Monday, March 03, 2014
Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)
ACTTION is a multi-year, multi-phase initiative that is closely aligned with the FDA's Critical Path Initiative. This public-private partnership has been designed to streamline the discovery and development process for new analgesic, anesthetic, and addiction medications and to more generally accelerate the development of treatments with improved efficacy and safety.
The key objectives of ACTTION involve initiating and supporting strategic collaborations among a broad spectrum of stakeholders — including, but not limited to, academia, the FDA and other government agencies, industry, professional organizations, patient advocacy groups, foundations, and philanthropic organizations — with the goals of sharing data and innovative thinking about the development of novel therapeutics. These strategic collaborations involve a wide range of research projects and other activities, for example, scientific workshops, consensus meetings, and in-depth analyses of clinical trial data to determine the effects of research methods on study assay sensitivity and efficiency.
Saturday, March 01, 2014
Last fall I acquired a walking treadmill. I raised my desk and placed the treadmill under it, allowing me to walk while I work. I quickly learned to walk, think, and dictate text to the computer with little cross-task interference. Walking at 2-3 km/h, I could comfortably cover 5 to 10 km a day, get some exercise, burn a few hundred calories and do some writing. This happy outcome lasted for about six weeks.
Then this arrangement fell apart for what seemed like a ridiculous reason. When I walked on the treadmill for progressively shorter periods of time, a powerful aversive sensation would build up in the soles of my feet. With every step, it felt as if I had one or more pieces of small, sharp gravel in my shoes. I kept stopping to inspect my shoes and socks and never found anything that could account for the sensation. Yes, perhaps there were tiny irregularities in the insoles of my shoes or inside my socks, but there was nothing like the sharp gravel my soles were reporting to my brain. I would rate the pain intensity at 3/10 and the unpleasantness at 8/10. The pain would stop a few minutes after I stopped walking on the treadmill, but would return quicker and stronger each time I resumed.
Interestingly, the problem never occurred during ordinary walking. I could easily walk 5 km outdoors without experiencing these aversive sensations in the soles of my feet.
At this point, two months after installing the desk treadmill, some serious catastrophizing set in. I told myself, "I wasted $1200. I'll never be able to use this treadmill. I'll have to go back to sitting at a desk. So much for my fitness plan," and similar discouraged thoughts. When I did attempt to walk on the treadmill while working, I could not concentrate on the work at all: my mind was almost fully occupied with the sensation in my feet and with those catastrophizing thoughts. Realizing this led to a vicious cycle of increased catastrophizing: "What an idiot – I ought to be able to focus on my work!"
After several weeks of this struggle, I finally remembered what should have been obvious to me as a pain researcher and as a person who has observed quantitative sensory testing in both clinical and research settings. I was experiencing neural sensitization to the prolonged and regular repetition of identical physical stimuli produced by walking on the treadmill.
In what has been called the "Chinese water torture" (which is probably not Chinese in origin and was described in Europe in the 16th century), a small drop of water falls at regular intervals on the restrained victim's forehead, becoming agonizing after a while. This is a classic example of sensitization. I realized that putting my feet down in a mechanically regular pattern had the same effect. The feelings in my feet corresponded to the classic phenomena of sensitization including allodynia (interpreting a normal touch as painful) and windup (progressively stronger response to the same stimulus).
With this insight, the cure was obvious: I had to vary the stimulus. This turned out to be easy. When the sharp gravel sensation starts, I kick off my shoes and continue walking in my socks or bare feet; if I am already barefoot when the sensitization begins, I put my socks and shoes back on. I vary the speed setting on the treadmill so that my footfalls occur at different intervals. I vary the way I walk, placing weight on different parts of my feet. Sometimes I just stand for a while. These actions vary the frequency, location, intensity and quality of the stimuli on my feet, thus reducing the sensitization.
Because of these minor changes I can continue my work with little interference. The sensitization still occurs (pain 1/10, unpleasantness 3/10), but it doesn't bother me because I know what to do. In other words, the sensitization is not amplified by catastrophizing and helplessness.
This experience helps me to understand patients whose pain is worsened by sensitization. I don't think this neurophysiological phenomenon is widely understood outside the circles of pain specialists. The combination of sensitization and catastrophizing is dramatically distressing and disabling. Changing either can influence the other.
Coincidentally, the day after I wrote the above, an article by Salomons and colleagues was published online in Pain, providing experimental confirmation of what I learned through direct experience. In this study, repeated thermal stimuli were applied to participants' forearms, producing hyperalgesia. Half the participants were given a cognitive intervention to reduce their stress response to the painful stimuli by identifying negative cognitions and reappraising the situation. In comparison with a control condition, the cognitive intervention led to reduced unpleasantness ratings. The authors conclude, "Reduction in secondary hyperalgesia was associated with reduced pain catastrophizing, suggesting that changes in central sensitization are related to changes in pain-related cognitions. Thus, we demonstrate that central sensitization can be modified volitionally by altering pain-related thoughts."
The take-home message: let's watch out for sensitization and catastrophizing and their mutually reinforcing interaction, in our patients and in ourselves.
Have you experienced sensitization and hyperalgesia in your own life? What did you do, physically and psychologically, to deal with it? Did you learn anything from that experience that informs your research or clinical practice? What other research bears on this relationship between sensitization and catastrophizing?
Tuesday, February 18, 2014
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
Tuesday, February 11, 2014
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.
Friday, February 07, 2014
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
Wednesday, January 29, 2014
Sunday, January 26, 2014
Toronto—One-third of results from registered clinical trials of neuropathic pain treatments are not readily available, according to an extensive survey of neuropathic pain literature.
According to Michael Rowbotham, MD, scientific director of the California Pacific Medical Center Research Institute in San Francisco, the unavailability of such a swath of trial results, compounded with selective publication bias, carry significant ethical, research and clinical implications.
"One problem is that the aggregating of these data tends to inflate treatment effect sizes," said Dr. Rowbotham. "If you overestimate the effect size, you really harm everyone. Physicians and patients get inappropriately high-efficacy expectations; future trials are designed to be underpowered because they're looking for a bigger effect than they really should be and from an ethical perspective, not sharing the findings wastes the contributions of patients who have entered clinical trials and agreed to the possibility of experiencing unknown risks."
Congress requires clinical trials conducted in the United States to be registered on clinicaltrials.gov and that some trial results be posted on the website within one year of a study's completion. However, previous research has found only 8% to 10% of all completed trials have accompanying findings on the registry (JAMA 2012;307:651-653).
To capture a snapshot of neuropathic pain–related registered clinical trials and trial result availability, Dr. Rowbotham and several of his colleagues created the Repository of Registered Analgesic Clinical Trials (RReACT), a project of the Analgesic Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION).
Their most recent research was a survey of the results from postherpetic neuralgia (PHN), fibromyalgia (FM) and diabetic peripheral neuropathy (DPN) trials registered on clinicaltrials.gov. They looked at the registry's website, as well as peer-reviewed journals, conference abstracts and press releases. The latter are referred to as "the grey literature."
Their results, which can be found at www.acttion.org, showed 373 registered studies on the three neuropathic pain conditions as of December 2011. In all, 184 trials were completed before December 2010, and therefore many should have had findings posted, as per the Congressional one-year deadline requirement.
However, the researchers' comprehensive search yielded no findings for 24% of the DPN studies, 25% of the FM trials and 33% of the PHN studies completed before December 2010.
The proportion of complete and incomplete trials that had results available in any format ranged from 63% to 68%. Furthermore, only 39% to 44% of all findings were published in peer-reviewed journals.
"If you work really hard, use sophisticated search strategies and look at all public websites including the grey literature, you can get results from about two-thirds of studies," Dr. Rowbotham said.
The grey literature is not a reliable source for findings, given that results are not peer-reviewed, Dr. Rowbotham said, adding that there are other problems with accessing these findings.
"One of the websites we relied on as a source for this analysis, disappeared," said Dr. Rowbotham. "It took with it results from hundreds of trials, several of which we couldn't find anywhere else."
According to Dr. Rowbotham, analyses and reviews of published evidence need to consider not only the absence of up to one-third of findings, but also the documented problem of publication bias.
Publication bias received widespread attention when a 2008 study in The New England Journal of Medicine found that of 74 large, multicenter, Phase III trials of 13 antidepressant drugs approved by the FDA, half were not published in the peer-reviewed literature, and findings that were published tended to be positive (N Engl J Med 2008;358:252-260).
"Not only were positive results more likely to be published, but studies that were not positive, in the researchers' evaluation, were often published in a way that conveyed a positive outcome," Dr. Rowbotham told attendees at the 4th International Congress on Neuropathic Pain. "One way to do this is to promote a positive secondary outcome and devote lots of text in the paper as if it were the most important outcome."
Although it is possible that some of the neuropathic pain trial findings that were found to be unavailable in the RReACT analysis may have been negative, Dr. Rowbotham's team did not set out to identify why results were not available. A less insidious explanation is the "file drawer problem," he said.
"Some studies seem to get published and others just languish, waiting for that final review and edit, or for time to start writing the manuscript," Dr. Rowbotham speculated.
Despite the worrisome RReACT findings, there are an increasing number of efforts by a spectrum of health care stakeholders to improve the accessibility of clinical trial findings, according to Swaroop Vedula, MD, PhD, postdoctoral fellow at Johns Hopkins University in Baltimore.
"We have a long way to go before trial protocols and findings are reported completely and transparently," said Dr. Vedula, who has studied the reporting of gabapentin trials and is not involved in RReACT. "However, there are several important initiatives, including a big push lately for open access to trial data, that are changing our understanding of the accuracy of clinical trial reporting and making clinical trial data and documents publicly available."
Saturday, January 25, 2014
The International Association for the Study of Pain will hold its 15th World Congress on Pain October 6-11, 2014, in Buenos Aires, Argentina! The Congress will attract more than 6,000 pain specialists from all over the world who will converge on Buenos Aires and present the most up-to-date information on the field of pain, from laboratory science to clinical diagnosis, management, and prevention.
The Buenos Aires Scientific Program Committee will organize a program to include plenary sessions, topical workshops, refresher courses, and poster sessions covering every aspect of acute and chronic pain from basic science to clinical practice. We hope to see you there!
IASP is pleased to announce the program of Distinguished Lectures, Refresher Courses, Plenary Lectures, Topical Workshops, and Satellite Symposia for the Congress. Browse the program today to find topics of interest to you.
Tuesday, January 14, 2014
America spends more than $80 billion a year on back pain treatments. But many specialists say less treatment is usually more effective.
In fact, there's evidence that many standard treatments for back pain — surgery, spinal injections and painkillers — are often ineffective and can even worsen and prolong the problem.
Dr. Jerome Groopman agrees with that premise. He suffered back pain for almost 20 years. He was a young marathon runner 32 years ago when back pain struck out of the blue.
"I couldn't run. It was difficult to sleep," he says. "I wasn't confined to bed, but I was hobbling around."
Groopman, a Harvard cancer specialist who writes about medicine for The New Yorker, wanted the problem fixed — right away. So he found a surgeon who removed a damaged disc, the jellylike cushioning between each vertebra.
The surgery didn't fix his pain.
Then, one day during brunch at a friend's house, something happened that altered the course of his life.
"I stood up from a chair and just had an explosive electric shock through my lower back," he remembers. "Basically, I fell to the floor and couldn't get up."
His previous pain was severe. But this was over the top. Groopman could hardly move.
"I was so desperate after almost three weeks that I found a neurosurgeon and orthopedist who said, 'You have spinal instability. We'll fuse you, and in three weeks you'll be playing football.' "
In a spinal fusion, surgeons weld together adjacent vertebrae with a bone graft. It's anincreasingly common operation.
But for Groopman, more surgery made things worse.
"I woke up from the surgery in excruciating pain, and basically could hardly move my legs," he says. "And I remember the orthopedic surgeon coming by and saying, 'Well, I don't know why you're having so much trouble. ... But, you know, if it doesn't get better in a few weeks we could reoperate.' "
Some research suggests that 1 in 5 patients who have surgery for back pain end up having more surgery. For some, like Jerry Groopman, it doesn't help at all.
There's "good reason to think that we are overprescribing painkillers, overprescribing injections, overprescribing back surgery," according to Dr. Richard Deyo. He is an authority on evidence-based medicine at Oregon Health Sciences University who has studied treatment of back pain.
One reason invasive treatments for back pain have been rising in recent years, Deyo says, is the ready availability of MRI scans. These detailed, color-coded pictures that can show a cross-section of the spine are a technological tour de force. But they can be dangerously misleading.
"Seeing is believing," Deyo says. "And gosh! We can actually see degenerated discs, we can see bulging discs. We can see all kinds of things that are alarming."
That is, they look alarming. But they're most likely not the cause of the pain.
Lots of people who are pain-free actually have terrible-looking MRIs. And among those who have MRI abnormalities and pain, many specialists question whether the abnormality is really the cause of the pain, and whether fixing it can make the pain go away.
Surgery can help for certain conditions, such as a herniated or bulging disc with leg pain called sciatica. But most age-related back pain usually can't be fixed with surgery.
Research is showing that the pain often has nothing to do with the mechanics of the spine, but with the way the nervous system is behaving, according to Dr. James Rainvilleof New England Baptist Hospital in Boston.
"It's a change in the way the sensory system is processing information," says Rainville, who is a physiatrist, or specialist in rehabilitation medicine. "Normal sensations of touch, sensations produced by movements, are translated by the nervous system into a pain message. That process is what drives people completely crazy who have back pain, because so many things produce discomfort."
This is a different way of thinking about pain. Normally pain is an alarm bell that says, "Stop what you're doing right now or you may hurt yourself!" But for many people, that pain is a false signal. It's not about looming danger; it's actually caused by hypersensitive nerves.
Rainville says that about 25 percent of patients with acute back trouble get stuck in an endless loop of pain. He thinks this chronic back pain is often due to persistent hypersensitivity of the nervous system.
Genetics may help explain why back pain becomes chronic for that 25 percent. But whatever the underlying cause, Rainville and others have discovered that many of them can learn to ignore their pain.
That process requires around six weeks of regular visits to a back pain "boot camp," where specially trained therapists gradually increase the intensity of exercises designed not only to increase the strength and flexibility of the back, but also to teach patients that it's OK to move normally again.
Janet Wertheimer is a 61-year-old Massachusetts woman who recently completed Rainville's boot camp. She has had severe back pain on and off for 10 years.
One recent morning, therapist Lisa Childs put Wertheimer through her paces, starting with a rotary torso machine that required her to twist her back this way and that against the resistance of a stack of iron plates.
Next she moved to a back extension device. Wertheimer arched her back against the weight stack — by this point in her rehabilitation, 100 pounds of weight. It's something most people with chronic back pain couldn't imagine doing.
"Do you feel like you could do 5 pounds more or 10 pounds?" Childs asks.
"You can try 10 and I'll see what happens," Wertheimer says.
Wertheimer has a sudden twinge in her back. But Childs, who's trained to evaluate these things, says it's OK. Wertheimer is building strength. And along the way, she's learning not to be afraid. "It's learning not to fear the pain, learning that you can live with pain," Wertheimer says. "Understand what that pain is, but then put it aside."
Most patients in Rainville's boot camp and similar programs find that the pain eventually lessens over a few months. Sometimes it even goes away.
For years after his spinal fusion, Groopman was never without back pain. He tried a long list of things without success. Then a friend suggested that he see Rainville.
Given his long search for relief, Groopman was skeptical. But he decided to give Rainville's boot camp a try.
"He was really tough," Groopman recalls. "He said to me, 'You are worshiping the volcano god of pain!' And I thought: 'What is this about?' "
Rainville explains: "In primitive cultures, if you lived near a volcano and the volcano started smoking and looking like something was going to happen, well, it was obvious[ly] because gods were mad at you. And you'd start doing silly things — sacrificing chickens or goats or whatever, thinking that that would appease the gods."
In a strange way, Rainville says, people with chronic back pain do something very similar. They sacrifice parts of their life — playing golf or softball, running, picking up bags of groceries or grandchildren. Patients get so afraid of pain, they do anything to avoid it.
"They keep putting things onto this altar, thinking that's going to change the situation," Rainville says.
But it usually doesn't work. Instead, they get more paranoid about any twinge of pain, and all the while they lose strength and flexibility.
Eventually that message sank in with the skeptical Dr. Groopman. "It took about two months for me to really buy in that this was the way to go," he says. "Just let it go. Don't pay attention to it. ... And after about nine months, I was basically without any back pain."
It doesn't work that well for everyone. Janet Wertheimer still has some back pain. But she says after graduating from boot camp she can pretty much do anything she wants to — ski, go on mountain hikes, walk her dogs.
And the pain? Most of the time, she says, she blocks it out and moves on.