chair in silent agony, his face going pink, then blister white, sweat pouring down his face. But this spectacle could only be seen on the weekends. In thirty years at the same company, tightening tolerances and measuring thresholds, he missed only a handful of days of work, even when Mom was sick, even after Rory's accident. We needed to eat, after all. Still, one fact seems cruel to me now: The company gave him an award for his attendance.

Toward the end, he softened. After college I moved down to Chicago and then, two years later, fled further away to go to grad school. I told myself he wasn't hurt that I drove home only once every couple of months, and always arrived hours later than I'd promised. I'd find him in his easy chair holding vigil, staring out the window, down the length of the driveway, drink in hand, his eyes dull and watery as the ice-​thinned whiskey. I knew he'd been sitting there as many hours as I was late, waiting for my car, the car Rory had once driven, to pull in. Over the course of an evening, he'd get so stewed he couldn't even hold a conversation, let alone finish cooking the elaborate dishes he'd labored over in advance of my arrival. (Now, he burned himself at the stove, too clumsy, too anesthetized to handle the saucepans trembling under the boil.) In this state, he would sometimes talk about Mom and Rory, halting, apologetic, fumbling for words, as if he didn't speak this language of regret, guilt, and loss. "You and me," he said, "we've got to stick together. We've got to keep the family going." He cried in front of me, and I felt ashamed for him.

On the morning of the day he died, he called me. He seemed to be in a cheerful mood. "Rise and shine, guy," he said. "Hands off cocks, on with socks!" He used to shout this up the stairs to Rory and me when it was time to get ready for school. Over the years his accent had faded, but his voice still had a musicality, a gruff singsong.

I was hungover and pissy about being woken early. At twenty-​four, I was already well on my way to my own Midwestern, ten-​beer-​a-​night-​every-​night drinking problem. He asked if I'd taken my car in for a tune-​up like he'd told me to last week. I lied and said I had. Was I doing okay on cash? "Yeah, fine." We had the same conversation two or three times a week. Sometimes we talked about music—​Bill Evans, Modern Jazz Quartet, Van Morrison—​but mostly practical stuff: car, money, news from Wisconsin, news from "across the pond."

He told me he'd added me to his AAA policy. He gave me the number, asked me to repeat it back to him, twice. He fretted paranoiacally about my safety and health, even as he seemed to care almost nothing for his own.

"Dad, quit worrying. I've got it, okay?"

"Have you rung your grandmother?"

"I'll call her this weekend."

"Guy, tell me you'll ring your grandmother."

"Christ, I'll call her," I said. "Anything else?"

Nothing else, Dad said, but then he went on about a Dilbert comic I'd torn out of the paper and mailed to him, what he'd had for dinner the night before, a few projects he was thinking of doing around the house, but would have to put on hold, just wasn't feeling up to them at the moment. And then he asked me—​a merry, almost giddy note coming into his voice—​how things were going with my love life, if I'd had "any romance" the last few weeks.

It was an odd thing for him to ask me. We never talked about those things. I never imagined he would want to talk about them. I'd recently broken up with my college sweetheart, whom I'd been dating for three years. I hadn't even had the guts to do it in person. She lived a block away, and I'd done it on the phone, coldly but not cruelly (I thought) informing her that whatever we'd had was over. I believed the breakup wouldn't hurt me—​after all, I wasn't in love anymore. That night, and into the early morning, I found myself roaming the streets of Bloomington, bawling and tearing my hair. When I told Dad that my girlfriend and I had split up, that I wanted to "see what else was out there," I could tell he was disappointed. I knew he'd always been taken with her. She had a great smile, a bright, quick laugh, and a pouncing interest in pretty much anything to do with England. He used to light up whenever we came home together—​he'd been hoping for a daughter-​in-​law. But when I told him she and I were through, he hardly said a word, only that I should make sure I knew what I was doing. Probably he was heartbroken.

"No one special at the moment," I told him on the phone. "Yeah, nothing much happening. Keeping busy."

"That's fine," he said. "That's fine. Concentrate on your studies." And then he said something else about the car.

Did he know he was going to die that day? When he felt that first stab to his guts, he must have known something was wrong, seriously wrong. My god, the self-​control! Before calling me, no doubt, he'd already had to rush to the bathroom and cough up blood. In less than nine hours, he'd take his last breath.

"Got a couple things I need to finish before class," I said, wanting to wrap up our conversation. "A couple of response papers."

"All right, guy. Don't forget to call your nanny."

"I'll try her this weekend."

"They say it's going to snow."

"Yeah, that's what they say."

"Drive careful, please."

"Dad, you don't have to say please. I'll be careful. I'll be fine."

That was the end, small talk and my impatient protests. All that pain we shared between us, and we were talking about the goddamn weather. If I sensed—​or Dad was trying to tell me—​this would be the last conversation we'd have, I was too distracted or too hungover to notice.

That evening, my father pulled to the side of County Road B, halfway between work and home. He stopped the car on the gravel shoulder, parked neatly, turned off the engine. The Wisconsin winter stretched out on both sides of him, the gray dark, the endless, flat fields stubbled with chewed-up stalks of corn. He sat sweating and hurting, staring up at the red button. All these years later, I'm still struggling to understand why he didn't just reach up, press it, and speak that single word: "Help."

He taught me that the worst, the weakest, the most shameful thing you could do was indulge your pain—​swallow it down, don't say a word. You didn't talk about it; you certainly didn't write about it. His methods killed him, but he did with his pain only what he'd been taught to do, all he knew how to do.

Now the question remains: What will I do with mine? 


Thursday, February 06, 2014

Ouch! Pain threshold genes amplified by lifestyle - life - 04 February 2014 - New Scientist

If you flinch where others merely frown, you might want to take a look at your lifestyle. That's because environmental factors may have retuned your genes to make you more sensitive to pain.

"We know that stressful life events such as diet, smoking, drinking and exposure to pollution all have effects on your genes, but we didn't know if they specifically affected pain genes," says Tim Spector of King's College London.

Now, a study of identical twins suggests they do. It seems that epigenetic changes – environmentally triggered chemical alterations that affect how active your genes are – can dial your pain threshold up or down. This implies that genetic tweaks of this kind, such as the addition of one or more methyl groups to a gene, may account for some differences in how our senses operate.

Spector and his colleagues assessed the ability of hundreds of pairs of twins to withstand the heat of a laser on their skin, a standard pain test. They selected 25 pairs who showed the greatest difference in the highest temperature they could bear. Since identical twins have the same genes, any variation in pain sensitivity can be attributed to epigenetic differences.

Pain thermostat

The researchers screened the twins' DNA for differences in methylation levels across 10 million gene regions. They found a significant difference in nine genes, most of which then turned out to have been previously implicated in pain-sensitivity in animal experiments.

The greatest difference was seen in the promoter "switch" of the TRPA1 gene, which makes an ion channel on the surface of nerve cells that detect pain. "[TRPA1 is] like a thermostat, dictating how we perceive heat and turn that into pain," says Spector. An increase in methylation of around 10 per cent inTRPA1 equated roughly to feeling pain at 2 °C lower.

The team then repeated the experiment with 50 unrelated individuals. Sure enough, differences in pain sensitivity correlated with differences in methylation levels in the nine genes they'd identified with the twins.

Identification of epigenetically altered pain genes opens up ways to screen people for which painkiller might work best, and potentially identify new drugs, says Spector.

"Variation in pain sensitivity between individuals is a long-standing matter of debate, so regulation of gene activity by DNA methylation is one possibility to explain it," says Ingo Kurth, who studies pain mechanisms at the Jena University Hospital in Germany. "TRPA1 is a hot candidate as mutations in the gene have previously been associated with familial pain problems," he says.

Journal reference: Nature Communications, DOI: 10.1038/ncomms3978